Deuterium-enriched pirfenidone and methods of use thereof

Abstract

To provide a method of treating edema.SOLUTION: The present invention provides a method of treating edema, comprising administering to a subject an effective amount of deuterium-enriched pirfenidone having the following structure or a pharmaceutically acceptable salt thereof, where R1 to R11 are selected from hydrogen and deuterium, with at least one of R1 to R11 being deuterium, and if R7 to R11 are deuterium, then at least one of R1 to R6 is deuterium.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] The present invention is directed to substituted, deuterium-enriched N-arylpyridinones, pharmaceutically acceptable salts and prodrugs thereof, their chemical syntheses, and the use of such compounds for the treatment and / or management of diseases, disorders, or conditions. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Nos. 62 / 731,570, filed September 14, 2018, 62 / 750,377, filed October 25, 2018, 62 / 839,256, filed April 26, 2019, and 62 / 884,984, filed August 9, 2019, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] Fibrosis is a common feature of most chronic diseases, and fibrotic disorders are estimated to account for 45% of deaths in the United States (Wynn, Nat. Rev. Immunol. 2004, Aug;4(8):583-594). In organs of epithelial origin, such as the lung, liver, skin, and kidney, normal cells and tissues are remodeled with scar tissue composed of collagen and other extracellular matrix molecules, ultimately leading to loss of organ function and ultimately to organ failure. Pulmonary fibrosis, renal fibrosis, and liver cirrhosis are more common fibrotic diseases, and together they represent a significant unmet clinical need.

[0003] Idiopathic pulmonary fibrosis (IPF) has attracted much attention due to the severe course of the disease. Drug development efforts in IPF have provided insights that can be translated to other fibrotic diseases and have led to the recognition of commonalities among fibrotic diseases of various origins. For example, the TGF-β pathway is known as a central mediator of fibrosis initiation and maintenance in many fibrotic diseases (Friedman, et al., Sci. Transl. Med. 2013, Jan. 9;5(167):167sr1). Mechanistic studies in vitro, preclinical animal studies, and solid evidence that this pathway is upregulated in human disease suggest targeting the TGF-β pathway as a therapeutic approach for fibrosis. Several drugs, including antibodies directed against TGF-β or other pathway molecules such as αvβ6 integrin, are currently in development and are being evaluated in clinical trials for the treatment of diseases such as progressive focal segmental glomerulosclerosis, scleroderma, and IPF. However, although elevated TGF-β signaling is a key component of fibrotic disease, the cytokine also performs important normal homeostatic activities, including immunomodulation and tumor suppression, and as a result, clinical trial design must consider and minimize the potentially adverse effects of systemic inhibition of TGF-β activity.

[0004] Lymphedema is a chronic, debilitating disease of fibrotic and inflammatory origin that most commonly occurs in developed countries such as the United States as a complication of cancer treatment. In such cases, lymphedema occurs as a result of iatrogenic damage to the lymphatic system, usually following lymph node dissection or biopsy. Extensive skin excision and adjuvant radiation therapy can also cause lymphedema. See, for example, Szuba, et al., Cancer, 95:2260-2267, (2002); Tsai, et al., Ann. Surg. Oncol. 16:1959-72, (2009); Purushotham, et al., J. Clin. Oncol. 23:4312-4321, (2005). Estimates suggest that as many as one in three patients undergoing lymph node dissection subsequently develop lymphedema. Conservative estimates suggest that as many as 50,000 new cases are diagnosed each year. For example, DiSipio, et al., Lancet. Oncol.14:500-515 (2013), Petrek, et al., Cancer, 83:2776-2781 (1998 ). Because lymphedema is a lifelong disease with no cure, the number of affected individuals increases annually, with current estimates ranging from 5 to 6 million Americans (Rockson, et al., Ann. NY. Acad. Sci. 1131:147-154 (2008)) and over 200 million worldwide. The incidence of lymphedema is approximately linearly associated with cancer survival, and with the increasing prevalence of known risk factors for lymphedema, such as obesity and radiation, this number is likely to continue to increase. See, e.g., Erickson, et al., J. Natl. Cancer Inst. 93:96-111 (2001).

[0005] Lymphedema is disfiguring and debilitating. Patients experience chronic swelling of the affected extremities, heaviness, pain, discomfort, skin breakdown, fibrosis, recurrent infections, limited mobility, and a reduced quality of life. See, for example, Hayes, et al., Cancer, 118:2237-2249 (2012). Severe symptoms can limit self-treatment. When lymphedema first develops, pitting and dimples appear in the skin. As the disease progresses, thickening and fibrosis occur, and the skin may have a leathery texture. This non-pitting edema represents the irreversible stage of lymphedema and has a lichen-like or cobblestone (hyperkeratotic) appearance. Fat deposition is a defining feature of late-stage lymphedema. The skin in chronic lymphedema is highly susceptible to tearing and recurrent cellulitis. Concurrent skin ulcers, bacterial and fungal infections, and impetigo, a red, sore skin condition, are also common. Lymphorrhea, the oozing of lymphatic fluid, is also frequently observed. Over time, recurrent erysipelas verrucae can develop and lead to severe disfigurement of the body part. Cosmetic deformities resulting from lymphedema are difficult to conceal, and psychosocial stigmatization, low self-esteem, depression, anxiety, and negative body image are common among lymphedema patients due to impaired mobility, difficulty fitting into clothing, and limb and genital deformities.

[0006] Additionally, patients with chronic lymphedema lasting longer than 10 years have a 10% risk of developing angiosarcoma, a highly aggressive malignancy with a poor prognosis and low 5-year survival rate. Other cancers have been associated with lymphedema as well.

[0007] Once lymphedema develops, it is usually progressive. Despite the fact that lymphedema is common and highly morbid, there is currently no cure, and treatments are palliative, aiming to prevent disease progression rather than restore lymphatic function. Beaulac, et al. al., Arch. Surg. 137;1253-1257 (2002). As a result, patients are required to wear tight, uncomfortable clothing and undergo intensive, time-consuming physical therapy treatments for the rest of their lives to prevent lymphatic fluid accumulation in the affected limbs. Koul, et al., Int. J. Radiat. Oncol. Biol. Phys., 67:841-846 (2007). Additionally, despite ongoing chronic treatment, some patients still experience a severe progression of the disease, accompanied by increasing lymphedematous limb swelling and frequent infections.

[0008] Currently, there are no approved drug therapies for the treatment of lymphedema. Furthermore, there are currently no known pharmacological treatments that can halt lymphedema progression or promote lymphedema resolution. Cormier, et al., Ann. Surg. Oncol. 19:642-651 (2012). Additionally, little progress has been made toward developing meaningful treatments for lymphatic disorders. Therefore, the development of targeted therapies for lymphedema is an important goal and unmet biomedical need. Summary of the Invention

[0009] The compounds described herein are designed to target the underlying fibrosis and inflammation seen in fibrotic and / or collagen-mediated disorders. The compounds described in are designed to target the underlying fibrosis and inflammation found in the lymphatic system to improve lymphatic function and reduce the symptoms of lymphedema and other lymphatic system disorders such as those described herein.

[0010] In one aspect, the present invention relates to a method for treating, preventing, and / or ameliorating a disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone. Deuterium-enriched pirfenidone has the structure shown in Formula I:

[0011] [ka]

[0012] or a pharmaceutically acceptable salt thereof. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is selected from hydrogen and deuterium. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 At least one of R is deuterium. 7 , R 8 , R 9 , R 10 , and R 11 If is deuterium, then R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 At least one of the atoms is deuterium.

[0013] In some embodiments, R 1 , R 2 , and R 3 At least one of R is deuterium. 1 , R 2 , and R 3 At least one of R independently has a deuterium enrichment of about 90% or greater. 1 , R 2 , and R 3 is deuterium.

[0014] Deuterium-enriched pirfenidone has the following structure:

[0015] [ka]

[0016] or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder, or condition is selected from an inflammation-mediated disorder, a fibrosis-mediated disorder, a collagen-mediated disorder, and a fibrosis- and collagen-mediated disorder, or any combination of these disorders. In some embodiments, the disease, disorder, or condition is selected from idiopathic pulmonary fibrosis, pneumococcal disease, silicosis, silicosis, asbestosis, anthrax, lymphedema (primary and / or secondary), systemic sclerosis (scleroderma) or conditions associated with scleroderma, scleroderma interstitial lung disease, focal segmental glomerulosclerosis, juvenile systemic sclerosis (J-SSC), diabetic nephropathy, lupus nephritis, polycystic kidney disease, ANCA vasculitis, membranous nephropathy, minimal change complex, chronic kidney disease, myocardial fibrosis, keloid scarring, cutaneous polymyositis, fibrosarcoidosis, graft-versus-host disease, medical device or implant rejection, fatty liver disease, nonalcoholic steatohepatitis (NASH), and hepatitis C fibrosis. In some embodiments, the disease, disorder, or condition is selected from neurofibromatosis, Hermansky-Pulloff syndrome, dlak syndrome, diabetic nephropathy, renal fibrosis, hypertrophic cardiomyopathy (HCM), hypertension-related nephropathy, glomerulosclerosis (FSGS), radiation-induced fibrosis, multiple sclerosis (including secondary progressive multiple sclerosis), uterine leiomyoma (fibroids), alcoholic liver disease selected from hepatic steatosis, hepatic fibrosis, and liver cirrhosis, proliferative disorders selected from angiogenesis-mediated disorders, cancer selected from glioma, glioblastoma, breast cancer, colon cancer, melanoma, and pancreatic cancer, fibrotic disorders, interstitial lung disease, atrial fibrillation (AF), organ transplant rejection, scleroderma and related fibrotic conditions of the skin, endotoxin-induced liver disease after partial hepatectomy or hepatic ischemia injury, allograft injury after organ transplantation, cystic fibrosis, atrial fibrillation, neutropenia, dermatomyositis, liver cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, splenic fibrosis due to sickle cell anemia, rheumatoid arthritis, systemic sclerosis-associated pulmonary fibrosis, sarcoidosis, sarcoidosis-associated pulmonary fibrosis, pulmonary fibrosis caused by infection, asbestos-induced pulmonary fibrosis, silica-induced pulmonary fibrosis, environmentally induced pulmonary fibrosis, radiation-induced pulmonary fibrosis, lupus-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, and hypersensitivity pneumonitis, and / or any disorder ameliorated by modulating fibrosis and / or collagen infiltration into tissues.

[0017] In some embodiments, the disease, disorder, or condition is selected from idiopathic pulmonary fibrosis, edema (primary and / or secondary), lymphedema (primary and / or secondary), and systemic sclerosis (scleroderma) or a condition associated with scleroderma. In some embodiments, the disease, disorder, or condition is scleroderma and at least one associated condition selected from interstitial lung disease, skin tightening, joint pain, exaggerated response to cold (Raynaud's disease), and heartburn. In some embodiments, the disease, disorder, or condition is selected from nonalcoholic steatohepatitis (NASH), fatty liver disease, or hepatitis C fibrosis.

[0018] Deuterium-enriched pirfenidone can have the structure shown in Formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the deuterium-enriched pirfenidone has the structure shown in Formula I and is administered orally. In some embodiments, the deuterium-enriched pirfenidone has the structure shown in Formula I and is administered topically. In some embodiments, the deuterium-enriched pirfenidone has the structure shown in Formula I and is administered orally or intravenously.

[0019] In some embodiments, the deuterium-enriched pirfenidone is LYT-100

[0020] [ka]

[0021] or a pharmaceutically acceptable salt thereof. In some embodiments, the following structure:

[0022] [ka]

[0023] Deuterium-enriched pirfenidone or a pharmaceutically acceptable salt thereof having can be.

[0024] In some embodiments, the following structure:

[0025] [ka]

[0026] Deuterium-enriched pirfenidone having the formula: or a pharmaceutically acceptable salt thereof is administered intravenously.

[0027] In some embodiments, the following structure:

[0028] [ka]

[0029] Deuterium-enriched pirfenidone having the formula: or a pharmaceutically acceptable salt thereof is administered topically.

[0030] In some embodiments, the following structure:

[0031] [ka]

[0032] Deuterium-enriched pirfenidone having the formula: or a pharmaceutically acceptable salt thereof is administered twice daily.

[0033] In some embodiments, the following structure:

[0034] [ka]

[0035] Deuterium-enriched pirfenidone having the formula: or a pharmaceutically acceptable salt thereof is administered once daily.

[0036] In some embodiments, the following structure:

[0037] [ka]

[0038] Deuterium-enriched pirfenidone having the formula: or a pharmaceutically acceptable salt thereof is administered three times daily.

[0039] In another aspect, the invention features a method of reducing inflammation and / or fibrosis in a subject having insufficient lymphatic flow, the method comprising administering to a subject in need thereof a compound of Formula I:

[0040] [ka]

[0041] The method includes administering an effective amount of deuterium-enriched pirfenidone having the structure shown in Figure 1 or a pharmaceutically acceptable salt thereof. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is selected from hydrogen and deuterium. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 At least one of R is deuterium. 7 , R 8 , R 9 , R 10 , and R 11 If is deuterium, then R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 At least one of the atoms is deuterium.

[0042] In some embodiments, R 1 , R 2 , and R 3 At least one of R is deuterium. 1 , R 2 , and R 3 At least one of R independently has a deuterium enrichment of about 90% or greater. 1 , R 2 , and R 3 is deuterium.

[0043] Deuterium-enriched pirfenidone has the following structure:

[0044] [ka]

[0045] or a pharmaceutically acceptable salt thereof. In another aspect, the invention features a method of regulating and / or maintaining interstitial fluid balance and / or lymphatic flow in a subject in need thereof, the method comprising administering to a subject a compound of Formula I:

[0046] [ka]

[0047] The method includes administering to a subject an effective amount of deuterium-enriched pirfenidone having the structure shown in Figure 1 or a pharmaceutically acceptable salt thereof. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is selected from hydrogen and deuterium. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 At least one of R is deuterium. 7 , R 8 , R 9 , R 10 , and R 11 If is deuterium, then R 1 , R 2 , R 3 , R4 , R 5 , and R 6 At least one of the atoms is deuterium.

[0048] In some embodiments, R 1 , R 2 , and R 3 At least one of R is deuterium. 1 , R 2 , and R 3 At least one of R independently has a deuterium enrichment of about 90% or greater. 1 , R 2 , and R 3 is deuterium.

[0049] In some embodiments, deuterium-enriched pirfenidone has the following structure:

[0050] [ka]

[0051] or a pharmaceutically acceptable salt thereof. In another aspect, the present invention relates to a method of treating edema, comprising administering to a subject in need thereof a compound of Formula I:

[0052] [ka]

[0053] The method comprises administering an effective amount of deuterium-enriched pirfenidone or a pharmaceutically acceptable salt thereof having the formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is selected from hydrogen and deuterium. 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 At least one of R is deuterium. 7 , R 8 , R 9 , R 10 , and R 11 If is deuterium, then R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 In some embodiments, the deuterium-enriched pirfenidone has the structure:

[0054] [ka]

[0055] or a pharmaceutically acceptable salt thereof. In some embodiments, the edema is lymphedema. In some embodiments, the lymphedema is secondary lymphedema. In some embodiments, the lymphedema is primary lymphedema.

[0056] In some embodiments, progression of a disease or condition, e.g., edema, is halted in a subject. In some embodiments, there is a reduction in disease stage in a subject. In some embodiments, treating includes reducing swelling, inflammation, fibrosis, pain, increasing range of motion, reducing heaviness, reducing tightness, reducing skin thickening, and / or improving lymphatic function. In some embodiments, treating includes improving a condition, e.g., edema, as measured by water content, limb volume, tissue stiffness, visual analog scale (VAS) score, Upper Limb Lymphedema Score (ULL27), Lymphedema Life Impact Scale (LLIS) score, Functional Assessment of Cancer Therapy Breast Cancer Specific Quality of Life Tool score (FACT-B+4), Lymphedema Quality of Life Score (LYMQOL), Disability of Arm, Shoulder, and Hand score (DASH), and / or Lymphedema Quality of Life Inventory (LQOLI).

[0057] The improvement of the water content of a subject with edema is a reduction in water content. Thus, in some embodiments, the water content of the limb of a subject with edema is reduced. In some embodiments, the water content of the limb of a subject with edema is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or more. In some embodiments, the water content of the limb of a subject with edema, as measured by, for example, bioelectrical impedance spectroscopy (BIS), is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more. In some embodiments, the water content of a subject's limb with edema, as measured by tissue dielectric constant (TDC), is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more. In some embodiments, in a subject with edema, limb volume is stabilized or reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or more. In some embodiments, limb volume is stabilized or reduced by at least 2%. In some embodiments, the tissue stiffness of a subject with edema is improved by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90% or more. In some embodiments, the tissue stiffness as measured by manometry is improved by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the tissue stiffness as measured by manometry is improved by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, or more. The quality improves by at least 20%.

[0058] In some embodiments, at least one of the positions designated as D independently has a deuterium enrichment of about 95% or greater. In some embodiments, at least one of the positions designated as D independently has a deuterium enrichment of about 98% or greater. In some embodiments, at least one of the positions designated as D independently has a deuterium enrichment of about 99% or greater.

[0059] In some embodiments, an effective amount of deuterium-enriched pirfenidone is maintained at the site of lymphedema in the subject.

[0060] In some embodiments, the subject is undergoing treatment for cancer and the lymphedema is associated with the treatment or diagnosis of cancer. In some embodiments, the subject has breast cancer-related arm lymphedema. In some embodiments, the subject has mild to moderate breast cancer-related lymphedema. In some embodiments, the subject is undergoing or may have undergone chemotherapy or radiation therapy.

[0061] In some embodiments, deuterium-enriched pirfenidone is administered topically twice daily. In some embodiments, deuterium-enriched pirfenidone is administered topically once daily. In some embodiments, deuterium-enriched pirfenidone is administered topically three times daily.

[0062] In another aspect, the invention features a method of treating interstitial lung disease (ILD). The method includes administering to a subject in need thereof a compound having the structure:

[0063] [ka]

[0064] The method comprises administering an effective amount of deuterium-enriched pirfenidone or a pharmaceutically acceptable salt thereof having the formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R8 , R 9 , R 10 , and R 11 is selected from hydrogen and deuterium. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 At least one of R is deuterium. 7 , R 8 , R 9 , R 10 , and R 11 If is deuterium, then R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 at least one of is deuterium. ILD is treated in a subject.

[0065] In some embodiments, deuterium-enriched pirfenidone has the structure:

[0066] [ka]

[0067] or a pharmaceutically acceptable salt thereof. In some embodiments, the ILD is idiopathic pulmonary fibrosis (IPF). Deuterium-enriched pirfenidone can be administered orally twice daily at a total daily dose of 1000 mg. In some embodiments, the initial dose is titrated from 250 mg to 1000 mg over two weeks.

[0068] In some embodiments, the subject experiences at least a 5% or 10% decline in percent of predicted forced vital capacity (%FVC).

[0069] In another aspect, the invention features a method of treating a fibrotic disorder or a collagen infiltration disorder. The method includes administering to a subject in need thereof a therapeutic agent having the structure:

[0070] [ka]

[0071] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is selected from hydrogen and deuterium. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 At least one of R is deuterium. 7 , R 8 , R 9 , R 10 , and R 11 If is deuterium, then R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 At least one of is deuterium. A fibrotic disorder or a collagen infiltration disorder is treated in the subject.

[0072] In some embodiments, deuterium-enriched pirfenidone has the structure:

[0073] [ka]

[0074] or a pharmaceutically acceptable salt thereof. In another aspect, the method includes measuring or monitoring a biomarker in the subject, e.g., a marker of inflammation. In some embodiments, the marker is one or more markers selected from G-CSF, MIG, FGF-2, IL-4, IL-10, lymphotoxin-α / TNF-β, leptin, IL-6, IL-1β, TNF-α, TGF-β1, MMP-9, TIMP-1, and MCP-1. In some embodiments, the biomarker is monitored to monitor treatment of the subject. [Brief explanation of the drawings]

[0075] [Figure 1A] 1 shows the pharmacokinetics of a single dose of an 801 mg dose of LYT-100 and an 801 mg dose of pirfenidone over 24 hours. [Figure 1B] 1 shows the pharmacokinetics of an individual single dose of an 801 mg dose of LYT-100 and an 801 mg dose of pirfenidone over 48 hours. [Figure 1C] A model of twice-daily administration of 500 mg of LYT-100 (total daily dose 1000 mg) and its metabolites on day 7 is shown. [Figure 1D] A model of 750 mg LYT-100 administered twice daily (total daily dose 1500 mg) and its metabolites on day 7 is shown. [Figure 1E] A model of the first 7 days of dosing is shown in FIG. 1D, showing accumulation to steady state. [Figure 1F] A model of once daily administration of 750 mg of LYT-100 (total daily dose 750 mg) and its metabolites on day 7 is shown. [Figure 1G] A model of the first 7 days of dosing is shown in FIG. 1F showing accumulation to steady state. [Figure 2] Representative photomicrographs of Sirius Red stained liver sections are shown, demonstrating that LYT-100 significantly reduced areas of fibrosis. [Figure 3]The percentage of fibrotic areas for LYT-100 compared to vehicle and control is shown. [Figure 4A] Figure 1 shows that LYT-100 does not induce survival of primary mouse lung fibroblasts (PMFL). [Figure 4B] Figure 1 shows that LYT-100 reduced TGF-β-induced total collagen levels in PMFL in a 6-well format. [Figure 4C] Figure 1 shows that LYT-100 reduced TGF-β-induced total collagen levels in PMFL in a 96-well format. [Figure 4D] 1 shows that LYT-100 reduced soluble fibronectin levels induced by TGF-β. [Figure 4E] 1 shows that LYT-100 reduced soluble collagen levels induced by TGF-β. [Figure 5A] 1 shows that LYT-100 does not affect the viability of L929 cells. [Figure 5B] Figure 1 shows that LYT-100 inhibits TGF-induced collagen synthesis. [Figure 5C] Figure 1 shows that LYT-100 significantly inhibits TGF-β-induced total collagen levels. [Figure 5D] 1 is a graph showing that LYT-100 significantly inhibits TGF-β-induced soluble collagen levels. [Figure 5E] Figure 1 shows that LYT-100 significantly reduced soluble fibronectin levels in the absence and presence of TGF-β induction. DETAILED DESCRIPTION OF THE INVENTION

[0076] 1. General Description of Certain Aspects of the Invention Deuterium-enriched pirfenidone Certain N-arylpyridinones of the present invention, including deuterium-enriched pirfenidone compounds, are described in WO2008 / 157786, WO2009 / 035598, WO2012 / 122165, and WO2015 / 112701, which are incorporated by reference in their entireties.

[0077] Pirfenidone (Deskar®), CAS#53179-13-8, Pirespa, AMR-69, Pirfenidona, Pirfenidonum, Esbriet, Pirfenex, 5-methyl-1-phenyl-1H-pyridin-2-one, 5-methyl-1-phenyl-2-(1H)-pyridone, 5-methyl-1-phenylpyridin-2(1H)-one is an orally administered antifibrotic agent. Pirfenidone is currently approved in the United States and other countries for idiopathic pulmonary fibrosis (IPF).

[0078] [ka]

[0079] The metabolism of pirfenidone is only partially understood. For example, without wishing to be bound by theory, it is believed that the methyl group is susceptible to oxidation, resulting in the corresponding hydroxymethyl metabolite "M1." M1 is believed to be further oxidized to the carboxylic acid metabolite "M2" (Wang, et al., Biomedical Chromatography, 2006, 20, 1375-1379). The third detected metabolite is believed to be a Phase II product, likely derived from M1 or M2. Pirfenidone has a very short half-life in humans.

[0080] Deuterium kinetic isotope effect To eliminate foreign substances from the circulatory system, animal tissues use enzymes such as cytochrome P 450They express a variety of enzymes, such as CYPs (cytochrome P450), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, that react with these xenobiotics and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) or carbon-carbon (CC) pi bonds. The resulting metabolites can be stable or unstable under physiological conditions and can have significantly different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles compared to the parent compound. For most drugs, such oxidation is generally rapid, ultimately necessitating the administration of multiple or high daily doses to maintain therapeutically effective levels of the drug in patients.

[0081] The relationship between activation energy and reaction rate is given by the Arrhenius equation, i.e., k = Ae -Eact / RT, where E act is the activation energy, T is the temperature, R is the molar gas constant, k is the rate constant of the reaction, and A (the frequency factor) is a constant specific to each reaction that depends on the probability of molecules colliding in the right direction. The Arrhenius equation shows that the fraction of molecules with enough energy to overcome the energy barrier, i.e., the fraction of molecules with energy at least equal to the activation energy, depends exponentially on the ratio of the activation energy to the heat energy, the average amount of heat energy a molecule has at a particular temperature (RT).

[0082] The transition state of a reaction is a short-lived state (10 -14 By definition, the activation energy of a reaction, E actis the energy required to reach the transition state of that reaction. Reactions that involve multiple steps necessarily have several transition states, and in these cases, the activation energy of the reaction is equal to the energy difference between the reactants and the most unstable transition state. Once the transition state is reached, the molecules can either revert, thereby reforming the original reactants, or new bonds can form, resulting in products. This dichotomy is possible because both the forward and reverse pathways result in the release of energy. Catalysts accelerate the reaction process by lowering the activation energy leading to the transition state. Enzymes are examples of biological catalysts that reduce the energy required to achieve a particular transition state.

[0083] Carbon-hydrogen bonds are essentially covalent chemical bonds. Such bonds form when two atoms with similar electronegativity share some of their valence electrons, thereby creating a force that holds the atoms together. This force, or bond strength, can be quantified and is expressed in units of energy. Covalent bonds between various atoms can be represented as follows:

[0084] Bond strength is directly proportional to the absolute value of the ground-state vibrational energy of the bond. This vibrational energy, also known as the zero-point vibrational energy, depends on the mass of the atoms forming the bond. The absolute value of the zero-point vibrational energy increases as the mass of one or both atoms forming the bond increases. Because deuterium (D) is twice as massive as hydrogen (H), it follows that a C-D bond is stronger than the corresponding C-H bond. Compounds with C-D bonds are often stable indefinitely in HO and are widely used in isotope studies. If a C-H bond is broken during the rate-determining step of a chemical reaction (i.e., the step with the highest transition state energy), the substitution of deuterium for its hydrogen will cause a decrease in the reaction rate, slowing the process. This phenomenon, known as the deuterium kinetic isotope effect (DKIE), can range from approximately 1 (no isotope effect) to very large numbers, e.g., greater than 50, meaning that the reaction can be more than 50 times slower when deuterium replaces hydrogen. High DKIE values ​​can be attributed in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling occurs because the small size of hydrogen atoms allows transition states involving protons to form in the absence of the required activation energy. Deuterium is larger and statistically has a much lower probability of undergoing this phenomenon. Substitution of tritium for hydrogen results in an even stronger bond than deuterium, imparting a numerically larger isotope effect.

[0085] Deuterium (D), discovered by Urey in 1932, is a stable, non-radioactive isotope of hydrogen. It was the first isotope isolated from the element in pure form, and it is twice as massive as hydrogen, accounting for approximately 0.02% of the total mass of hydrogen on Earth (which in this usage means all hydrogen isotopes). When two deuterium atoms combine with one oxygen atom, deuterium oxide (DO or "heavy water") is formed.

[0086] Deuterated pyridinone derivatives Pirfenidone is a substituted pyridinone fibrosis and / or collagen infiltration modulator. The carbon-hydrogen bonds of pirfenidone exhibit a naturally occurring distribution of hydrogen isotopes, i.e., 1 H or protium (approximately 99.9844%), 2 H or deuterium (approximately 0.0156%), and 3 H or tritium (10 18 (between about 0.5 and 67 tritium atoms per protium atom). Increased levels of deuterium incorporation, relative to compounds with naturally occurring levels of deuterium, can result in a detectable kinetic isotope effect (KIE) that can affect the pharmacokinetic, pharmacological, and / or toxicological profiles of such fibrosis modulators and / or collagen invasion modulators.

[0087] Pirfenidone is likely metabolized in humans by oxidation of the methyl group. Other sites on the molecule may also undergo transformations leading to metabolites with unknown pharmacology and toxicology. Limiting the production of these metabolites may reduce the risk of administering such drugs and even allow for increased dosage and therefore efficacy. All of these transformations can occur via polymorphically expressed enzymes, thus amplifying patient-to-patient variability.

[0088] Various deuterium patterns can be used to (a) reduce or eliminate undesired metabolites, (b) increase the half-life of the parent drug, (c) reduce the number of doses required to achieve a desired effect, (d) reduce the amount of dose required to achieve a desired effect, and (e) increase the formation of active metabolites, if formed. and / or (f) reduce production of harmful metabolites in specific tissues and / or create more effective and / or safer drugs for polypharmacy, whether or not polypharmacy is intended. The deuteration approach has strong potential to slow metabolism via various oxidative and racemization mechanisms.

[0089] In one aspect, the present invention provides a compound of formula I:

[0090] [ka]

[0091] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is selected from hydrogen and deuterium, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 At least one of R is deuterium. 7 , R 8 , R 9 , R 10 , and R 11 If is deuterium, then R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 At least one of the atoms is deuterium.

[0092] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R10 , and R 11の At least one of independently has a deuterium enrichment of about 1% or more, about 5% or more, about 10% or more, about 20% or more, about 50% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.1% or more, about 99.2% or more, about 99.3% or more, about 99.4% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more. In some embodiments comprising any of the deuterium-enriched pirfenidone compounds described below and elsewhere herein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 At least one of independently has a deuterium enrichment of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 100%, or any incremental numerical fraction within the stated range of deuterium enrichment.

[0093] In yet another embodiment, R 1 , R 2 , and R 3 At least one of the is deuterium.

[0094] In yet another embodiment, R 1 , R 2 , and R 3 At least two of the are deuterium.

[0095] In yet another embodiment, R 1 , R 2 , and R 3 is deuterium. In yet another embodiment, R4 is deuterium.

[0096] In yet another embodiment, R 5 and R 6 At least one of the is deuterium. In yet another embodiment, R 5 and R 6 is deuterium.

[0097] In yet another embodiment, R 5 and R 6 is deuterium and R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , and R 11 At least one of the is deuterium.

[0098] In yet another embodiment, R 7 , R 8 , R 9 , R 10 , and R 11 At least one of the is deuterium.

[0099] In yet another embodiment, R 7 , R 8 , R 9 , R 10 , and R 11 is deuterium. In yet another embodiment, R 7 , R 8 , and R 9 is deuterium and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 10 , and R 11 At least one of the is deuterium.

[0100] In yet another embodiment, R 1 , R2 , and R 3 At least one of R is deuterium. 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen.

[0101] In yet another embodiment, R 1 , R 2 , and R 3 At least two of the atoms are deuterium, and R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen.

[0102] In yet another embodiment, R 1 , R 2 , and R 3 is deuterium and R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen.

[0103] In yet another embodiment, R 4 is deuterium and R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen.

[0104] In yet another embodiment, R 5 and R 6 At least one of R is deuterium. 1 , R2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen.

[0105] In yet another embodiment, R 5 and R 6 is deuterium and R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen.

[0106] In yet another embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 At least one of R is deuterium. 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen.

[0107] In yet another embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is deuterium and R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen.

[0108] In yet another embodiment, R 7 , R 8 , R 9 , R 10 , and R 11 is deuterium and R 1 , R 2 , R3 , R 4 , R 5 , and R 6 is hydrogen.

[0109] In yet another embodiment, R 7 , R 8 , R 9 , R 10 , and R 11 is deuterium and R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 At least one of the is deuterium.

[0110] In other embodiments, R 1 is hydrogen. In yet another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In yet another embodiment, R 4 is hydrogen. In some embodiments, R 5 is hydrogen. In yet another embodiment, R 6 is hydrogen. In yet another embodiment, R 7 is hydrogen. In yet another embodiment, R 8 is hydrogen. In some embodiments, R 9 is hydrogen. In other embodiments, R 10 is hydrogen. In yet another embodiment, R 11 is hydrogen.

[0111] In other embodiments, R 1 is deuterium. In yet another embodiment, R 2 is deuterium In yet another embodiment, R 3 is deuterium. In yet another embodiment, R 4 is deuterium. In some embodiments, R 5 is deuterium. In yet another embodiment, R 6 is deuterium. In yet another embodiment, R 7is deuterium. In yet another embodiment, R 8 is deuterium. In some embodiments, R 9 is deuterium. In other embodiments, R 10 is deuterium. In yet another embodiment, R 11 is deuterium.

[0112] In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof. LYT-100 has the following structure:

[0113] [ka]

[0114] In some embodiments, the deuterium-enriched pirfenidone is a compound or a pharmaceutically acceptable salt thereof, or a metabolite thereof, described in WO2008 / 157786, WO2009 / 035598, WO2012 / 122165, or WO2015 / 112701, the entireties of which are incorporated herein by reference.

[0115] In one aspect, the present invention provides a deuterium-enriched compound shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0116] [Table 1] TIFF2025000646000025.tif230156 TIFF2025000646000026.tif70156

[0117] In some embodiments, the present invention provides a compound as shown in Table 1 above, or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the present invention provides a compound as set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, wherein at least one of the positions designated as D independently has a deuterium enrichment of about 1% or more, about 5% or more, about 10% or more, about 20% or more, about 50% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.1% or more, about 99.2% or more, about 99.3% or more, about 99.4% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more. In other embodiments, at least one of the positions designated as D independently has a deuterium enrichment of 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 100%, or any incremental numerical fraction within the stated range of deuterium enrichment.

[0119] In further embodiments, the compound is substantially a single enantiomer, a mixture of about 90% by weight or more of the (-)-enantiomer and about 10% by weight or less of the (+)-enantiomer, a mixture of 90% by weight or more of the (+)-enantiomer and about 10% by weight or less of the (-)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% by weight or more of an individual diastereomer and about 10% by weight or less of the other diastereomer.

[0120] In certain embodiments, compounds as disclosed herein contain about 60% or more by weight of the (-)-enantiomer of the compound and about 40% or less by weight of the (+)-enantiomer of the compound. In certain embodiments, compounds as disclosed herein contain about 70% or more by weight of the (-)-enantiomer of the compound and about 30% or less by weight of the (+)-enantiomer of the compound. In certain embodiments, compounds as disclosed herein contain about 80% or more by weight of the (-)-enantiomer of the compound and about 20% or less by weight of the (+)-enantiomer of the compound. In certain embodiments, compounds as disclosed herein contain about 90% or more by weight of the (-)-enantiomer of the compound and about 10% or less by weight of the (+)-enantiomer of the compound. In certain embodiments, compounds as disclosed herein contain about 95% or more by weight of the (-)-enantiomer of the compound and about 5% or less by weight of the (+)-enantiomer of the compound. In certain embodiments, compounds as disclosed herein contain about 99% or more by weight of the (-)-enantiomer of the compound and about 1% or less by weight of the (+)-enantiomer of the compound. Contains.

[0121] In certain embodiments, compounds as disclosed herein contain about 60% or more by weight of the (+)-enantiomer of the compound and about 40% or less by weight of the (-)-enantiomer of the compound. In certain embodiments, compounds as disclosed herein contain about 70% or more by weight of the (+)-enantiomer of the compound and about 30% or less by weight of the (-)-enantiomer of the compound. In certain embodiments, compounds as disclosed herein contain about 80% or more by weight of the (+)-enantiomer of the compound and about 20% or less by weight of the (-)-enantiomer of the compound. In certain embodiments, compounds as disclosed herein contain about 90% or more by weight of the (+)-enantiomer of the compound and about 10% or less by weight of the (-)-enantiomer of the compound. In certain embodiments, compounds as disclosed herein contain about 95% or more by weight of the (+)-enantiomer of the compound and about 5% or less by weight of the (-)-enantiomer of the compound. In certain embodiments, the compounds as disclosed herein contain about 99% or more by weight of the (+)-enantiomer of the compound and about 1% or less by weight of the (-)-enantiomer of the compound.

[0122] Deuterated compounds as disclosed herein also have a carbon 13 C or 14 C, for nitrogen 15 N, or oxygen 17 O or 18 It may also contain less common isotopes of other elements, including but not limited to O.

[0123] Hydrogen isotopes can be introduced into compounds of the present invention as disclosed herein by synthetic techniques employing deuteration reagents, whereby the incorporation rate is predetermined, and / or by exchange techniques, whereby the incorporation rate is predetermined by equilibrium conditions and can vary widely depending on the reaction conditions. Synthetic techniques in which tritium or deuterium is directly and specifically inserted by tritium or deuteration reagents of known isotopic content can produce large amounts of tritium or deuterium, but can be limited by the chemistry required. Additionally, the labeled molecule may vary depending on the stringency of the synthetic reaction employed. On the other hand, exchange techniques can produce low incorporation of tritium or deuterium, often with the isotope distributed over many sites on the molecule, but offer the advantages of not requiring a separate synthetic step and being less likely to disrupt the structure of the labeled molecule.

[0124] Compounds as disclosed herein can be prepared by any method known to those skilled in the art and routine modifications thereof, and / or by any of the methods described in Esaki et al., each of which is incorporated herein by reference in its entirety. et al., Tetrahedron, 2006, 62, 10954-10961; Smith et al., Organic Syntheses, 2002, 78, 51-56; U.S. Pat. No. 3,974,281; U.S. Pat. No. 8,680,123; WO2003 / 014087; WO2008 / 157786; WO2009 / 035598; WO2012 / 122165; or WO2015 / 112701, and the references cited therein, and routine modifications thereof.

[0125] Methods, compositions and dosages for treating fibrosis- and / or collagen-mediated disorders Disclosed herein are methods for the treatment, prevention, and / or amelioration of a fibrosis-mediated and / or collagen-mediated and / or inflammatory disorder, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. Disclosed herein are methods for the treatment, prevention, and / or amelioration of one or more symptoms of a fibrosis-mediated and / or collagen-mediated and / or inflammatory disorder, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., LYT-100. The present invention relates to a method for treating, preventing, and / or ameliorating a fibrosis-mediated disorder, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., LYT-100, e.g., a compound listed in Table 1. Disclosed herein is a method for treating, preventing, and / or ameliorating a fibrosis-mediated disorder, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., LYT-100, e.g., a compound listed in Table 1. Disclosed herein is a method for treating, preventing, and / or ameliorating one or more symptoms of a fibrosis-mediated disorder, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., LYT-100, e.g., a compound listed in Table 1. Disclosed herein are methods for the treatment, prevention, and / or amelioration of collagen-mediated disorders, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. Disclosed herein are methods for the treatment, prevention, and / or amelioration of one or more symptoms of collagen-mediated disorders, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. Disclosed herein are methods for the treatment, prevention, and / or amelioration of inflammatory disorders, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. Disclosed herein are methods for treating, preventing, and / or ameliorating one or more symptoms of an inflammatory disorder, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100.

[0126] Fibrosis- and / or collagen-mediated disorders include, but are not limited to, idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial fibrillation, neutropenia, scleroderma, dermatomyositis, cirrhosis of the liver, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, splenic fibrosis due to sickle cell anemia, rheumatoid arthritis, edema, lymphedema, and / or disorders that are ameliorated by modulating fibrosis and / or collagen infiltration into tissues.

[0127] In some embodiments, the deuterium-enriched pirfenidone compound used in the disclosed methods has at least one of the following properties: (a) reduced inter-individual variability in plasma levels of the compound or its metabolites compared to non-isotopically enriched compounds; (b) increased mean plasma levels of the compound per dosage unit compared to non-isotopically enriched compounds; (c) reduced mean plasma levels of at least one metabolite of the compound per dosage unit compared to non-isotopically enriched compounds; (d) increased mean plasma levels of at least one metabolite of the compound per dosage unit compared to non-isotopically enriched compounds; and (e) improved clinical effect during treatment in subjects per dosage unit compared to non-isotopically enriched compounds. Thus, disclosed herein are methods for treating a subject, including a human, having or suspected of having a fibrosis-mediated and / or collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to provide one or more of the above-described properties (a)-(e) during treatment of the disorder, relative to a corresponding non-isotopically enriched compound. In some embodiments, the deuterium-enriched pirfenidone compound exhibits at least two of the above-described properties (a)-(e). In some embodiments, the deuterium-enriched pirfenidone compound has three or more of the above properties (a)-(e).

[0128] In one embodiment, the present invention relates to a method for treating, preventing, or ameliorating one or more symptoms of a fibrosis- and / or collagen-mediated disorder, including, but not limited to, idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial fibrillation, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, splenic fibrosis due to sickle cell anemia, rheumatoid arthritis, and / or disorders ameliorated by modulating fibrosis and / or collagen infiltration into tissues.

[0129] Disclosed herein is a method for treating a subject, including a human, suffering from or suspected of suffering from a fibrosis-mediated disorder and / or a collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in a reduction in inter-individual variability in the plasma level of the compound or its metabolite during treatment of the disorder, compared to the corresponding non-isotopically enriched compound. In certain embodiments, the inter-individual variability in the plasma level of the compound disclosed herein or its metabolite is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0130] Disclosed herein is a method for treating a subject, including a human, who has or is suspected of having a fibrosis-mediated disorder and / or a collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in an increase in the average plasma level of the compound or a decrease in the average plasma level of at least one metabolite of the compound per dosage unit, compared to the corresponding non-isotopically enriched compound. In certain embodiments, the average plasma level of the compound disclosed herein is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound. In certain embodiments, the mean plasma levels of metabolites of the compounds disclosed herein are reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0131] Plasma levels of compounds as disclosed herein, or their metabolites, can be measured using the method described by Li et al. (Rapid Communications in Mass Spectrometry, 2005, 19, 1943-1950).

[0132] In some embodiments, the compound reduces the expression of at least one polymorphic cytochrome P in a subject per dosage unit compared to a non-isotopically enriched compound. 450 It has a decreased metabolism due to isoforms.

[0133] In some embodiments, cytochrome P 450The isoform is selected from CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

[0134] In some embodiments, the compound increases the activity of at least one cytochrome P in a subject per dosage unit compared to a non-isotopically enriched compound. 450 or characterized by reduced inhibition of monoamine oxidase isoforms.

[0135] In certain embodiments, cytochrome P 450 or monoamine oxidase isoforms CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4 B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A 1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO A , and MAO B is selected from.

[0136] In some embodiments, the deuterium-enriched pirfenidone compound has at least one of the following properties: (a) a half-life of greater than 2.5 hours, (b) a reduced tablet burden, (c) improved patient tolerability, (d) a lower effective dose, (e) increased bioavailability, (f) a higher Cmax, and (g) an increased systemic exposure in a subject during treatment per dosage unit thereof compared to a non-isotopically enriched compound. Disclosed herein is a method for treating a subject, including a human, having or suspected of having a fibrosis-mediated and / or collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in one or more of the above (a)-(g) during treatment of the disorder compared to a corresponding non-isotopically enriched compound.

[0137] Disclosed herein is a method for treating a subject, including a human, having or suspected of having a fibrosis-mediated disorder and / or a collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to provide a longer half-life. In some embodiments, the half-life of the deuterium-enriched pirfenidone compound or its metabolite as disclosed herein is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound. In some embodiments, the half-life of a deuterium-enriched pirfenidone compound as disclosed herein, or a metabolite thereof, is increased by about 1.5-fold, about 2-fold, more than about 2-fold, more than about 3-fold, more than about 4-fold, more than about 5-fold, more than about 10-fold, or more (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0138] Disclosed herein is a method for treating a subject, including a human, having or suspected of having a fibrosis-mediated and / or collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to the disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to reduce the tablet burden during treatment of the disorder compared to the corresponding non-isotopically enriched compound, e.g., to result in a tablet burden of less than 9 capsules of the compound or its metabolites per day (TID dosing).

[0139] In certain embodiments, the tablet loading of a compound as disclosed herein is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0140] Disclosed herein are methods for treating a subject, including a human, having or suspected of having a fibrosis-mediated and / or collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to the disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in improved patient tolerability of the compound or its metabolites during treatment of the disorder, compared to a corresponding non-isotopically enriched compound. In some embodiments, patient tolerability is improved by altering the pharmacokinetics of pirfenidone, e.g., by increasing bioavailability (such as using lower doses) and / or by extending the half-life of the compound, and / or by other means that reduce the side effects of pirfenidone.

[0141] In certain embodiments, the patient tolerability of a compound as disclosed herein, or a metabolite thereof, compared to the corresponding non-isotopically enriched compound is improved by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including the numerical increments between the recited percentages). In certain embodiments, the patient tolerability of a compound as disclosed herein, or a metabolite thereof, compared to the corresponding non-isotopically enriched compound is improved by about 1.5-fold, about 2-fold, more than about 2-fold, more than about 3-fold, more than about 4-fold, more than about 5-fold, more than about 10-fold, or more (including the numerical increments between the recited percentages).

[0142] Disclosed herein is a method for treating a subject, including a human, having or suspected of having a fibrosis-mediated and / or collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to the disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in a lower effective dose per administration of the compound or its metabolite during treatment of the disorder compared to a corresponding non-isotopically enriched compound.

[0143] In certain embodiments, the effective dose per dose of a compound as disclosed herein, or a metabolite thereof, is greater than about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 100% (see columns 1 and 2) relative to the corresponding non-isotopically enriched compound. In certain embodiments, the effective dose per dose of a compound as disclosed herein, or a metabolite thereof, is reduced by about 1.5-fold, about 2-fold, more than about 2-fold, more than about 3-fold, about 4-fold, more than about 5-fold, about 10-fold, or more (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0144] Disclosed herein is a method for treating a subject, including a human, having or suspected of having a fibrosis-mediated and / or collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to the disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to increase the bioavailability per dose of the compound or its metabolite during treatment of the disorder compared to a corresponding non-isotopically enriched compound.

[0145] In certain embodiments, the bioavailability per dose of a compound as disclosed herein, or a metabolite thereof, is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound. In certain embodiments, the bioavailability per dose of a compound as disclosed herein, or a metabolite thereof, is increased by about 1.5-fold, about 2-fold, more than about 2-fold, more than about 3-fold, more than about 4-fold, more than about 5-fold, more than about 10-fold, or more (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0146] Disclosed herein is a method for treating a subject, including a human, having or suspected of having a fibrosis-mediated and / or collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in increased systemic exposure of the compound per dosage unit compared to the corresponding non-isotopically enriched compound.

[0147] In certain embodiments, the systemic exposure per dose of a compound as disclosed herein or its metabolites is increased by more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, or more than about 50% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound. In one embodiment, the systemic exposure per dose of a compound as disclosed herein is increased by more than about 35% compared to the corresponding non-isotopically enriched compound. In one embodiment, the systemic exposure per dose of a compound as disclosed herein is increased by about 35% compared to the corresponding non-isotopically enriched compound.

[0148] Disclosed herein is a method for treating a subject, including a human, having or suspected of having a fibrosis-mediated and / or collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in an increased Cmax of the compound per dosage unit compared to the corresponding non-isotopically enriched compound.

[0149] In certain embodiments, the Cmax per dose of a compound as disclosed herein or its metabolites is increased by more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, or more than about 50% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax per dose of a compound as disclosed herein is increased by more than about 25% compared to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax per dose of a compound as disclosed herein is increased by about 25% compared to the corresponding non-isotopically enriched compound.

[0150] In some embodiments, the method treats the disorder while reducing or eliminating the adverse changes in diagnostic hepatobiliary function endpoints compared to corresponding non-isotopically enriched compounds, such as pirfenidone.Disclosed herein is a method for treating a subject, including a human, who has or is suspected to have a fibrosis-mediated disorder and / or a collagen-mediated disorder (e.g., any of the disorders disclosed herein), or for preventing such disorders in a subject who is prone to such disorders, comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to reduce or eliminate the adverse changes in diagnostic hepatobiliary function endpoints compared to corresponding non-isotopically enriched compounds. In some embodiments, the diagnostic hepatobiliary function endpoints are selected from alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase ("SGPT"), aspartate aminotransferase ("AST", "SGOT"), ALT / AST ratio, serum aldolase, alkaline phosphatase ("ALP"), ammonia level, bilirubin, gamma-glutamyl transpeptidase ("GGTP", "γ-GTP", "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasound, liver nuclear scan, 5'-nucleotidase, and blood proteins.

[0151] Disclosed herein are methods for the treatment, prevention, and / or amelioration of fibrosis- and / or collagen-mediated disorders, as well as methods for the treatment, prevention, and / or amelioration of one or more symptoms of fibrosis- and / or collagen-mediated disorders, the methods comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and further comprising administering one or more additional therapeutic agent(s) selected from an anti-T cell agent, an anti-inflammatory agent, an anti-TGF-βI agent, and an anti-angiotensin agent. In some embodiments, the additional therapeutic agent is an anti-inflammatory agent. In some embodiments, the additional therapeutic agent is an anti-T cell agent. In some embodiments, the additional therapeutic agent is an anti-TGF-βI agent. In some embodiments, the additional therapeutic agent is an anti-angiotensin agent.

[0152] In some embodiments, the therapeutic agent is deuterium-enriched pirfenidone, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is LYT-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is deuterium-enriched pirfenidone, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents, such as any of the additional therapeutic agents disclosed herein.

[0153] In any of the above embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered twice daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, deuterium-enriched pirfenidone is administered orally at 750 mg twice daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 500 mg twice daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 250 mg twice daily.

[0154] In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered once daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 1000 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 750 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 500 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 250 mg once daily.

[0155] In any of the above embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered three times daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 500 mg three times daily. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 333 mg three times daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 166 mg three times daily.

[0156] In some embodiments, the deuterium-enriched pirfenidone is in the form of a tablet. In some embodiments, the deuterium-enriched pirfenidone is taken orally with food.

[0157] Accordingly, provided herein are methods for treating, preventing, and / or ameliorating fibrosis- and / or collagen-mediated disorders, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered twice daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for treating, preventing, and / or ameliorating fibrosis- and / or collagen-mediated disorders, comprising administering LYT-100 to a subject in need thereof, wherein the LYT-100 is orally administered twice daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. The daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 750 mg twice a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 500 mg twice a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 250 mg twice a day.

[0158] In some embodiments, provided herein are methods for treating, preventing, and / or ameliorating fibrosis- and / or collagen-mediated disorders, the methods comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered once daily in a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for treating, preventing, and / or ameliorating fibrosis- and / or collagen-mediated disorders, the methods comprising administering LYT-100 to a subject in need thereof, wherein the LYT-100 is orally administered once daily in a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 1000 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 750 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally at 500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally at 250 mg once daily.

[0159] Thus, provided herein are methods for treating, preventing, and / or ameliorating fibrosis- and / or collagen-mediated disorders, the methods comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered three times daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for treating, preventing, and / or ameliorating fibrosis- and / or collagen-mediated disorders, the methods comprising administering LYT-100 to a subject in need thereof, wherein the LYT-100 is orally administered three times daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally at 500 mg three times daily. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally at 333 mg three times daily. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally at 166 mg twice daily.

[0160] In other embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-2000 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-1000 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg / day. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered three times daily (TID). In some embodiments, the deuterium-enriched pirfenidone compound is orally administered twice daily (BID). In some embodiments, the deuterium-enriched pirfenidone compound is orally administered once daily (QD). In any of these embodiments, the deuterium-enriched pirfenidone compound has the structure of Formula I, eg, the compounds listed in Table 1, including, eg, LYT-100.

[0161] Methods, compositions and medications for treating edema As used herein, the term "edema" or "oedema" refers to the abnormal accumulation of fluid under the skin and within body cavities, including, but not limited to, the limbs, hands / feet, upper body (chest / chest wall, shoulders, back), lower body (buttocks, abdomen), genitals (scrotum, penis, vulva), head, neck, or face. Abnormal accumulation of fluid can occur when capillary filtration exceeds lymphatic drainage. Thus, all edemas have a lymphatic component. Edema includes lymphedema, lymphatic dysfunction, lymphatic tissue fibrosis, idiopathic edema, peripheral edema, and ocular edema. Edema includes acute edema, chronic edema, postoperative edema, gradual onset edema, primary edema, and secondary edema. Chronic edema is edema present for more than three months and can include lymphedema (primary disorders of lymphatic vessel development and secondary to damage to lymphatic vessels), venous edema, chronic swelling due to immobility, edema associated with advanced cancer, chronic swelling associated with lymphedema, chronic swelling associated with obesity, and chronic swelling associated with rare vascular malformations such as Klippel-Trenaunay syndrome. Symptoms of edema can include fluid accumulation under the skin or within body cavities, tissue swelling, fullness or swelling, inflammation, fibrosis, heaviness, pain, decreased range of motion, soreness, recurrent infections, thickened skin, or discomfort. In some embodiments, "edema" does not include pulmonary edema or cerebral edema. In some embodiments, the edema is lymphedema. In some embodiments, the lymphedema is primary lymphedema. In some embodiments, the lymphedema is secondary lymphedema.

[0162] Lymphedema is a chronic disease affecting millions of people and characterized by severe swelling of a body part, usually an arm or leg, due to the accumulation of lymphatic fluid and inflammation, fibrosis, and fatty deposits. Lymph is a clear fluid collected from body tissues that transports fats and proteins from the small intestine, removes bacteria, viruses, toxins, and certain proteins from tissues, and supplies white blood cells, particularly lymphocytes, to the bloodstream to help fight infections and other diseases. Lymphedema is a chronic, debilitating disease of fibrotic and inflammatory origin that most often occurs as a complication of cancer treatment in developed countries such as the United States. Therefore, secondary lymphedema is the most common form of lymphedema and can develop after surgery, infection, or trauma, and can be a major cause of cancer, radiation, and chemotherapy. Lymphedema is often caused by cancer treatments such as rheumatoid arthritis, trauma, or infection that results in lymph node damage or removal. As a complication of cancer treatment, lymphedema occurs as a result of iatrogenic damage to the lymphatic system, usually as a result of lymph node dissection. It is estimated that one in three patients who undergo lymph node dissection will subsequently develop lymphedema. Extensive skin excision and adjuvant radiation therapy can also cause lymphedema. Additionally, obesity and radiation are known risk factors for the development of lymphedema.

[0163] Lymphedema of the legs and its progressive form, known as elephantiasis, are significant causes of disability and morbidity in lymphatic filariasis-endemic areas, affecting an estimated 14 million people worldwide (Stocks et al., PLoS Negl. Trop. Dis. 2015, Oct. 23;9(10):e0004171). More than 1.1 billion people worldwide are at risk for lymphatic filariasis (Walsh et al., PLoS Negl. Trop. Dis. 2016, Aug. 22;10(8):e0004917). Lymphatic filariasis is found in regions ranging from Latin America to Central Africa, South Asia, and the Pacific Islands. Filarial infections are transmitted by mosquitoes, but efforts to control transmission based solely on mosquito control have met with limited success (Lammie et al., Ann. NY Acad. Sci. 2002, Dec;979:131-42; discussion, 188-96). Wuchereria bancrofti (Wb) is the most widespread of the three nematodes known to cause lymphatic filariasis (LF), the others being Brugia malayi and Brugia timori. Wuchereria bancrofti is the species responsible for 90% of human lymphatic filariasis cases. Filarial infections can cause a variety of clinical manifestations, including lymphedema of the limbs, genital disease (testicular cysts, chyloceles, and swelling of the scrotum and penis), and recurrent acute attacks. These acute attacks are caused by secondary infections that predispose to lymphatic damage in the lower extremities, causing extreme pain and fever. Most infected individuals are asymptomatic, but virtually all have silent lymphatic damage, and as many as 40% have renal damage accompanied by proteinuria and hematuria.

[0164] Lymphedema is a serious disease with significant health consequences, including disfigurement and weakness. Patients experience chronic swelling in the affected limbs, heaviness, pain, discomfort, skin breakdown, fibrosis, recurrent infections, limited mobility, and a reduced quality of life.

[0165] Lymphatic dysfunction remains largely untreated or inadequately addressed by current therapies. There are currently no approved drug therapies for the treatment of lymphedema. Furthermore, there are currently no known pharmacological therapies that can halt lymphedema progression or promote its resolution. The current standard of care for lymphedema is primarily compression management and physical therapy to control swelling. These approaches are cumbersome, uncomfortable, non-curative, and do not address the underlying condition, especially in patients with more severe lymphedema. Despite management, some patients progress from mild to moderate lymphedema to more severe forms. In later stages, patients may seek excision surgery, including liposuction or weight loss. These procedures reduce volume but do not restore lymphatic flow, leading to compression dependency. Given the current lack of drug therapies that treat the underlying cause of lymphedema, the development of targeted treatments for lymphedema is an unmet biomedical need.

[0166] Little progress has been made toward developing meaningful treatments for lymphatic disorders. Previous experimental treatments for lymphedema have focused on the delivery of lymphangiogenic cytokines (Skobe et al., Nat. Med. 7:192-198 (2001)). For example, some previous studies have focused on repairing damaged lymphatic vessels using lymphangiogenic cytokines such as vascular endothelial growth factor-c (VEGF-C) (Tammela et al., Nat. Med. 13:1458-1466 (2007)). Baker et al. t al., Breast Cancer Res. 12:R70 (2010). However, the application of this approach specifically to cancer patients is untenable because these same mechanisms regulate tumor growth and metastasis, increasing the risk of cancer metastasis or recurrence.

[0167] In some embodiments, the present disclosure provides a method of treating edema, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., LYT-100, e.g., a compound listed in Table 1. In some embodiments, the present disclosure provides a method of treating lymphedema, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., LYT-100, e.g., a compound listed in Table 1. In some embodiments, the present disclosure provides a method of treating secondary lymphedema, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., LYT-100, e.g., a compound listed in Table 1. In some embodiments, the present disclosure provides a method of treating primary lymphedema, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100.

[0168] In some embodiments, the lymphedema occurs in one or both arms, such as the hand, wrist, forearm, elbow, upper arm, shoulder, armpit, or a combination of arm regions or the entire arm. In some embodiments, the lymphedema occurs in one or both legs, such as the foot, ankle, leg, knee, upper leg, or thigh, groin, hip, or a combination of leg regions or the entire leg. In some embodiments, the lymphedema occurs in the head, neck, jaw, chest, breast, thorax, abdomen, pelvis, genitalia, or other areas of a body cavity. In some embodiments, the lymphedema occurs in one or more limbs, or one or more limbs and another area of ​​the body.

[0169] In some embodiments, the lymphedema results from vascular disorders, including venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphatic vascular malformations, or cardiovascular disease.

[0170] In some embodiments, the subject has or has had cancer, e.g., cancer including solid tumors. In some embodiments, the subject has or has had breast cancer or cancer affecting the female reproductive organs, the skin system, the musculoskeletal system, the soft tissue of the limbs or trunk, the male reproductive system, the urinary system, or the head and neck. In some embodiments, the subject has undergone axillary lymph node dissection. In some embodiments, the subject is undergoing treatment for cancer, and the edema, lymphedema, or lymphatic damage is associated with cancer treatment or diagnosis. For example, the subject may be undergoing or have undergone chemotherapy or radiation therapy for cancer treatment or other indications, or may have had surgical removal of one or more lymph nodes during the course of cancer treatment or diagnosis.

[0171] In some embodiments, the subject has suffered lymphatic damage (e.g., as a result of removal, ligation, or obstruction of lymph nodes or lymphatic vessels, or fibrosis of lymphatic tissue), or the subject is obese, or has or has had an infection that leads to edema, such as lymphedema. In some embodiments, the infection is a skin infection or a history of skin infection associated with lymphedema or lymphatic vessel damage. In some embodiments, the infection is a parasitic infection that disrupts lymphatic flow or damages the lymphatic system. In some embodiments, the subject has suffered lymphatic vessel damage due to joint replacement, trauma, burns, radiation, or chemotherapy.

[0172] In some embodiments, the present disclosure provides a method of preventing edema, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. In some embodiments, the present disclosure provides a method of preventing lymphedema, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. In some embodiments, the present disclosure provides a method of preventing secondary lymphedema, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. In some embodiments, the present disclosure provides a method of preventing primary lymphedema, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100.

[0173] In some embodiments, the lymphedema occurs in one or both arms, such as the hand, wrist, forearm, elbow, upper arm, shoulder, armpit, or a combination of arm regions or the entire arm. In some embodiments, the lymphedema occurs in one or both legs, such as the foot, ankle, leg, knee, upper leg or thigh, groin, hip, or a combination of leg regions or the entire leg. In some embodiments, the lymphedema occurs in the head, neck, jaw, chest, breast, thorax, abdomen, pelvis, genitalia, or other region of a body cavity. In some embodiments, the lymphedema occurs in one or more limbs, or one or more limbs and another region of the body.

[0174] In some embodiments, the lymphedema results from vascular disorders, including venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphatic vascular malformations, or cardiovascular disease.

[0175] In some embodiments, the present disclosure provides methods for ameliorating one or more symptoms of edema, the methods comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. In some embodiments, the present disclosure provides methods for ameliorating one or more symptoms of lymphedema, the methods comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. In some embodiments, the present disclosure provides methods for ameliorating one or more symptoms of secondary lymphedema, the methods comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. In some embodiments, the present disclosure provides a method of ameliorating one or more symptoms of primary lymphedema, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100.

[0176] In some embodiments, the lymphedema occurs in one or both arms, such as the hand, wrist, forearm, elbow, upper arm, shoulder, armpit, or a combination of arm regions or the entire arm. In some embodiments, the lymphedema occurs in one or both legs, such as the foot, ankle, leg, knee, upper leg or thigh, groin, hip, or a combination of leg regions or the entire leg. In some embodiments, the lymphedema occurs in the head, neck, jaw, chest, thorax, abdomen, pelvis, genitals, or other areas of a body cavity. In some embodiments, the lymphedema occurs in one or more limbs, or one or more limbs and another area of ​​the body.

[0177] In some embodiments, the lymphedema results from vascular disorders, including venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphatic vascular malformations, or cardiovascular disease.

[0178] In any of the above methods for treating, preventing, or ameliorating one or more symptoms of edema or lymphedema, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered twice daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 750 mg twice daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 500 mg twice daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 250 mg twice daily.

[0179] In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered once daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 1000 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 750 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 500 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 250 mg once daily.

[0180] In any of the above embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered three times daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 500 mg three times daily. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 333 mg three times daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 166 mg three times daily.

[0181] In some embodiments, the deuterium-enriched pirfenidone is in the form of a tablet. In some embodiments, the deuterium-enriched pirfenidone is taken orally with food.

[0182] Accordingly, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is administered to a subject in need thereof. The phenidone compound is orally administered twice daily at a total daily dose of 100 to 1500 mg. In some embodiments, provided herein are methods for treating, preventing, and / or ameliorating edema, e.g., lymphedema, comprising administering LYT-100 to a subject in need thereof, wherein the LYT-100 is orally administered twice daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 500 mg. In some embodiments, the daily dose of deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at 750 mg twice a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 500 mg twice a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 250 mg twice a day.

[0183] In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered once daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof LYT-100, wherein the LYT-100 is orally administered once daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 1000 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 750 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally at 500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally at 250 mg once daily.

[0184] Accordingly, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is administered orally three times daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof LYT-100, wherein the LYT-100 is administered orally three times daily at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at a total daily dose of 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 500 mg three times a day. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally at 333 mg three times daily. In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally at 166 mg twice daily.

[0185] In other embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-2000 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-1000 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg / day. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered three times daily (TID). In some embodiments, the deuterium-enriched pirfenidone compound is orally administered twice daily (BID). In some embodiments, the deuterium-enriched pirfenidone compound is orally administered once daily (QD). In any of these embodiments, the deuterium-enriched pirfenidone compound has, for example, the structure of Formula I, eg, a compound listed in Table 1, including, for example, LYT-100.

[0186] In some embodiments, the present disclosure provides methods of treating edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. In some embodiments, the method comprises administering an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, including LYT-100.

[0187] [ka]

[0188] or a pharmaceutically acceptable salt thereof, wherein edema, e.g., lymphedema, is treated in the subject.

[0189] In some embodiments, the lymphedema is secondary lymphedema. Edema can occur after surgery, infection, or trauma, and is often caused by cancer, for example, surgery, biopsy, cancer treatments such as radiation and chemotherapy, trauma, or infection resulting in lymph node damage or removal. Thus, in some embodiments, the present disclosure provides a method for treating edema, comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0190] [ka]

[0191] In some embodiments, the present disclosure provides a method of treating lymphedema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0192] [ka]

[0193] In some embodiments, the present disclosure provides a method of treating secondary lymphedema, comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0194] [ka]

[0195] In some embodiments, the present disclosure provides a method of treating primary lymphedema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0196] [ka]

[0197] In some embodiments, the present disclosure provides methods for preventing edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. In some embodiments, the methods comprise administering an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, including LYT-100.

[0198] [ka]

[0199] or a pharmaceutically acceptable salt thereof, wherein edema, such as lymphedema, is prevented in a subject. In some embodiments, the lymphedema is secondary lymphedema. Secondary lymphedema can develop after surgery, infection, or trauma, and is often caused by cancer, for example, surgery, biopsy, cancer treatments such as radiation and chemotherapy, trauma, or infection resulting in lymph node damage or removal. Thus, in some embodiments, the present disclosure provides a method for preventing edema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0200] [ka]

[0201] In some embodiments, the present disclosure provides a method of preventing lymphedema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0202] [ka]

[0203] In some embodiments, the present disclosure provides a method of preventing secondary lymphedema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0204] [ka]

[0205] In some embodiments, the present disclosure provides a method of preventing primary lymphedema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0206] [ka]

[0207] In some embodiments, the present disclosure provides methods for ameliorating one or more symptoms of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100. In some embodiments, the methods comprise administering an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., LYT-100.

[0208] [ka]

[0209] or a pharmaceutically acceptable salt thereof, wherein one or more symptoms of edema, e.g., lymphedema, are improved in the subject. In some embodiments, the lymphedema is secondary lymphedema. Secondary lymphedema can develop after surgery, infection, or trauma, and is often caused by cancer, e.g., cancer treatments such as radiation and chemotherapy, trauma, or infection resulting in lymph node damage or removal. Thus, in some embodiments, the present disclosure provides a method for improving one or more symptoms of edema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0210] [ka]

[0211] In some embodiments, the present disclosure provides a method of ameliorating one or more symptoms of lymphedema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0212] [ka]

[0213] In some embodiments, the present disclosure provides a method of ameliorating one or more symptoms of secondary lymphedema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0214] [ka]

[0215] In some embodiments, the present disclosure provides a method of ameliorating one or more symptoms of primary lymphedema, the method comprising administering to a subject in need thereof a deuterated pirfenidone compound having the following structure:

[0216] [ka]

[0217] In any of the above embodiments, the one or more symptom(s) that are improved are selected from fluid accumulation under the skin and within body cavities, swelling, distension, tissue swelling or swelling, inflammation, fibrosis, heaviness, pain, disfigurement, decreased range of motion, soreness, recurrent infections, thickened skin, and discomfort.

[0218] In any of these embodiments for treating various forms of lymphedema, the lymphedema may occur in one or both arms, such as the hand, wrist, forearm, elbow, upper arm, shoulder, axilla, or a combination of arm regions or the entire arm. In some embodiments, the lymphedema occurs in one or both legs, such as the foot, ankle, leg, knee, upper leg or thigh, groin, hip, or a combination of leg regions, or the entire leg. In some embodiments, the lymphedema occurs in the head, neck, jaw, chest, breast, thorax, abdomen, pelvis, genitalia, or other areas of a body cavity. In some embodiments, the lymphedema occurs in one or more limbs, or one or more limbs and another area of ​​the body.

[0219] In any of these embodiments for treating lymphedema, the lymphedema may result from venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphatic vascular malformations, or vascular disorders, including cardiovascular disease.

[0220] Cellulitis is a serious, potentially life-threatening infection that can affect patients with lymphedema. Cellulitis increases inflammation and can further worsen lymphedema. Patients with lymphedema may experience recurrent and progressive episodes of cellulitis, requiring intravenous antibiotics. Prophylactic antibiotics are the only intervention available to alleviate cellulitis. In some embodiments, disclosed herein are methods for alleviating cellulitis in a subject, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., LYT-100, e.g., a compound listed in Table 1. In some embodiments, the episodes of cellulitis are reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. In some embodiments, the severity of the infection is reduced from severe to moderate, or from moderate to mild. In some embodiments, treatment-related or prophylactic antibiotic use is reduced.

[0221] In any of the above methods for treating, preventing, or ameliorating one or more symptoms of edema or lymphedema, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered twice daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 750 mg twice daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 500 mg twice daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 250 mg twice daily.

[0222] In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered once daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 1000 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 750 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 500 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 250 mg once daily.

[0223] In any of the above embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered three times daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1500 mg. The dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, deuterium-enriched pirfenidone is orally administered at 500 mg three times a day. In some embodiments, deuterium-enriched pirfenidone is orally administered at 333 mg three times a day. In some embodiments, deuterium-enriched pirfenidone is orally administered at 166 mg three times a day.

[0224] In some embodiments, the deuterium-enriched pirfenidone is in the form of a tablet. In some embodiments, the deuterium-enriched pirfenidone is taken orally with food.

[0225] Thus, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered twice daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering LYT-100 to a subject in need thereof, wherein the LYT-100 is orally administered twice daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 750 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 500 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 250 mg twice daily.

[0226] In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered once daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering LYT-100 to a subject in need thereof, wherein the LYT-100 is orally administered once daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 1500 mg once a day. In some embodiments, the deuterium-enriched pirfenidone compound, For example, LYT-100 is orally administered at 1000 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 750 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 250 mg once daily.

[0227] Thus, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered three times daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof LYT-100, wherein the LYT-100 is orally administered three times daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 500 mg three times a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 333 mg three times a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 166 mg twice a day.

[0228] In other embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-2000 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-1000 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg / day. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered three times daily (TID). In some embodiments, the deuterium-enriched pirfenidone compound is orally administered twice daily (BID). In some embodiments, the deuterium-enriched pirfenidone compound is orally administered once daily (QD). In any of these embodiments, the deuterium-enriched pirfenidone compound has the structure of Formula I, eg, the compounds listed in Table 1, including, eg, LYT-100.

[0229] Lymphedema typically progresses through multiple stages with extensive fibrosis, limb volume, and tissue changes. Of the estimated 250,000+ Americans diagnosed with breast cancer each year who undergo surgery, up to one in five will develop secondary lymphedema. In addition to breast cancer, lymphedema can also occur in It can occur in up to 15 percent of cancer survivors with malignancies ranging from melanoma to sarcoma. A subset of patients with lymphedema also experience cellulitis, a bacterial skin infection that can enter through wounds in lymphedematous skin. Cellulitis often requires hospitalization and intravenous antibiotics for treatment, and approximately half of patients with cellulitis have recurrent episodes. Rarely, patients with chronic lymphedema can develop lymphangiosarcoma, a malignant tumor. Lymphedema is classified by clinical stage and severity, as shown in the table below.

[0230] [Table 2]

[0231] In some embodiments, the subject or patient has Stage I lymphedema. In some embodiments, the subject or patient has Stage II lymphedema. In some embodiments, the subject or patient has Stage III lymphedema. In some embodiments, the subject or patient recovers gradually from Stage III to Stage II or Stage I, or from Stage II to Stage I.

[0232] The International Society of Lymphology classifies lymphedematous limbs based on a staging system that describes the condition of the limb. As the disease progresses to later stages, affected limbs may develop a "woody skin" due to fibrosis. In addition to clinical staging, clinicians use measurements of limb swelling to assess disease severity. Cancer treatments result in new lymphedema patients each year, the majority of whom have mild lymphedema. Over 70% of patients with secondary lymphedema have a mild form of lymphedema, while the remainder have moderate to severe lymphedema. The following table summarizes the percentage of patients with secondary breast cancer-related lymphedema who experience various stages of lymphedema severity.

[0233] [Table 3]

[0234] Thus, in some embodiments, the patient has mild, moderate, or severe secondary lymphedema. In some embodiments, the patient has mild to moderate secondary lymphedema. In some embodiments, the patient has moderate to severe secondary lymphedema. In some embodiments, the patient has mild to severe secondary lymphedema.

[0235] The natural history of lymphedema is a chronic, progressive disorder, reflected by increasing limb swelling severity. The relative increase in limb volume of the affected limb compared with the unaffected limb worsens over time. In patients with mild lymphedema, approximately 48% progress to a more severe stage during the first 5 years of follow-up. Due to the progressive nature of the disease, many patients progress to a point where limb volume reduction with bandaging and compression is no longer possible. The potential loss of limb range and function, risk of secondary infection and complications, and disfigurement cause physical and emotional distress to cancer survivors. Secondary lymphedema is a lifelong condition, and the affected population is increasing annually due to improved cancer patient survival, patient transitions, and disease factors including obesity, an aging population, and increased use of radiation therapy.

[0236] Millions of patients have lymphedema other than breast cancer-related arm lymphedema. The deuterium-enriched pirfenidone compounds disclosed herein, such as LYT-100, can be used to treat the underlying mechanisms of other forms of secondary or primary lymphedema, such as lymphatic filariasis.

[0237] Deuterium-enriched pirfenidone compounds disclosed herein, such as LYT-100, can be used to treat various forms of lymphedema. In some embodiments, the lymphedema treated occurs in one or both arms, such as the hand, wrist, forearm, elbow, upper arm, shoulder, axilla, or a combination of arm regions or the entire arm. In some embodiments, the lymphedema occurs in one or both legs, such as the foot, ankle, leg, knee, upper leg or thigh, groin, hip, or a combination of leg regions, or the entire leg. In some embodiments, the lymphedema occurs in the head, neck, jaw, chest, breast, thorax, abdomen, pelvis, genitalia, or other areas of a body cavity. In some embodiments, the lymphedema occurs in one or more limbs, or one or more limbs and another area of ​​the body.

[0238] In any of these embodiments for treating lymphedema, the lymphedema may result from venous insufficiency, venous malformations, arterial malformations, capillary malformations, lymphatic vascular malformations, or vascular disorders, including cardiovascular disease.

[0239] The deuterium-enriched pirfenidone compounds disclosed herein, such as LYT-100, can be used to treat cellulitis, a serious and potentially life-threatening infection that can affect patients with lymphedema. In some embodiments, provided herein is a method for alleviating cellulitis in a subject, the method comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound disclosed herein, such as a compound of Formula I, for example, a compound listed in Table 1, including LYT-100.

[0240] In some embodiments, the patient underwent breast cancer surgery at least 3, 6, 9, or 12 months prior and completed breast cancer radiation therapy at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months prior. In some embodiments, they are free of recurrent cancer more than 6 months after breast cancer surgery. In some embodiments, the patient has pitting edema and at least one of the following: a relative limb volume increase of between 10-20% as measured by the frustum method of circumferential tape measurement, or an L-Dex bioimpedance rating of greater than +6.5. In some embodiments, the patient also has standard therapeutic compression or has a relative limb volume greater than 10% compared to pre-surgery and / or pre-radiation volume, or an L-Dex greater than 14. Accordingly, in some embodiments, the present disclosure provides a method of treating lymphedema, the method comprising administering LYT-100 to a subject in need thereof, wherein the subject's pre-treatment limb volume is increased. and have a relative limb volume increase of at least 10% compared to pre-treatment limb volume. Thus, in some embodiments, the present disclosure provides a method of treating lymphedema, the method comprising administering LYT-100 to a subject in need thereof, wherein the subject has a relative limb volume increase of at least 10-20% compared to pre-treatment limb volume. In some embodiments, the present disclosure provides a method of treating lymphedema, the method comprising administering LYT-100 to a subject in need thereof, wherein the subject has a relative limb volume increase of more than 20% compared to pre-treatment limb volume. In some embodiments, the present disclosure provides a method of treating lymphedema, the method comprising administering LYT-100 to a subject in need thereof, wherein the subject has a relative limb volume increase of at least 20%-40% compared to pre-treatment limb volume. In some embodiments, the present disclosure provides a method of treating lymphedema, the method comprising administering LYT-100 to a subject in need thereof, wherein the subject has a relative limb volume increase of more than 40% compared to pre-treatment limb volume. In some embodiments, the present disclosure provides a method of treating lymphedema, the method comprising administering LYT-100 to a subject in need thereof, wherein the subject has a bioimpedance metric of at least +6.5 L-Dex compared to pre-treatment limb volume. In some embodiments, the present disclosure provides a method of treating lymphedema, the method comprising administering LYT-100 to a subject in need thereof, wherein the subject has a bioimpedance metric of at least +14 L-Dex compared to pre-treatment limb volume.

[0241] In some embodiments, the present disclosure provides methods of treating edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula 1, including compounds listed in Table 1, wherein the treatment measures (a) bioimpedance (e.g., as measured by BIS), (b) limb volume (e.g., as measured by perometer or tape measurement), (c) local tissue water content (e.g., as measured by tissue permittivity), (d) tissue stiffness (e.g., as measured by a pressure measuring device), (e) fibrosis (e.g., as measured by tissue stiffness), (f) pain, (g) swelling, (h) discomfort, (i) function, (j) visual analog pain score, (h) Upper Limb Lymphedema Score (ULL27), (i) Lymphedema Life Impact Scale (LLIS), (j) Functional Assessment of Cancer Therapy Score (FACT-B+4), (k) Lymphedema Quality of Life Score (LYMQOL), (l) Disability of Arm, Shoulder, and Hand Score (DASH), (m) Lymphedema Quality of Life Inventory (LQOLI), (n) granulocyte colony-stimulating factor (G-CSF), (o) skin histology (CHA), and (p) skin thickness (e.g., measured by caliper).

[0242] In some embodiments, the present disclosure provides a method of improving one or more symptoms of edema, the method comprising administering LYT-100 to a subject in need thereof, wherein the improvement in one or more symptoms is an improvement in: (a) bioimpedance (e.g., as measured by BIS), (b) limb volume (e.g., as measured by perometer or tape measurement), (c) local tissue water content (e.g., as measured by tissue permittivity), (d) tissue stiffness (e.g., as measured by a pressure measurement device), (e) fibrosis (e.g., as measured by tissue stiffness), (f) pain, (g) swelling, (h) discomfort, (i) aches, (j) pain, (k) swelling, (k ... (i) function, (j) visual analog pain score, (h) Upper Limb Lymphedema Score (ULL27), (i) Lymphedema Life Impact Scale (LLIS), (j) Functional Assessment of Cancer Therapy Score (FACT-B+4), (k) Lymphedema Quality of Life Score (LYMQOL), (l) Disability of Arm, Shoulder, and Hand Score (DASH), (m) Lymphedema Quality of Life Inventory (LQOLI), (n) Granulocyte Colony-Stimulating Factor (G-CSF), (o) Skin Histology (CHA), and (p) Skin Thickness (e.g., measured by caliper).

[0243] Bioimpedance or water content can be measured via bioelectrical impedance spectroscopy (BIS). Multi-frequency bioelectrical impedance spectroscopy (BIS) provides an accurate relative measurement of protein-rich fluid in a patient's upper limbs. BIS is a non-invasive technique that involves passing a very small current through the body and measuring the impedance (or resistance) to this current flow. The current is primarily conducted by water-containing fluids in the body. BIS quantifies the amount of protein-rich fluid in lymphedema by comparing affected and unaffected limbs. In some embodiments, the present disclosure provides a method for reducing bioimpedance in a subject's limb, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone compound is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method for reducing bioimpedance in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein are methods for treating lymphedema in at least one limb, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject with lymphedema, wherein the bioimpedance in the subject's limb is reduced compared to the bioimpedance in the subject's limb prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, the bioimpedance is significantly reduced by 3, 4, or 6 months. In some embodiments of the disclosed methods, the bioimpedance is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% (and any numerical increment therebetween), or more compared to the bioimpedance in the subject's limb prior to administration of the deuterium-enriched pirfenidone compound. In some embodiments, this reduction is observed at 3, 4, or 6 months.Thus, in some embodiments, the present disclosure provides a method of reducing bioimpedance in a subject's limb, comprising administering LYT-100 to the subject, wherein bioimpedance is reduced. In some embodiments, the present disclosure provides a method of reducing bioimpedance in a subject's limb, comprising administering LYT-100 to the subject, wherein bioimpedance is reduced compared to bioimpedance in the subject's limb prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing bioimpedance in a subject's limb, comprising administering LYT-100 to the subject, wherein bioimpedance is reduced by at least 2% compared to bioimpedance in the subject's limb prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing bioimpedance in a limb of a subject, comprising administering LYT-100 to the subject, wherein bioimpedance is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to bioimpedance in the limb of the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing bioimpedance in a limb of a subject, comprising administering LYT-100 to the subject, wherein bioimpedance is reduced by more than 20% compared to bioimpedance in the limb of the subject prior to administration of LYT-100.

[0244] Limb Volume (Perometry). Relative limb volume can be measured by the truncated cone method of circumferential tape measurements. Perometry is a non-invasive technique involving a perometer (Pero system) that uses infrared light to scan a limb and obtain a measurement of the limb's circumference. In some embodiments, the present disclosure provides a method for reducing (decreasing) limb volume in a subject's limb, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, The deuterium-enriched pirfenidone compound is LYT-100. Thus, in some embodiments, the present disclosure provides a method for reducing limb volume in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein is a method for treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject having lymphedema in at least one limb, wherein the limb volume in the subject's limb is reduced compared to the limb volume in the subject's limb prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, limb volume is reduced by at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the limb volume in the subject's limb prior to administration of deuterium-enriched pirfenidone. In some embodiments, the severity is reduced from severe to moderate, or from moderate to mild. In some embodiments, this reduction in limb volume is seen at 3, 4, or 6 months. Thus, in some embodiments, the present disclosure provides a method of reducing limb volume in a subject's limb, comprising administering LYT-100 to the subject, wherein the limb volume is reduced. In some embodiments, the present disclosure provides a method of reducing limb volume in a subject's limb, comprising administering LYT-100 to the subject, wherein the limb volume is reduced compared to the limb volume in the subject's limb prior to administration of LYT-100. In some embodiments, the present disclosure provides a method for reducing limb volume in a limb of a subject, comprising administering LYT-100 to the subject, wherein the limb volume is reduced by at least 2% compared to the limb volume in the subject's limb prior to administration of LYT-100.In some embodiments, the present disclosure provides a method of reducing limb volume in a limb of a subject, comprising administering LYT-100 to the subject, wherein the limb volume is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the limb volume in the subject's limb prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing limb volume in a limb of a subject, comprising administering LYT-100 to the subject, wherein the limb volume is reduced by more than 20% compared to the limb volume in the subject's limb prior to administration of LYT-100. In some embodiments, the present disclosure provides a method for reducing limb volume in a limb of a subject, comprising administering LYT-100 to the subject, wherein the limb volume is reduced by 20% to 40% compared to the limb volume in the subject's limb prior to administration of LYT-100. In some embodiments, the present disclosure provides a method for reducing limb volume in a limb of a subject, comprising administering LYT-100 to the subject, wherein the limb volume is reduced by more than 40% compared to the limb volume in the subject's limb prior to administration of LYT-100.

[0245] Tissue Dielectric Constant (MoistureMeterD). Tissue dielectric constant measures the water content of local tissue below the skin at various depths, from the dermis to the subcutaneous tissue. Results are converted to a 0-100% scale to reflect subcutaneous fluid accumulation that may occur in early stages of lymphedema. In some embodiments, the present disclosure provides a method of decreasing tissue dielectric constant in a subject, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone compound is LYT-100. In some embodiments, provided herein is a method of treating lymphedema in at least one limb, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject having lymphedema, wherein the dielectric constant of tissue in the subject's limb is decreased compared to the dielectric constant of tissue in the subject's limb prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. Thus, in some embodiments, the present disclosure provides a method for treating edema, e.g., lymphedema, in a subject, comprising administering an effective amount of LYT-100. In some embodiments, the dielectric constant of tissue is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the dielectric constant of tissue in the limb of a subject prior to administration of deuterium-enriched pirfenidone. In some embodiments, the present disclosure provides a method for reducing the dielectric constant of tissue in a limb of a subject, comprising administering LYT-100 to the subject, wherein the dielectric constant of the tissue is reduced. In some embodiments, the present disclosure provides a method for reducing the dielectric constant of tissue in a limb of a subject, comprising administering LYT-100 to the subject, wherein the dielectric constant of the tissue is reduced compared to the dielectric constant of tissue in the limb of the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of decreasing the dielectric constant of tissue in a limb of a subject, comprising administering LYT-100 to the subject, wherein the dielectric constant of the tissue is decreased by at least 2% compared to the dielectric constant of the tissue in the limb of the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of decreasing the dielectric constant of tissue in a limb of a subject, comprising administering LYT-100 to the subject, wherein the dielectric constant of the tissue is decreased by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the dielectric constant of the tissue in the limb of the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method for reducing the dielectric constant of tissue in a limb of a subject, comprising administering LYT-100 to the subject, wherein the dielectric constant of the tissue is reduced by more than 20% compared to the dielectric constant of the tissue in the limb of the subject prior to administration of LYT-100.

[0246] Tissue Stiffness (Tonometry / Skin FibroMeter). A tonometry device is pressed into the skin and the amount of force required to create an indentation in the tissue is measured. The resulting measurements determine the degree of stiffness or fibrosis (tissue scarring) beneath the skin to assess the severity of lymphedema. In some embodiments, the present disclosure provides a method for reducing tissue stiffness in a limb of a subject, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone compound is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method for reducing tissue stiffness in a limb of a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein are methods of treating lymphedema in at least one limb, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject having lymphedema, wherein tissue stiffness in the subject's limb is reduced compared to tissue stiffness in the subject's limb prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, tissue stiffness is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to tissue stiffness in the subject's limb prior to administration of the deuterium-enriched pirfenidone compound. In some embodiments, the present disclosure provides a method of reducing tissue stiffness in a limb of a subject, comprising administering LYT-100 to the subject, wherein tissue stiffness is reduced. In some embodiments, the present disclosure provides a method of reducing tissue stiffness in a limb of a subject, comprising administering LYT-100 to the subject, wherein the tissue stiffness is reduced compared to the tissue stiffness in the limb of the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing tissue stiffness in a limb of a subject, comprising administering LYT-100 to the subject, wherein the tissue stiffness is reduced by at least 2% compared to the tissue stiffness in the limb of the subject prior to administration of LYT-100.In some embodiments, the present disclosure provides a method of reducing tissue stiffness in a limb of a subject, comprising administering LYT-100 to the subject, wherein the tissue stiffness is less than the tissue stiffness in the limb of the subject prior to administration of LYT-100. In some embodiments, the stiffness of tissue in a limb of a subject is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20%. In some embodiments, the present disclosure provides a method of reducing tissue stiffness in a limb of a subject, comprising administering LYT-100 to the subject, wherein the tissue stiffness is reduced by more than 20% compared to the tissue stiffness in the limb of the subject prior to administration of LYT-100.

[0247] Visual analog scale for pain, swelling, discomfort, and function. This graphical scale has a line with a rating of 0 to 10 that the patient marks to correlate with the extremes of pain, swelling, discomfort, and function, ranging from "none at all" to "as bad as possible." Higher marks on the line indicate a worse condition. In some embodiments, the present disclosure provides a method for reducing a visual analog pain score of 1 or more in a subject, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone compound is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method for reducing a visual analog pain score of 1 or more in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein are methods for treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject with lymphedema, wherein one or more of the subject's visual analog pain score(s) is reduced compared to the subject's visual analog pain score prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, one or more visual analog pain score(s) is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to the corresponding visual analog pain score in the subject prior to administration of the deuterium-enriched pirfenidone compound. In some embodiments, the present disclosure provides a method of reducing one or more visual analog pain score(s) in a subject, comprising administering LYT-100 to the subject, wherein the one or more visual analog pain score(s) are reduced. In some embodiments, the present disclosure provides a method of reducing one or more visual analog pain score(s) in a subject, comprising administering LYT-100 to the subject, wherein the one or more visual analog pain score(s) are reduced compared to the one or more visual analog pain score(s) in the subject prior to administration of LYT-100.In some embodiments, the disclosure provides a method of reducing one or more visual analog pain score(s) in a subject, comprising administering LYT-100 to the subject, wherein the one or more visual analog pain score(s) is reduced by at least 2% compared to the one or more visual analog pain score(s) in the subject prior to administration of LYT-100. In some embodiments, the disclosure provides a method of reducing one or more visual analog pain score(s) in a subject, comprising administering LYT-100 to the subject, wherein the one or more visual analog pain score(s) is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the one or more visual analog pain score(s) in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing one or more visual analog pain score(s) in a subject, comprising administering LYT-100 to the subject, wherein the one or more visual analog pain score(s) is reduced by more than 20% compared to the one or more visual analog pain score(s) in the subject prior to administration of LYT-100.

[0248] The Upper Limb Lymphedema Score 27 (ULL27) is a 27-question self-report tool for assessing arm lymphedema and related symptoms in breast cancer survivors. Responses are given on a 5-point Likert scale ranging from "never" to "always." At least the following domains are addressed: physical (15 items), psychological (7 items), and social (5 items), with scores ranging from 0 to 100 (100 being the highest possible score). Lower scores indicate better quality of life. In some embodiments, the present disclosure provides methods for reducing ULL27 in a subject, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. Accordingly, in some embodiments, the present disclosure provides methods for reducing ULL27 in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein are methods of treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject having lymphedema in at least one limb, wherein the subject's ULL27 score is reduced compared to the subject's ULL27 score prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, ULL27 is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the ULL27 in the subject prior to administration of the deuterium-enriched pirfenidone compound. In some embodiments, the present disclosure provides a method of reducing ULL27 in a subject, comprising administering LYT-100 to the subject, wherein ULL27 is reduced. In some embodiments, the present disclosure provides a method of reducing ULL27 in a subject, comprising administering LYT-100 to the subject, wherein ULL27 is reduced compared to ULL27 in the subject prior to administration of LYT-100.In some embodiments, the present disclosure provides a method of lowering ULL27 in a subject, comprising administering LYT-100 to the subject, wherein ULL27 is reduced by at least 2% compared to ULL27 in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of lowering ULL27 in a subject, comprising administering LYT-100 to the subject, wherein ULL27 is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to ULL27 in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of lowering ULL27 in a subject, comprising administering LYT-100 to the subject, wherein ULL27 is reduced by more than 20% compared to ULL27 in the subject prior to administration of LYT-100.

[0249] The Lymphedema Life Impact Scale (LLIS) is a comprehensive lymphedema-specific instrument for measuring functional impairment, activity limitations, and participation limitations in patients with limb lymphedema. It is an 18-question assessment tool that includes physical, psychosocial, and functional domains. The Life Impact Scale works in conjunction with a disability calculator and is designed to determine the severity of functional impairment. In some embodiments, the present disclosure provides a method for reducing or lowering a subject's LLIS (e.g., reducing functional impairment severity) comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method for reducing the LLIS in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein is a method of treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject having lymphedema in at least one limb, wherein the The LLIS of the subject is reduced compared to the LLIS in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, the LLIS is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the LLIS in the subject prior to administration of the deuterium-enriched pirfenidone compound. In some embodiments, the disclosure provides a method of reducing LLIS in a subject, comprising administering LYT-100 to the subject, wherein the LLIS is reduced. In some embodiments, the disclosure provides a method of reducing LLIS in a subject, comprising administering LYT-100 to the subject, wherein the LLIS is reduced compared to the LLIS in the subject prior to administration of LYT-100. In some embodiments, the disclosure provides a method of reducing LLIS in a subject, comprising administering LYT-100 to the subject, wherein the LLIS is reduced by at least 2% compared to the LLIS in the subject prior to administration of LYT-100. In some embodiments, the disclosure provides a method of reducing LLIS in a subject, comprising administering LYT-100 to the subject, wherein the LLIS is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the LLIS in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method for reducing LLIS in a subject, comprising administering LYT-100 to the subject, wherein the LLIS is reduced by more than 20% compared to the LLIS in the subject prior to administration of LYT-100.

[0250] The Functional Assessment of Cancer Therapy Breast Cancer-Specific Quality of Life Tool (FACT-B+4) is a 5-point Likert scale, with higher quality of life corresponding to higher scores once negatively worded item scores are reversed. The score is calculated by summing the subscale scores for physical well-being, social well-being, emotional well-being, functional well-being, and additional breast cancer concerns. In some embodiments, the present disclosure provides a method for increasing a subject's FACT-B+4 score (e.g., improving quality of life), comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method for increasing a subject's FACT-B+4 score in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein are methods of treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject with lymphedema, wherein the FACT-B+4 score is increased compared to the FACT-B+4 score in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, the FACT-B+4 score is increased by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the FACT-B+4 score in the subject prior to administration of the deuterium-enriched pirfenidone compound. In some embodiments, the present disclosure provides methods of increasing FACT-B+4 in a subject, comprising administering LYT-100 to the subject, wherein FACT-B+4 is increased. In some embodiments, the present disclosure provides a method of increasing FACT-B+4 in a subject, comprising administering LYT-100 to the subject, wherein FACT-B+4 is elevated compared to FACT-B+4 in the subject prior to administration of LYT-100.In some embodiments, the present disclosure provides a method of increasing FACT-B+4 in a subject, comprising administering LYT-100 to the subject, wherein FACT-B+4 is increased by at least 2% compared to FACT-B+4 in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of increasing FACT-B+4 in a subject, comprising administering LYT-100 to the subject, wherein FACT-B+4 is increased by at least 2% compared to FACT-B+4 in the subject prior to administration of LYT-100. ACT-B+4 is increased by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to FACT-B+4 in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of increasing FACT-B+4 in a subject comprising administering LYT-100 to the subject, wherein FACT-B+4 is increased by more than 20% compared to FACT-B+4 in the subject prior to administration of LYT-100.

[0251] The Lymphedema Quality of Life Scale (LYMQOL) for limb lymphedema covers four domains: symptoms, body image / appearance, function, and mood. It also includes an assessment of overall quality of life. Subjects with more severe limb dysfunction have higher scores, corresponding to decreased quality of life. In some embodiments, the present disclosure provides a method of decreasing overall LYMQOL in a subject, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method of decreasing overall LYMQOL in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein are methods of treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject having lymphedema in at least one limb, wherein LYMQOL is decreased in the subject compared to the LYMQOL in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, the LYMQOL is decreased by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to the overall LYMQOL in the subject prior to administration of the deuterium-enriched pirfenidone compound. In some embodiments, provided herein are methods of treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject having lymphedema in at least one limb, wherein LYMQOL is decreased in the subject compared to the LYMQOL in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, the LYMQOL is decreased by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more compared to the LYMQOL in the subject prior to administration of the deuterium-enriched pirfenidone compound.In some embodiments, the present disclosure provides a method of reducing LYMQOL in a subject, comprising administering LYT-100 to the subject, wherein LYMQOL is reduced. In some embodiments, the present disclosure provides a method of reducing LYMQOL in a subject, comprising administering LYT-100 to the subject, wherein LYMQOL is reduced in the subject compared to the LYMQOL in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing LYMQOL in a subject, comprising administering LYT-100 to the subject, wherein LYMQOL is reduced by at least 2% compared to the LYMQOL in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing LYMQOL in a subject comprising administering LYT-100 to the subject, wherein LYMQOL is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the LYMQOL in the subject prior to administration of LYT-100. ... The LYMQOL is reduced by more than 20% compared to the subject's LYMQOL prior to administration.

[0252] The Disability of the Arm, Shoulder, and Hand Score (DASH) is a 30-item disability / symptom scale, scored from 0 (no disability) to 100. Each item has five response options. Scores on all items are then used to calculate a scale score ranging from 0 (no disability) to 100 (most severe disability). Items inquire about the degree of difficulty performing various physical activities due to arm, shoulder, or hand problems (21 items); the severity of symptoms of pain, activity-related pain, tingling, weakness, and stiffness (5 items); and problems affecting social activities, work, sleep, and self-image (4 items). The DASH can detect and differentiate between minor and major changes in disability over time after surgery in patients with upper limb musculoskeletal disorders. A 10-point difference in the mean DASH score is considered a significant change, indicating treatment efficacy. DASH scores can be scored raw, converted to a 0-100 scale, or converted to a logit scale. In some embodiments, the present disclosure provides a method for reducing the DASH score (e.g., reducing impairment / symptoms) in a subject, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone compound is LYT-100. Thus, in some embodiments, the present disclosure provides a method for reducing the DASH score in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein is a method for treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject having lymphedema in at least one limb, wherein the subject's DASH score is reduced compared to the subject's DASH score prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100.In some embodiments, the subject's DASH score is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more over a 3-month, 6-month, 9-month, or 12-month period compared to the subject's DASH score before administration of the deuterium-enriched pirfenidone compound. In some embodiments, the present disclosure provides a method for reducing a DASH score in a subject, comprising administering LYT-100 to the subject, wherein the DASH score is reduced. In some embodiments, the present disclosure provides a method for reducing a DASH score in a subject, comprising administering LYT-100 to the subject, wherein the DASH score is reduced compared to the subject's DASH score before administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing a DASH score in a subject, comprising administering LYT-100 to the subject, wherein the DASH score in the subject is reduced by at least 5 points compared to the DASH score in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing a DASH score in a subject, comprising administering LYT-100 to the subject, wherein the DASH score in the subject is reduced by at least 10 points compared to the DASH score in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method for reducing a DASH score in a subject, comprising administering LYT-100 to the subject, wherein the DASH score in the subject is reduced by 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more over a 3-month, 6-month, 9-month, or 12-month period compared to the DASH score in the subject prior to administration of the deuterium-enriched pirfenidone compound. In some embodiments, the present disclosure provides a method for reducing a DASH score in a subject, comprising administering LYT-100 to the subject, wherein the DASH score in the subject is reduced by more than 10% compared to the DASH score in the subject prior to administration of LYT-100.

[0253] The Lymphedema Quality of Life Inventory (LQOLI) is the only HRQOL instrument developed and tested in patients with various types of lymphedema. The questionnaire has three parts: The LQOLI is comprised of physical, psychosocial, and practical components. In some embodiments, the present disclosure provides a method of reducing LQOLI in a subject with edema, e.g., lymphedema, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method of reducing LQOLI in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, the LQOLI is reduced compared to the subject's LQOLI prior to administration of the deuterium-enriched pirfenidone. Accordingly, in some embodiments, the present disclosure provides a method of reducing overall LQOLI in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein are methods of treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject with lymphedema, wherein LQOLI is decreased in the subject compared to the LQOLI in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, the present disclosure provides methods of decreasing LQOLI in a subject, comprising administering LYT-100 to the subject, wherein LQOLI is decreased. In some embodiments, the present disclosure provides methods of decreasing LQOLI in a subject, comprising administering LYT-100 to the subject, wherein LQOLI is decreased in the subject compared to the LQOLI in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing LQOLI in a subject, comprising administering LYT-100 to the subject, wherein LQOLI is reduced by at least 2% compared to the LQOLI in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing LQOLI in a subject, comprising administering LYT-100 to the subject, wherein LQOLI is reduced by more than 20% compared to the LQOLI in the subject prior to administration of LYT-100.

[0254] Granulocyte colony-stimulating factor (G-CSF), a systemic inflammatory mediator, is a proinflammatory cytokine and can be used as a metric for assessing a patient's systemic inflammatory response. It can be assessed by Luminex-bead inflammasome analysis of pre- and post-treatment plasma samples. In some embodiments, the present disclosure provides a method for reducing G-CSF in a subject, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method for reducing G-CSF in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein are methods for treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject with lymphedema, wherein G-CSF in the subject is reduced compared to the G-CSF in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, there is a significant reduction in the systemic inflammatory mediator granulocyte colony-stimulating factor (G-CSF). In some embodiments, there is a reduction of at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more compared to the G-CSF in the subject prior to administration of the deuterium-enriched pirfenidone compound. In some embodiments, the disclosure provides a method of lowering G-CSF in a subject, comprising administering LYT-100 to the subject, wherein G-CSF is lowered. In some embodiments, the disclosure provides a method of lowering G-CSF in a subject, comprising administering LYT-100 to the subject, wherein G-CSF is lowered compared to the G-CSF in the subject prior to administration of LYT-100. In some embodiments, the disclosure provides a method of lowering G-CSF in a subject, comprising administering LYT-100 to the subject, wherein G-CSF is lowered by at least 2% compared to the G-CSF in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of lowering G-CSF in a subject, comprising administering LYT-100 to the subject, wherein G-CSF is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to G-CSF in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of lowering G-CSF in a subject, comprising administering LYT-100 to the subject, wherein G-CSF is reduced by more than 20% compared to G-CSF in the subject prior to administration of LYT-100.

[0255] In some embodiments, there is a significant change from baseline in skin histology (CHA) based on histological specimens of lymphedema skin before and after treatment with LYT-100. The score is based on a scoring system that assesses dermal thickness (0-5), internal mucin content (0-5), deep dermal collagen content (0-5), and perivascular infiltration (0-5), for a total score of 0-20. In some embodiments, the present disclosure provides a method of reducing the CHA score in a subject, comprising administering to the subject a deuterium-enriched pirfenidone compound disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method of reducing the CHA score in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein are methods for treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject with lymphedema, wherein the subject's CHA score is reduced compared to the CHA score in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, there is at least a 50% reduction in CHA. In some embodiments, the CHA is reduced by at least 40%, at least 30%, at least 25%, at least 20%, at least 15%, at least 10%, at least 5%, at least 2%, or at least 1% compared to the CHA in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, this reduction is observed within 3, 4, or 6 months. In some embodiments, the present disclosure provides a method for reducing a CHA score in a subject, comprising administering LYT-100 to the subject, wherein the CHA score is reduced. In some embodiments, the present disclosure provides a method of reducing a CHA score in a subject, comprising administering LYT-100 to the subject, wherein the CHA score is reduced compared to the CHA score in the subject prior to administration of LYT-100.In some embodiments, the disclosure provides a method of reducing a CHA score in a subject, comprising administering LYT-100 to the subject, wherein the CHA score is reduced by at least 2% compared to the CHA score in the subject prior to administration of LYT-100. In some embodiments, the disclosure provides a method of reducing a CHA score in a subject, comprising administering LYT-100 to the subject, wherein the CHA score is reduced by at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the CHA score in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing a CHA score in a subject, comprising administering LYT-100 to the subject, wherein the CHA score is reduced by more than 20% compared to the CHA score in the subject prior to administration of LYT-100.

[0256] In some embodiments, the present disclosure provides a method for preparing deuterium-enriched pills as disclosed herein. A method for reducing skin thickness in a subject is provided, comprising administering to the subject a phenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. Accordingly, in some embodiments, the present disclosure provides a method for reducing skin thickness in a subject with edema, e.g., lymphedema, comprising administering an effective amount of LYT-100. In some embodiments, provided herein is a method for treating lymphedema, comprising administering a deuterium-enriched pirfenidone compound, e.g., LYT-100, to a subject with lymphedema, wherein the skin thickness in the subject is reduced compared to the skin thickness in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, a caliper measurement of the skin thickness is reduced by at least 50% compared to the skin thickness in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, caliper measurements of skin thickness are reduced by at least 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, or 5% compared to the skin thickness in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, the skin thickness is reduced by 25% compared to the skin thickness in the subject prior to administration of the deuterium-enriched pirfenidone compound, e.g., LYT-100. In some embodiments, this reduction is observed within 3, 4, or 6 months. In some embodiments, the present disclosure provides a method of reducing skin thickness in a subject, comprising administering LYT-100 to the subject, wherein the skin thickness is reduced. In some embodiments, the present disclosure provides a method of reducing skin thickness in a subject, comprising administering LYT-100 to the subject, wherein the skin thickness is reduced compared to the skin thickness in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing skin thickness in a subject, comprising administering LYT-100 to the subject, wherein the skin thickness is reduced by at least 10% compared to the skin thickness in the subject prior to administration of LYT-100.In some embodiments, the present disclosure provides a method of reducing skin thickness in a subject, comprising administering LYT-100 to the subject, wherein the skin thickness is reduced by at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 35%, or at least 40% compared to the skin thickness in the subject prior to administration of LYT-100. In some embodiments, the present disclosure provides a method of reducing skin thickness in a subject, comprising administering LYT-100 to the subject, wherein the skin thickness is reduced by at least 20% compared to the skin thickness in the subject prior to administration of LYT-100.

[0257] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone for treating, preventing, and / or ameliorating one or more symptoms associated with edema. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating, preventing, and / or ameliorating one or more symptoms of edema, the method comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone for treating, preventing, and / or ameliorating one or more symptoms of lymphedema. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating, preventing, and / or ameliorating one or more symptoms of lymphedema, the method comprising administering to a patient in need thereof, The method includes administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched pirfenidone administered to a subject in need thereof is LYT-100, or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone for treating, preventing, and / or ameliorating one or more symptoms of secondary lymphedema. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating, preventing, and / or ameliorating one or more symptoms of secondary lymphedema, the method comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched pirfenidone administered to a subject in need thereof is LYT-100, or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone for treating, preventing, and / or ameliorating one or more symptoms of breast cancer-associated arm lymphedema. In some embodiments, the deuterium-enriched pirfenidone is LYT-100 or a pharmacologically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating, preventing, and / or ameliorating one or more symptoms of breast cancer-associated arm lymphedema, the method comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched pirfenidone administered to a subject in need thereof is LYT-100 or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone to treat, prevent, and / or ameliorate one or more symptoms of lymphedema other than breast cancer-related arm lymphedema. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating, preventing, and / or ameliorating one or more symptoms of lymphedema other than breast cancer-related arm lymphedema, the method comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched pirfenidone administered to a subject in need thereof is LYT-100, or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone for treating, preventing, and / or ameliorating one or more symptoms of primary lymphedema. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method for treating, preventing, and / or ameliorating one or more symptoms of primary lymphedema, the method comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched pirfenidone administered to a subject in need thereof is LYT-100, or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone to treat, prevent, and / or ameliorate one or more symptoms of lymphatic filariasis. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods for treating, preventing, and / or ameliorating one or more symptoms of lymphatic filariasis, the methods comprising administering a deuterium-enriched pirfenidone to a patient in need thereof. The method includes administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound in Table 1. In some embodiments, the deuterium-enriched pirfenidone administered to a subject in need thereof is LYT-100, or a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone to treat, prevent, and / or ameliorate one or more symptoms of other lymphatic and / or fibrotic disorders. Because inflammation and fibrosis affect lymphatic flow, the pirfenidone formulations described herein, e.g., deuterium-enriched pirfenidone, can be used to treat other lymphatic flow conditions. As discussed herein, patients may have lymphedema other than breast cancer-related arm lymphedema, and the pirfenidone formulations described herein, e.g., deuterium-enriched pirfenidone, can be used to treat the underlying mechanisms of other forms of secondary or primary lymphedema. In some embodiments, the pirfenidone formulations described herein, e.g., deuterium-enriched pirfenidone, have anti-inflammatory and / or anti-fibrotic activity and can be used to treat fibrotic diseases, including IPF and FSGS. In some embodiments, the deuterium-enriched pirfenidone is LYT-100 or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating, preventing, and / or ameliorating one or more symptoms of other lymphatic and / or fibrotic disorders, the methods comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone. In some embodiments, the deuterium-enriched pirfenidone administered to a subject in need thereof is LYT-100, or a pharmaceutically acceptable salt thereof.

[0265] Lymphatic vessels are present in most tissues of the body. These lymphatic vessels consist of an extensive network of thin-walled vessels that drain protein-rich lymph from the extracellular space. Primary functions of the lymphatic system include maintaining tissue fluid homeostasis, absorbing fatty acids, and mediating immune responses under normal circumstances. The lymphatic system also plays an important role in disease processes such as lymphedema, fibrosis, and inflammation. In such lymphatic disorders, lymphatic flow is altered and interstitial fluid balance is disrupted. As a result, maintaining or restoring interstitial fluid balance and / or maintaining lymphatic flow constitutes one approach to treating these disorders. Without wishing to be bound by theory, administering an agent that modulates, e.g., increases, lymphatic flow to a subject with lymphatic disorders can alleviate, treat, or prevent the disorder.

[0266] In some embodiments, provided herein are methods of regulating and / or maintaining interstitial fluid balance and / or lymphatic flow in a subject in need thereof. In some embodiments, regulating lymphatic flow in a subject in need thereof comprises increasing lymphatic flow in the subject. In some embodiments, the method comprises administering an effective amount of a compound, e.g., an effective amount of deuterium-enriched pirfenidone having the structure shown in Formula I. In some embodiments, the compound is LYT-100. In some embodiments, provided herein are methods for treating a lymphatic disorder described herein, comprising regulating and / or maintaining interstitial fluid balance and / or lymphatic flow. In some embodiments, the method comprises increasing lymphatic flow in a subject in need thereof. In some embodiments, the method comprises administering an effective amount of a compound, e.g., an effective amount of deuterium-enriched pirfenidone having the structure shown in Formula I. In some embodiments, the compound is LYT-100.

[0267] Further methods are provided herein that include reducing inflammation and / or fibrosis in a subject with insufficient lymphatic flow, the methods comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone having the structure shown in Formula I. In some embodiments, the compound is LYT-100. In some embodiments, methods are provided herein for treating a lymphatic disorder described herein, including reducing inflammation and / or fibrosis in a subject with insufficient lymphatic flow. In some embodiments, the method includes administering an effective amount of a compound, e.g., an effective amount of deuterium-enriched pirfenidone having the structure shown in Formula I. In some embodiments, the compound is LYT-100.

[0268] In some embodiments, the deuterium-enriched pirfenidone compounds disclosed herein have the ability to produce one or more of the following: (a) reduce tissue swelling, (b) reduce lymphatic congestion or "pooling," (c) reduce tissue fibrosis, (d) reduce tissue inflammation, (e) reduce leukocyte infiltration, (f) reduce macrophage infiltration, (g) reduce naive and differentiated T cell infiltration, (h) reduce TGF-β1 expression and the expression and / or activation of downstream mediators (e.g., pSmad3), (i) reduce angiotensin and / or ACE levels, (j) reduce collagen deposition and / or scar formation, (k) improve or increase lymphatic system function, (l) improve or increase lymphatic transport (e.g., lymphatic flow), (m) improve or increase lymphangiogenesis, and / or (n) improve or increase lymphatic pulsation frequency.

[0269] Accordingly, disclosed herein is a method of treating a subject, including a human subject, having or suspected of having edema, e.g., lymphedema, or a method of preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound disclosed herein (e.g., a compound of Formula I, including, e.g., LYT-100), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in one or more of (a) through (n) above during treatment of the disorder.

[0270] Accordingly, disclosed herein is a method of treating a subject, including a human subject, having or suspected of having edema, e.g., lymphedema, or a method of preventing edema, e.g., lymphedema, in a subject susceptible to edema, e.g., lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound disclosed herein (e.g., a compound of Formula I, including LYT-100), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in one or more of (a) through (n) above during treatment of the edema, e.g., lymphedema.

[0271] In some embodiments, the present disclosure provides a method for reducing tissue swelling in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or for preventing tissue swelling in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0272] In some embodiments, the present disclosure provides a method for reducing lymphatic congestion or retention in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or for preventing lymphatic congestion or retention in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0273] In some embodiments, the present disclosure provides a method of improving or increasing lymphatic transport (e.g., increasing lymphatic flow) in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or a method of improving or increasing lymphatic transport (e.g., increasing lymphatic flow) in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0274] In some embodiments, the present disclosure provides a method for reducing tissue fibrosis in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or for preventing tissue fibrosis in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0275] In some embodiments, the present disclosure provides a method for reducing tissue inflammation in a subject, including a human subject, having or suspected of having edema, e.g., lymphedema, or for preventing tissue inflammation in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0276] In some embodiments, the present disclosure provides a method for reducing leukocyte infiltration in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or for preventing leukocyte infiltration in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0277] In some embodiments, the present disclosure provides a method for reducing macrophage infiltration in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or for preventing macrophage infiltration in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0278] In some embodiments, the present disclosure provides a method of reducing the infiltration of naive and differentiated T cells in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or reducing the infiltration of naive and differentiated T cells in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Methods for preventing cell invasion are provided. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0279] In some embodiments, the present disclosure provides a method of reducing TGF-β1 expression and reducing the expression and / or activation of downstream mediators (e.g., pSmad3) in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or a method of preventing TGF-β1 expression and preventing the expression and / or activation of downstream mediators (e.g., pSmad3) in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0280] In some embodiments, the present disclosure provides methods for reducing angiotensin and / or ACE levels in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or suppressing angiotensin and / or ACE levels in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0281] In some embodiments, the present disclosure provides a method of improving or enhancing lymphatic function in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0282] In some embodiments, the present disclosure provides a method for reducing collagen deposition and / or scar formation in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or for preventing collagen deposition and / or scar formation in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0283] In some embodiments, the present disclosure provides a method of improving or increasing lymphangiogenesis in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0284] In some embodiments, the present disclosure provides a method of improving or increasing lymph pulsation frequency in a subject, including a human subject having or suspected of having edema, e.g., lymphedema, or a method of improving or increasing lymph pulsation frequency in a subject susceptible to edema or lymphedema, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, e.g., a compound of Formula I, e.g., a compound listed in Table 1, e.g., LYT-100, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0285] Provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, wherein cellulitis is reduced, the methods comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100.

[0286] Provided herein are methods for the treatment, prevention, and / or amelioration of cellulitis, the methods comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100.

[0287] In any of the above methods for treating, preventing, or ameliorating one or more symptoms of edema or lymphedema, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered twice daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 750 mg twice daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 500 mg twice daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 250 mg twice daily.

[0288] In some embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is orally administered once daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 1500 mg once daily. In some embodiments, the deuterium-enriched pirfenidone is orally administered at 1000 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 750 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 500 mg once daily. In some embodiments, deuterium-enriched pirfenidone is orally administered at 250 mg once daily.

[0289] In any of the above embodiments, the deuterium-enriched pirfenidone compound, e.g., LYT-100, is administered orally three times daily at a total daily dose of 100 to 1500 mg. In some embodiments, the daily dose is 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, or 1500 mg. In some embodiments, the daily dose is 1500 mg. In some embodiments, the daily dose is 1000 mg. In some embodiments, the daily dose is 750 mg. In some embodiments, the daily dose is 500 mg. In some embodiments, the daily dose is 250 mg. In some embodiments, deuterium-enriched pirfenidone is administered orally at 500 mg three times daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 333 mg three times daily. In some embodiments, deuterium-enriched pirfenidone is administered orally at 166 mg three times daily.

[0290] In some embodiments, the deuterium-enriched pirfenidone is in the form of a tablet. In some embodiments, the deuterium-enriched pirfenidone is taken orally with food.

[0291] Thus, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered twice daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof LYT-100, wherein the LYT-100 is orally administered twice daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 750 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 500 mg twice daily. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 250 mg twice daily.

[0292] In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered once daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering LYT-100 to a subject in need thereof, wherein the LYT-100 is orally administered once daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1500 mg. It is orally administered once a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 1000 mg once a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 750 mg once a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 500 mg once a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 250 mg once a day.

[0293] Thus, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering to a subject in need thereof a deuterium-enriched pirfenidone compound, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, wherein the deuterium-enriched pirfenidone compound is orally administered three times daily at a total daily dose of 100-1500 mg. In some embodiments, provided herein are methods for the treatment, prevention, and / or amelioration of edema, e.g., lymphedema, comprising administering LYT-100 to a subject in need thereof, wherein the LYT-100 is orally administered three times daily at a total daily dose of 100-1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, e.g., LYT-100, is 1500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 1000 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 750 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 500 mg. In some embodiments, the daily dose of the deuterium-enriched pirfenidone compound, for example, LYT-100, is 250 mg. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 500 mg three times a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 333 mg three times a day. In some embodiments, the deuterium-enriched pirfenidone compound, for example, LYT-100, is orally administered at 166 mg twice a day.

[0294] In other embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-2500 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-2000 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-1500 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-1000 mg. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered at a total daily dose of 100-500 mg. In some embodiments, the daily dose is selected from 100, 200, 250, 300, 400, 500, 600, 700, 750, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, and 2500 mg / day. In some embodiments, the deuterium-enriched pirfenidone compound is orally administered three times daily (TID). In some embodiments, the deuterium-enriched pirfenidone compound is orally administered twice daily (BID). In some embodiments, the deuterium-enriched pirfenidone compound is orally administered once daily (QD). In any of these embodiments, the deuterium-enriched pirfenidone compound has the structure of Formula I, eg, the compounds listed in Table 1, including, eg, LYT-100.

[0295] In some embodiments, the methods described herein involve escalating doses of deuterium-enriched pirfenidone over a certain period of time until a full maintenance dose is reached. In some embodiments, the titration period is 7 days. In some embodiments, the titration period is 14 days. In some embodiments, the titration period is 21 days. In some embodiments, the methods described herein include reducing the dose. In any of these embodiments, the daily dose is administered in a single dose or divided into two or three doses, i.e., administration is once, twice, or three times daily.

[0296] In some embodiments, the daily dose is escalated from 250 mg to 500 mg. In some embodiments, the daily dose is escalated from 250 mg to 750 mg, optionally including 500 mg steps. In some embodiments, the daily dose is escalated from 250 mg to 1000 mg, optionally including 500 mg and / or 750 mg steps. In some embodiments, the daily dose is escalated from 250 mg to 1500 mg, optionally including 500 mg and / or 750 mg and / or 100 mg steps. In some embodiments, the daily dose is escalated from 500 mg to 750 mg. In some embodiments, the daily dose is escalated from 500 mg to 1000 mg, optionally including 750 mg steps. In some embodiments, the daily dose is titrated from 500 mg to 1500 mg, optionally including 750 mg and / or 100 mg steps. In any of these embodiments, the daily dose is administered in a single dose or divided into two or three doses, i.e., administration is once, twice, or three times daily.

[0297] In some embodiments, the daily dose is gradually increased from 250 mg to 500 mg over a 5-day period. In some embodiments, the daily dose is gradually increased from 250 mg to 750 mg, optionally including 500 mg steps. In some embodiments, the daily dose is gradually increased from 250 mg to 1000 mg over a 5-day period, optionally including 500 mg steps and / or 750 mg steps. In some embodiments, the daily dose is gradually increased from 250 mg to 1500 mg over a 5-day period, optionally including 500 mg steps and / or 750 mg steps and / or 100 mg steps. In some embodiments, the daily dose is gradually increased from 500 mg to 750 mg over a 5-day period. In some embodiments, the daily dose is gradually increased from 500 mg to 1000 mg over a 5-day period, optionally including 750 mg steps. In some embodiments, the daily dose is titrated from 500 mg to 1500 mg over a 5-day period, optionally including 750 mg and / or 100 mg steps. In any of these embodiments, the daily dose is administered in a single dose or divided into two or three doses, i.e., administration is once, twice, or three times daily.

[0298] In some embodiments, the daily dose is gradually increased from 500 mg to 250 mg over a 5-day period. In some embodiments, the daily dose is decreased from 750 mg to 250 mg over a 5-day period, in 500 mg steps. In some embodiments, the daily dose is decreased from 1000 mg to 250 mg over a 5-day period, optionally including 750 mg and / or 500 mg steps. In some embodiments, the daily dose is decreased from 1500 mg to 250 mg over a 5-day period, optionally including 1000 mg and / or 750 mg and / or 500 mg steps. In some embodiments, the daily dose is reduced from 750 mg to 500 mg over a 5-day period, optionally including 750 mg steps. In some embodiments, the daily dose is reduced from 1000 mg to 500 mg over a 5-day period, optionally including 750 mg steps. In some embodiments, the daily dose is reduced from 1500 mg to 500 mg over a 5-day period, optionally including 100 mg steps and / or 750 mg steps. In any of these embodiments, the daily dose is administered in a single dose or divided into two or three doses, i.e., administration is Once, twice or three times a day.

[0299] In some embodiments, the daily dose is gradually increased from 250 mg to 500 mg over a 14-day period. In some embodiments, the daily dose is gradually increased from 250 mg to 750 mg over a 14-day period, optionally including 500 mg steps. In some embodiments, the daily dose is gradually increased from 250 mg to 1000 mg over a 14-day period, optionally including 500 mg steps and / or 750 mg steps. In some embodiments, the daily dose is gradually increased from 250 mg to 1500 mg over a 14-day period, optionally including 500 mg steps and / or 750 mg and / or 100 mg steps. In some embodiments, the daily dose is gradually increased from 500 mg to 750 mg over a 14-day period. In some embodiments, the daily dose is gradually increased from 500 mg to 1000 mg over a 14-day period, optionally including 750 mg steps. In some embodiments, the daily dose is titrated from 500 mg to 1500 mg over a 14 day period, optionally including 750 mg and / or 100 mg steps. In any of these embodiments, the daily dose is administered in a single dose or divided into two or three doses, i.e., administration is once, twice, or three times daily.

[0300] In some embodiments, the daily dose is titrated from 250 mg to 500 mg on days 1 through 7, then titrated from 500 mg to 1000 mg on days 7 through 14. In some embodiments, the titration from 500 mg to 1000 mg includes 750 mg steps. In some embodiments, the daily dose is titrated from 500 mg to 750 mg on days 1 through 7, then titrated from 750 mg to 1000 mg on days 7 through 14. In any of these embodiments, the daily dose is administered in a single dose or divided into two or three doses, i.e., administration is once, twice, or three times daily.

[0301] In some embodiments, the daily dose is gradually increased from 250 mg to 500 mg over a 21-day period. In some embodiments, the daily dose is gradually increased from 250 mg to 750 mg over a 21-day period, optionally including 500 mg steps. In some embodiments, the daily dose is gradually increased from 250 mg to 1000 mg over a 21-day period, optionally including 500 mg steps and / or 750 mg steps. In some embodiments, the daily dose is gradually increased from 250 mg to 1500 mg over a 21-day period, optionally including 500 mg steps and / or 750 mg and / or 100 mg steps. In some embodiments, the daily dose is gradually increased from 500 mg to 750 mg over a 21-day period. In some embodiments, the daily dose is gradually increased from 500 mg to 1000 mg over a 21-day period, optionally including 750 mg steps. In some embodiments, the daily dose is titrated from 500 mg to 1500 mg over a 21 day period, optionally including 750 mg and / or 100 mg steps. In any of these embodiments, the daily dose is administered in a single dose or divided into two or three doses, i.e., administration is once, twice, or three times daily.

[0302] In some embodiments, the daily dose is titrated from 250 mg to 500 mg on days 1-7, then titrated from 500 mg to 750 mg on days 7-14, then titrated from 750 mg to 1000 mg on days 14-21. In some embodiments, the daily dose is titrated from 500 mg to 750 mg on days 1-7, then titrated from 750 mg to 1000 mg on days 7-14, then titrated from 1000 mg to 1500 mg. In any of these embodiments, the daily dose is administered in a single dose or divided into two or three doses, i.e., administration may be once, twice, or multiple times daily. Usually it's three times.

[0303] In a prophylactic setting, the pharmaceutical compositions of the present invention can be administered any time before or after an event that places a subject at risk of lymphatic damage and / or developing edema or that predisposes the subject to lymphatic damage and / or developing edema, e.g., radiation therapy, chemotherapy, or surgical lymph node dissection. In some embodiments, the pharmaceutical composition is prophylactically administered up to about one week before the event, e.g., 1, 2, 3, 4, 5, 6, or 7 days before the event. In some cases, the pharmaceutical composition is prophylactically administered the same day as the event. In some embodiments, the pharmaceutical composition is prophylactically administered within 6 weeks of the event, e.g., within about 1, 2, 3, 4, 5, or 6 days, or within about 1, 2, 3, 4, 5, or 6 weeks, of the event. In some embodiments, the pharmaceutical composition is prophylactically administered for about 2-4 weeks, or for about 1, 2, 3, 4, 5, or 6 weeks.

[0304] In one embodiment, provided herein is a method of treating lymphedema in a subject comprising administering LYT-100, wherein the treatment period is selected from 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, and 25 weeks, and any increment therein.

[0305] In one embodiment, provided herein is a method of treating lymphedema in a subject comprising administering LYT-100, wherein the treatment period is selected from 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months, and any increment therein. In one embodiment, provided herein is a method of treating lymphedema in a subject comprising administering LYT-100, wherein the treatment period is 1 year, 2 years, 3 years, 4 years, 5 years, or more.

[0306] In some embodiments, LYT-100 may be administered with or without food. In some embodiments, LYT-100 is administered with food. In some embodiments, LYT-100 is administered without food.

[0307] In some embodiments, the pharmaceutical composition is administered topically once a day or at least once a day. In other embodiments, the pharmaceutical composition is administered topically twice a day or at least twice a day. When the pharmaceutical composition or method includes preventing edema, particularly lymphedema, the composition can be administered within about 6 weeks of lymphatic vessel damage, for example, within about 2 weeks of lymphatic vessel damage.

[0308] In some embodiments, the pharmaceutical composition is orally administered once daily or at least once daily. In other embodiments, the pharmaceutical composition is orally administered twice daily or at least twice daily. When the pharmaceutical composition or method includes preventing edema, particularly lymphedema, the composition can be administered within about 6 weeks of lymphatic vessel injury, for example, within about 2 weeks of lymphatic vessel injury.

[0309] Methods, compositions and medications for treating interstitial lung disease Idiopathic pulmonary fibrosis (IPF) affects approximately 100,000 people in the United States, and the drugs nintedanib and pirfenidone are the only available treatments. In preclinical studies, LYT-100 demonstrated favorable anti-fibrotic and anti-inflammatory activity compared to pirfenidone.

[0310] Accordingly, provided herein is a method of treating interstitial lung disease (ILD), the method comprising administering to a subject in need thereof a compound having the structure:

[0311] [ka]

[0312] or a pharmaceutically acceptable salt thereof, wherein the subject is treated for ILD.

[0313] In certain embodiments, the ILD is idiopathic pulmonary fibrosis (IPF). In some embodiments, the ILD is chILD. Clinical Benefits of Deuterium-Enriched Pirfenidone Pirfenidone is a small molecule with antifibrotic and anti-inflammatory properties. Recent studies suggest that this activity is due, at least in part, to inhibition of TGF-β production and activity. Iyer et al., J. Pharmacol. Exp. Ther. 291:367-373 (1999); Tada et al., Clin. Exper. Pharmacol. Physiol. 28:522-527 (2001); Oku et al., Eur. J. Pharmacol. 590:400-408 (2008). It is currently approved in the United States and other countries for oral administration in the treatment of idiopathic pulmonary fibrosis (IPF). Taniguchi et al., Eur. Respir. J. 35:821-829 (2010); Noble et al., Lancet, 377:1760-1769 (2011); King et al., N. Engl. J. Med. 370:2083-2092 (2014). Idiopathic pulmonary fibrosis (IPF) is a debilitating, progressive, and fatal fibrotic lung disease with a median survival of approximately 2-5 years from the time of diagnosis. IPF is one of the most commonly encountered interstitial lung diseases (ILDs) and is increasing in incidence and prevalence worldwide. Pirfenidone is one of two therapies approved for the treatment of IPF. Randomized controlled clinical trials and subsequent post-hoc analyses have demonstrated that pirfenidone attenuates the decline in lung function, reduces mortality, and improves progression-free survival.

[0314] However, pirfenidone has a very short half-life in humans, requiring relatively frequent dosing. The recommended daily maintenance dose of pirfenidone is 801 mg three times daily (2403 mg·day−1) (a total of 9 tablets per day), with a titration period of 14 days at the start of treatment.

[0315] In addition, for IPF patients to achieve the maximum benefit from pirfenidone treatment, pirfenidone-related adverse events (AEs) must be managed. The most common AEs are gastrointestinal (GI) and skin-related adverse events, such as nausea, rash, diarrhea, fatigue, dyspepsia, anorexia, dizziness, gastroesophageal reflux disease, decreased appetite, weight loss, photosensitivity, and cough. Additionally, several treatment-related adverse events, including upper respiratory tract infections and bronchitis, have been reported. A recent study of patients treated with pirfenidone under a compassionate use program found that 44% of patients had pirfenidone-related adverse events, and only half of those patients continued pirfenidone after dose reduction. Raghu & Thickett. Thorax; 68: 605-608 (2013). Common adverse events with 2403 mg / day pirfenidone include nausea, rash, fatigue, diarrhea, vomiting, dyspepsia, photosensitivity, and anorexia. Noble et al. Lancet; 377: 1760-69 (2011). Results from several extended clinical trials have shown that treatment-emergent adverse events (TEAEs) occur per 100 PEYs (when physicians follow 100 IPF patients for 1 year). These TEAEs are summarized in Lancaster et al., Eur. Resp. Rev. 2017:26:170057, which reports these TEAEs as TEAEs (corresponding to expected frequencies). Herein, the most commonly reported AEs leading to discontinuation were nausea, fatigue, diarrhea, and / or rash, with high incidences of 62.1 per 100 PEY (nausea), 27.6 per 100 PEY (diarrhea), and 52.4 per 100 PEY (fatigue). In a single-center, retrospective, observational study of 351 patients receiving pirfenidone, 75% of reported AEs were GI-related, similar to those observed in Phase III studies, with anorexia (17%) and nausea / vomiting (15%) being the most frequent. Anorexia and nausea / vomiting were the most common causes of treatment discontinuation. The incidence of AEs and discontinuation increases with age. The proportion of patients with ADRs leading to dose modification / interruption or discontinuation increased with age, with ADRs leading to dose modification / interruption occurring in 32.7% of patients aged 80 years or older and 18.0% of patients under 65 years, while ADRs leading to discontinuation occurred in 20.9% of patients aged 80 years or older and 7.5% of patients under 65 years.

[0316] Several methods have been proposed for managing AEs associated with pirfenidone, including modifying the titration schedule with more lenient titration and employing dose modifications, including dose reductions or discontinuations (dose reductions and discontinuations occurred in 46% and 41% of patients taking pirfenidone, respectively, with median durations of 28 and 14 days, respectively, in Phase III studies). Overall, 30% of pirfenidone patients had dose modifications, and 29% were permanently discontinued due to AEs in Phase III studies. In addition, modifying patients' dietary habits is necessary when adjusting the pirfenidone dose. Taking pirfenidone with a significant amount of food, specifically taking the entire dose at the end of a substantial meal or spreading three capsules throughout the meal, may decrease pirfenidone absorption and reduce the incidence of GI-related AEs.

[0317] Although more lenient titration and dose modification may help address patient AEs, adopting such measures has significant therapeutic implications, particularly as patients taking pirfenidone 1197 mg / day were reported to experience greater declines in pulmonary function than patients taking a full dose of 2403 mg / day.

[0318] Additionally, because pirfenidone treatment has an adverse effect on liver function, monitoring liver function is also important during pirfenidone treatment. Elevations of aspartate transaminase (AST) and alanine transaminase (ALT) levels greater than three times the upper limit of normal (ULN) occurred in Phase III trials (3.2%) and were managed by dose modification or discontinuation. If AST and ALT elevations (greater than 3 × ULN to less than 5 × ULN) occur without symptoms or hyperbilirubinemia, the dose may be reduced or temporarily discontinued until values ​​return to normal. However, if AST and ALT elevations (greater than 3 × ULN to less than 5 × ULN) are accompanied by hyperbilirubinemia, or if patients exhibit levels greater than 5 × ULN, pirfenidone should be permanently discontinued.

[0319] In addition, patients taking other oral medications concomitantly should be monitored for drug-drug interactions, as these medications may significantly affect pirfenidone metabolism by inhibiting or inducing hepatic enzyme systems (cytochrome P450 1A2 (CYP1A2), CYP3A4, and P-glycoprotein). For example, for strong CYP1A2 inhibitors such as fluvoxamine and enoxacin, pirfenidone should be reduced to 267 mg three times daily (801 mg·day). For moderate CYP1A2 inhibitors such as ciprofloxacin at a dose of 750 mg twice daily, pirfenidone should be reduced to 534 mg three times daily (1602 mg·day). Patients should also be evaluated for gastrointestinal intolerance, skin reactions, and elevated liver enzymes.

[0320] Therefore, pirfenidone treatment requires various AE management strategies, including more lenient titration for initiating treatment, taking pirfenidone with sufficient food, spacing capsules throughout meals, dietary modifications, weight-based dosing schedules and dose reductions and interruptions, and continuous liver function monitoring.

[0321] Thus, limitations of pirfenidone include a short half-life of only about 2.5 hours, a high tablet burden (9 capsules per day (TID dosing)), poor tolerability including nausea, diarrhea, and photosensitivity, high doses required for efficacy that induce side effects, and significant inter-patient variability.

[0322] In contrast, deuterium-enriched pirfenidone compounds address the deficiencies associated with pirfenidone. The metabolism of pirfenidone is only partially understood. For example, without wishing to be bound by theory, it is believed that the methyl group is susceptible to oxidation, leading to the corresponding hydroxymethyl metabolite "M1." It is believed that M1 is further oxidized to the carboxylic acid metabolite "M2" (Wang, et al., Biomedical Chromatography, 2006, 20, 1375-1379). The third metabolite detected is thought to be a phase II product, likely derived from M1 or M2.

[0323] Pirfenidone is a substituted pyridinone-based fibrosis modulator and / or collagen invasion modulator. The carbon-hydrogen bonds of pirfenidone contain a naturally occurring distribution of hydrogen isotopes: 1H or protium (approximately 99.9844%), 2H or deuterium (approximately 0.0156%), and 3H or tritium (ranging from approximately 0.5 to 67 tritium atoms per 1018 protium atoms). Increased levels of deuterium incorporation may result in detectable kinetic isotope effects (KIEs) that can affect the pharmacokinetic, pharmacological, and / or toxicological profiles of such fibrosis modulators and / or collagen invasion modulators compared to compounds with naturally occurring levels of deuterium.

[0324] Pirfenidone is likely metabolized in humans by oxidation of the methyl group. Other sites on the molecule may also undergo transformations leading to metabolites with unknown pharmacological and toxicological properties. Limiting the production of these metabolites may reduce the risk of administering such drugs and even allow for increased dosage and therefore increased efficacy. All of these transformations can occur via polymorphically expressed enzymes, exacerbating patient-to-patient variability.

[0325] Thus, various deuteration patterns can be used to (a) reduce or eliminate undesirable metabolites, (b) increase the half-life of the parent drug, (c) reduce the number of doses required to achieve a desired effect, (d) reduce the amount of dose required to achieve a desired effect, (e) increase the formation of active metabolites, if formed, and / or (f) reduce the production of harmful metabolites in specific tissues and / or create more effective and / or safer drugs for polypharmacy, whether or not polypharmacy is intended. Deuteration approaches have the powerful potential to slow metabolism via various oxidation and racemization mechanisms.

[0326] In one embodiment, the deuterated compounds disclosed herein, e.g., LYT-100, while maintaining the beneficial aspects of the corresponding non-isotopically enriched molecules, significantly increase the maximum tolerated dose, reduce toxicity, increase half-life (T), lower the minimum effective dose (MED), maximum plasma concentration (C), lower the effective dose, thus reducing non-mechanism-related toxicity, and / or reducing the potential for drug-drug interactions.

[0327] In some embodiments, the deuterium-enriched pirfenidone compound used in the disclosed methods has at least one of the following properties: (a) reduced inter-individual variability in plasma levels of the compound or its metabolites compared to non-isotopically enriched compounds; (b) increased mean plasma levels of the compound per dosage unit compared to non-isotopically enriched compounds; (c) reduced mean plasma levels of at least one metabolite of the compound per dosage unit compared to non-isotopically enriched compounds; (d) increased mean plasma levels of at least one metabolite of the compound per dosage unit compared to non-isotopically enriched compounds; and (e) improved clinical efficacy during treatment in subjects per dosage unit compared to non-isotopically enriched compounds. Thus, disclosed herein are methods for treating a subject, including a human, having or suspected of having edema, e.g., lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in one or more of the above-described (a)-(e) during treatment of the disorder, relative to the corresponding non-isotopically enriched compound. In some embodiments, the deuterium-enriched pirfenidone compound has at least two of the above properties (a)-(e). In some embodiments, the deuterium-enriched pirfenidone compound has three or more of the above properties (a)-(e).

[0328] One embodiment is a method for the treatment, prevention, or amelioration of one or more symptoms of edema, eg, lymphedema.

[0329] Disclosed herein is a method for treating a subject, including a human, who has or is suspected to have edema, such as lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to reduce the inter-individual variability of the plasma level of the compound or its metabolite during the treatment of such a disorder, compared with the corresponding non-isotopically enriched compound.In certain embodiments, the inter-individual variability of the plasma level of the compound as disclosed herein or its metabolite is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including the numerical increments between the listed percentages) compared with the corresponding non-isotopically enriched compound.

[0330] Disclosed herein is a method for treating a subject, including a human, who has or is suspected to have edema, such as lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to cause an increase in the average plasma level of the compound or a decrease in the average plasma level of at least one metabolite of the compound per dosage unit compared with the corresponding non-isotopically enriched compound.In certain embodiments, the average plasma level of the compound as disclosed herein is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including the numerical increments between the listed percentages) compared with the corresponding non-isotopically enriched compound. In certain embodiments, the mean plasma levels of metabolites of a compound as disclosed herein are reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0331] Plasma levels of a compound as disclosed herein or a metabolite thereof may be measured using the method described by Li et al. (Rapid Communications in Mass Spectrometry, 2005, 19, 1943-1950).

[0332] In some embodiments, the compound has a specific activity that increases the expression of at least one polymorphic cytochrome P in a subject per dosage unit compared to a non-isotopically enriched compound. 450 It has a decreased metabolism due to isoforms.

[0333] In some embodiments, cytochrome P 450The isoform is selected from CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

[0334] In some embodiments, the compound reduces the activity of at least one cytochrome P in a subject per dosage unit compared to a non-isotopically enriched compound. 450 or characterized by reduced inhibition of monoamine oxidase isoforms.

[0335] In certain embodiments, cytochrome P 450 or monoamine oxidase isoforms CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4 B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A 1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO A , and MAO B is selected from.

[0336] In some embodiments, the deuterium-enriched pirfenidone compound has at least one of the following properties compared to the non-isotopically enriched compound: (a) a half-life of greater than 2.5 hours, (b) a reduced tablet burden, (c) improved patient tolerability, (d) a lower effective dose, (e) increased bioavailability, (f) a higher Cmax, and (g) an increased systemic exposure in a subject during treatment per dosage unit. Disclosed herein is a method for treating a subject, including a human, having or suspected of having edema, e.g., lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in one or more of the above (a)-(g) during treatment of the disorder compared to the corresponding non-isotopically enriched compound.

[0337] Disclosed herein is a method for treating a subject, including a human, having or suspected of having edema, e.g., lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to provide a longer half-life. In some embodiments, the half-life of the deuterium-enriched pirfenidone compound or its metabolite as disclosed herein is greater than about 2%, greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 100% of the corresponding non-isotopically enriched compound. In some embodiments, the half-life of a deuterium-enriched pirfenidone compound or metabolite thereof as disclosed herein is increased by about 1.5-fold, about 2-fold, more than about 2-fold, more than about 3-fold, more than about 4-fold, more than about 5-fold, more than about 10-fold, or more (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0338] Disclosed herein is a method for treating a subject, including a human, having or suspected of having edema, e.g., lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to reduce tablet burden compared to the corresponding non-isotopically enriched compound, e.g., to provide a tablet burden of less than 9 capsules per day (TID dosing) of the compound or its metabolite during treatment of the disorder.

[0339] In certain embodiments, the tablet loading of a compound as disclosed herein is reduced by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, or more than about 50% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0340] Disclosed herein are methods for treating a subject, including a human, having or suspected of having edema, e.g., lymphedema, or for preventing such a disorder in a subject susceptible to the disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in increased patient tolerability of the compound or its metabolites during treatment of the disorder, compared to the corresponding non-isotopically enriched compound. In some embodiments, patient tolerability is enhanced by altering the pharmacokinetics, e.g., by increasing bioavailability (such as using lower doses) and / or by extending the half-life of the compound, and / or by other means that reduce the side effects of pirfenidone.

[0341] In certain embodiments, the patient tolerability of a compound as disclosed herein, or a metabolite thereof, is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound. In certain embodiments, the patient tolerability of a compound as disclosed herein, or a metabolite thereof, is increased by about 1.5-fold, about 2-fold, more than about 2-fold, more than about 3-fold, more than about 4-fold, more than about 5-fold, or more than about 10-fold (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0342] Disclosed herein is a method for treating a subject, including a human, having or suspected of having edema, e.g., lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in a lower effective dose per dose of the compound or its metabolite during treatment of the disorder compared to the corresponding non-isotopically enriched compound.

[0343] In certain embodiments, the effective dose per dose of a compound as disclosed herein, or a metabolite thereof, is greater than about 2% to about 10% of the corresponding non-isotopically enriched compound. The effective dose per dose of a compound as disclosed herein or a metabolite thereof is reduced by more than 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including the numerical increments between the recited percentages). In certain embodiments, the effective dose per dose of a compound as disclosed herein, or a metabolite thereof, is reduced by about 1.5-fold, about 2-fold, more than about 2-fold, more than about 3-fold, more than about 4-fold, more than about 5-fold, more than about 10-fold, or more (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0344] Disclosed herein is a method for treating a subject, including a human, having or suspected of having edema, e.g., lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to increase the bioavailability per dose of the compound or its metabolite during treatment of the disorder compared to the corresponding non-isotopically enriched compound.

[0345] In certain embodiments, the bioavailability per dose of a compound as disclosed herein, or a metabolite thereof, is increased by more than about 2%, more than about 5%, more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, more than about 90%, or more than about 100% (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound. In certain embodiments, the bioavailability per dose of a compound as disclosed herein, or a metabolite thereof, is increased by about 1.5-fold, about 2-fold, more than about 2-fold, more than about 3-fold, more than about 4-fold, more than about 5-fold, more than about 10-fold, or more (including the numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound.

[0346] Disclosed herein is a method for treating a subject, including a human, having or suspected of having edema, e.g., lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in increased systemic exposure of the compound per dosage unit compared to the corresponding non-isotopically enriched compound.

[0347] In certain embodiments, the systemic exposure per dose of a compound as disclosed herein is increased by more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, or more than about 50% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound. In one embodiment, the systemic exposure per dose of a compound as disclosed herein is increased by more than about 35% compared to the corresponding non-isotopically enriched compound. In one embodiment, the systemic exposure per dose of a compound as disclosed herein is increased by about 35% compared to the corresponding non-isotopically enriched compound.

[0348] Disclosed herein is a method for treating a subject, including a human, having or suspected of having edema, e.g., lymphedema, or for preventing such a disorder in a subject susceptible to such a disorder, comprising administering to the subject a therapeutically effective amount of a deuterium-enriched pirfenidone compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, so as to result in an increased Cmax of the compound per dosage unit compared to the corresponding non-isotopically enriched compound.

[0349] In certain embodiments, the Cmax per dose of a compound as disclosed herein or its metabolites is increased by more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, or more than about 50% (including numerical increments between the recited percentages) compared to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax per dose of a compound as disclosed herein is increased by more than about 25% compared to the corresponding non-isotopically enriched compound. In one embodiment, the Cmax per dose of a compound as disclosed herein is increased by about 25% compared to the corresponding non-isotopically enriched compound.

[0350] In some embodiments, the method treats the disorder while reducing or eliminating the adverse changes in diagnostic hepatobiliary function endpoints compared to corresponding non-isotopically enriched compounds, such as pirfenidone.Disclosed herein is a method for treating a subject, including a human, who has or suspects to have edema, such as lymphedema, or for preventing such disorders in a subject who is prone to such disorders, comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or its pharmaceutically acceptable salt, solvate or prodrug, so as to reduce or eliminate the adverse changes in diagnostic hepatobiliary function endpoints compared to corresponding non-isotopically enriched compounds. In some embodiments, the diagnostic hepatobiliary function endpoints are selected from alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase ("SGPT"), aspartate aminotransferase ("AST", "SGOT"), ALT / AST ratio, serum aldolase, alkaline phosphatase ("ALP"), ammonia level, bilirubin, gamma-glutamyl transpeptidase ("GGTP", "γ-GTP", "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasound, liver nuclear scan, 5'-nucleotidase, and blood proteins. In some embodiments, the disease, disorder, or condition is selected from idiopathic pulmonary fibrosis, pneumoconiosis, silicosis, silicosis, asbestosis, anthracosis, lymphedema (primary and / or secondary), systemic sclerosis (scleroderma) and / or scleroderma-related conditions, juvenile systemic sclerosis (J-SSC), interstitial lung disease, scleroderma interstitial lung disease, focal segmental glomerulosclerosis (FSGS), diffuse lung disease such as diffuse parenchymal lung disease, diabetic nephropathy, lupus nephritis, polycystic kidney disease, ANCA vasculitis, membranous nephropathy, minimal change complex, chronic kidney disease, myocardial fibrosis, keloid scarring, cutaneous polymyositis, fibrosarcoidosis, medical device or transplant rejection (e.g., breast capsular contracture), fatty liver disease such as nonalcoholic steatohepatitis (NASH), and hepatitis C fibrosis.

[0351] In some embodiments, the disease, disorder, or condition is selected from idiopathic pulmonary fibrosis, lymphedema (primary and / or secondary), systemic sclerosis (scleroderma), juvenile systemic sclerosis (J-SSC), scleroderma interstitial lung disease, or a condition associated with scleroderma. In some embodiments, the disease, disorder, or condition is myocardial fibrosis. In some embodiments, the disease, disorder, or condition is keloid scarring.

[0352] In some embodiments, the disease, disorder, or condition is cutaneous polymyositis. Cutaneous polymyositis (also known as PM / DM) is a family of myositis disorders that includes polymyositis and dermatomyositis. In some embodiments, the disease, disorder, or condition is selected from dermatomyositis, juvenile dermatomyositis polymyositis, and inclusion body myositis.

[0353] In some embodiments, the disease, disorder, or condition is scleroderma, progressive systemic sclerosis, mixed connective tissue disease, or CREST syndrome.

[0354] In some embodiments, the disease, disorder, or condition is fibrotic sarcoidosis. In some embodiments, the disease, disorder, or condition is an immune response to an implanted medical device. Reactions such as surgical graft rejection, or capsular contracture such as breast capsular contracture.

[0355] The compounds and combinations of the present invention may be used to treat a variety of diseases, disorders, and conditions. In some embodiments, the disease, disorder, or condition is selected from idiopathic pulmonary fibrosis, neurofibromatosis, Hermansky-Pudlak syndrome, diabetic nephropathy, renal fibrosis, hypertrophic cardiomyopathy (HCM), hypertension-related nephropathy, glomerulosclerosis (FSGS), radiation-induced fibrosis, multiple sclerosis (including secondary progressive multiple sclerosis), uterine leiomyomas (fibroids), alcoholic liver disease (including hepatic steatosis, hepatic fibrosis, and hepatic cirrhosis), keloid scars, hepatitis C virus (HCV) infection, proliferative diseases (including angiogenesis-mediated disorders), cancer (including glioma, glioblastoma, breast cancer, colon cancer, melanoma, and pancreatic cancer), fibrotic disorders, interstitial lung disease, atrial fibrillation (AF), organ transplant rejection, and scleroderma and related fibrotic conditions of the skin.

[0356] In some embodiments, the disease, disorder, or condition is diabetic nephropathy, Kimmelstiel-Wilson disease or syndrome, diabetic kidney disease, diabetic nephritis, or intercapillary or intracapillary glomerulosclerosis.

[0357] In some embodiments, the methods of the invention are used to treat a disease or condition selected from idiopathic pulmonary fibrosis, neurofibromatosis, Hermansky-Pudlak syndrome, diabetic nephropathy, renal failure, hypertrophic cardiomyopathy (HCM), glomerulosclerosis (FSGS), radiation-induced fibrosis, multiple sclerosis, and uterine leiomyomas (fibroids) in a patient in need thereof.

[0358] In another specific embodiment, the methods of the invention are used to treat renal fibrosis, liver fibrosis, uterine leiomyoma, keloid scars, multiple sclerosis, radiation-associated fibrosis, organ transplant rejection, or cancer in a patient in need thereof.

[0359] In yet another specific embodiment, the method is used to treat idiopathic pulmonary fibrosis in a patient in need thereof. In another specific embodiment, the method of the invention is used to treat secondary progressive multiple sclerosis in a patient in need thereof. In another specific embodiment, the method of the invention is used to treat pancreatic cancer in a patient in need thereof. In another even more specific embodiment, the method of the invention is used to treat renal fibrosis in a patient in need thereof. More particularly, the method is used to treat renal fibrosis as a result of diabetic nephropathy, glomerulopathy / FSGS, or hypertension-related nephropathy. In yet another embodiment, the amount of a compound of the invention administered to treat liver fibrosis in a patient in need thereof. Additional diseases, disorders, and conditions that may be treated according to the present invention include those described herein and below.

[0360] In some embodiments, the present invention provides methods for treating, preventing, or ameliorating a disease, disorder, or condition selected from a fibrosis-mediated disorder, a collagen-mediated disorder, or a fibrosis-mediated and collagen-mediated disorder, the method comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering an effective amount of an additional therapeutic agent, such as those described herein.

[0361] In some embodiments, the deuterium-enriched pirfenidone is a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0362] In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or and pharmaceutically acceptable salts thereof.

[0363] In some embodiments, deuterium-enriched pirfenidone is co-administered with one or more additional therapeutic agents, such as those described herein.

[0364] In some embodiments, the disease, disorder, or condition is selected from systemic sclerosis, systemic sclerosis-associated pulmonary fibrosis, sarcoidosis, sarcoidosis-associated pulmonary fibrosis, pulmonary fibrosis caused by infection, asbestos-induced pulmonary fibrosis, silica-induced pulmonary fibrosis, environmentally induced pulmonary fibrosis, radiation-induced pulmonary fibrosis, lupus-induced pulmonary fibrosis, drug-induced pulmonary fibrosis, and hypersensitivity pneumonitis, and / or any disorder that is ameliorated by modulating fibrosis and / or collagen infiltration into tissues.

[0365] In some embodiments, the disease, disorder, or condition is selected from idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial fibrillation, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, splenic fibrosis caused by sickle cell anemia, rheumatoid arthritis, and / or a disorder ameliorated by modulating fibrosis and / or collagen infiltration into tissues.

[0366] In some embodiments, the disease, disorder, or condition is selected from idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial fibrillation, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, splenic fibrosis caused by sickle cell anemia, and rheumatoid arthritis.

[0367] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone for treating or preventing inflammatory diseases, disorders, or conditions. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. In some embodiments, the present disclosure provides a method for treating or preventing inflammatory diseases, disorders, or conditions, the method comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.

[0368] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone for treating or preventing fibrotic diseases, disorders, or conditions. In some embodiments, the deuterium-enriched pirfenidone is LYT-100. In some embodiments, the present disclosure provides a method for treating or preventing fibrotic diseases, disorders, or conditions, the method comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.

[0369] In some embodiments, the present disclosure relates to the use of deuterium-enriched pirfenidone for treating or preventing idiopathic pulmonary fibrosis. In some embodiments, the deuterium-enriched pirfenidone is LYT-100.

[0370] In some embodiments, the present disclosure provides a method for treating or preventing idiopathic pulmonary fibrosis, the method comprising administering to a subject in need thereof an effective amount of deuterium-enriched pirfenidone. In some embodiments, the deuterium-enriched pirfenidone is LYT-100, or a pharmaceutically acceptable salt thereof.

[0371] In some embodiments, the disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF). In some embodiments, the disease, disorder, or condition is chronic fibrosing alveolitis, fibrosing alveolitis, fibrosing alveolitis lung, fibrosing lung disease, Hamman-Rich syndrome, or alveolar fibrosis.

[0372] In some embodiments, the disease, disorder, or condition is systemic sclerosis (scleroderma) and / or related interstitial lung disease.

[0373] In some embodiments, the disease, disorder, or condition is pediatric interstitial lung disease (CHILD). In some embodiments, the pediatric interstitial lung disease is a surfactant dysfunction mutation, a pediatric lung development disorder such as alveolar capillary dysplasia, pulmonary growth abnormalities, neuroendocrine hyperplasia of infancy (NEHI), pulmonary interstitial glycogen storage disease (PIG), idiopathic interstitial pneumonia (e.g., nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia), alveolar hemorrhage syndrome, aspiration syndrome, hypersensitivity pneumonitis, infectious or post-infectious diseases (e.g., bronchiole obstruction syndrome ... pneumonia), eosinophilic pneumonia, pulmonary alveolar proteinosis, pulmonary infiltrates with eosinophilia, pulmonary lymphatic disorders (lymphangiomatosis, lymphangiectasia), pulmonary vascular disorders (hemangiomatosis), interstitial lung diseases associated with a systemic disease process (e.g., connective tissue diseases, histiocytosis, malignancy-associated lung disease, sarcoidosis, storage diseases), or disorders of the immune deficiency system (e.g., opportunistic infections, disorders associated with therapeutic interventions, lung and bone marrow transplant-associated lung disease, diffuse alveolar damage of unknown cause).

[0374] Various types of childhood interstitial lung disease (CHILD) can affect many parts of the lung, including the alveoli (air sacs), bronchi (airways), and capillaries.

[0375] In some embodiments, the disease, disorder, or condition is scleroderma and at least one associated condition selected from interstitial lung disease, skin pressure, joint pain, exaggerated reaction to cold (Raynaud's disease), and heartburn.

[0376] In some embodiments, the disease, disorder, or condition is selected from abnormal wound healing, skin ulcers or scars, pulmonary fibrosis, fibrosis of the lung, liver, kidney, or skin, or Dupuytren's contracture.

[0377] In some embodiments, the inflammatory disease is selected from inflammatory diseases of the liver or those affecting liver function, hi some embodiments, the inflammatory disease is selected from non-alcoholic steatohepatitis (NASH), fatty liver disease, or hepatitis C fibrosis.

[0378] In some embodiments, the method for treating, preventing, or ameliorating one or more symptoms of a fibrosis-mediated disorder and / or a collagen-mediated disorder in a subject comprises administering a therapeutically effective amount of a compound disclosed herein.

[0379] In some embodiments, the fibrosis-mediated disorder and / or collagen-mediated disorder is selected from idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial fibrillation, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, splenic fibrosis caused by sickle cell anemia, and rheumatoid arthritis.

[0380] In some embodiments, fibrosis-mediated disorders and / or said collagen-mediated disorders can be reduced, alleviated, or prevented by modulating fibrosis. In some embodiments, fibrosis-mediated disorders and / or said collagen-mediated disorders can be reduced, alleviated, or prevented by modulating fibrosis. The effects of steroids can be reduced, alleviated, or prevented by regulating the infiltration of steroids.

[0381] In some embodiments, the methods of treatment and / or prevention described herein may be practiced in combination with one or more additional methods of treatment and / or prevention of edema or lymphedema known in the art, such as methods of treatment involving the administration of other therapeutic agents and / or methods of treatment involving surgery, massage, compression therapy, drainage therapy, acupuncture, laser, or other suitable treatments.

[0382] definition Although the terms used herein are believed to be well understood by those of ordinary skill in the art, definitions are set forth herein to facilitate description of the presently disclosed subject matter.

[0383] The term "pharmaceutical formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the subject to which the composition is administered. Pharmaceutical compositions can be in many dosage forms, such as tablets, capsules, liquids, solutions, softgels, suspensions, emulsions, syrups, elixirs, tinctures, films, powders, hydrogels, ointments, pastes, creams, lotions, gels, mousses, foams, lacquers, sprays, aerosols, inhalers, nebulizers, eye drops, patches, suppositories, and / or enemas. Pharmaceutical compositions typically contain a pharmaceutically acceptable carrier and may include one or more of a buffer (e.g., acetate buffer, phosphate buffer, or citrate buffer), a surfactant (e.g., polysorbate), a stabilizer (e.g., human albumin), a preservative (e.g., benzyl alcohol), a penetration enhancer, an absorption promoter to enhance bioavailability, and / or other conventional solubilizers or dispersants. The choice of dosage form and excipients depends on the active agent to be delivered and the disease or disorder to be treated or prevented, and is routine for those skilled in the art.

[0384] The term "deuterium enrichment" refers to the percentage of deuterium incorporated at a given position in a molecule in place of hydrogen. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the naturally occurring distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position of a compound synthesized using unenriched starting materials is approximately 0.0156%. Deuterium enrichment can be determined using conventional analytical methods, such as mass spectrometry or nuclear magnetic resonance spectroscopy.

[0385] The term "deuterium" when used to describe a given variable position in a molecule or formula, or the symbol "D" when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched in deuterium above the naturally occurring distribution of deuterium. In some embodiments, the deuterium enrichment is about 1% or more, about 5% or more, about 10% or more, about 20% or more, about 50% or more, about 70% or more, about 80% or more, about 90% or more, about 98% or more, or in some embodiments, about 99% or more deuterium at the specified position. In some embodiments, the deuterium enrichment is greater than 90% at each specified position. In some embodiments, the deuterium enrichment is greater than 95% at each specified position. In some embodiments, the deuterium enrichment is greater than 99% at each specified position.

[0386] The term "isotopic enrichment" refers to the percentage of incorporation of a less common isotope of an element at a given position in a molecule in place of a more common isotope of that element.

[0387] The term "non-isotopically enriched" refers to a molecule in which the proportions of various isotopes are substantially the same as those present in nature.

[0388] The term "fibrosis" refers to the development of excess fibrous connective tissue within an organ or tissue. The term "collagen infiltration" refers to the invasion of connective tissue collagen into cells or the extracellular matrix surrounding cells, which occurs naturally and normally in organs and tissues, but which may occur in excess and be associated with or cause disease.

[0389] The term "collagen-mediated disorder" refers to a disorder characterized by abnormal or unwanted collagen infiltration, in which correction of collagen infiltration activity results in a desired response, depending on the route of administration and the desired end result. Collagen-mediated disorders can be fully or partially mediated by modulation of collagen infiltration. In particular, collagen-mediated disorders are those in which modulation of collagen infiltration activity results in some effect on the underlying disease, e.g., administering a collagen infiltration modulator results in some improvement in at least some patients being treated.

[0390] The term "fibrosis-mediated disorder" refers to a disorder characterized by aberrant or unwanted fibrotic activity, where correction of the fibrotic activity results in a desired response, depending on the route of administration and the desired end result. Fibrosis-mediated disorders can be mediated completely or partially by modulation of fibrosis. In particular, fibrosis-mediated disorders are those in which modulation of fibrotic activity results in some effect on the underlying disease, e.g., administering a fibrosis modulator results in some improvement in at least some of the treated patients.

[0391] The terms "fibrosis modulator" or "modulating fibrosis" are intended to be synonymous and refer to the ability of a compound disclosed herein to alter the occurrence and / or amount of fibrosis. A fibrosis modulator may increase the occurrence or level of fibrosis, may increase or decrease the occurrence and / or amount of fibrosis depending on the concentration of the compound exposed to the adrenergic receptor, or may decrease the occurrence and / or amount of fibrosis. Such activation or inhibition may be associated with the occurrence of a specific event, such as activation of a signaling pathway, and / or may be expressed only in specific cell types.

[0392] The terms "collagen invasion modulator" or "modulating collagen invasion" are intended to be synonymous and refer to the ability of a compound disclosed herein to alter the occurrence and / or amount of collagen invasion. A fibrosis modulator may increase the occurrence or level of collagen invasion, may increase or decrease the occurrence or amount of collagen invasion depending on the concentration of the compound exposed to the adrenergic receptor, or may decrease the occurrence and / or amount of collagen invasion. Such activation or inhibition may be associated with the occurrence of a specific event, such as activation of a signaling pathway, and / or may be expressed only in specific cell types.

[0393] An "effective amount" of a composition as disclosed herein is an amount sufficient to carry out a specifically stated purpose. An "effective amount" can be determined empirically and routinely for the stated purpose, route of administration, and dosage form.

[0394] Terms such as "treating" or "treatment" or "treat" or "alleviating" or "alleviating" refer to a therapeutic procedure that cures, slows, improves, or alleviates one or more symptoms of a diagnosed pathological condition or disorder, halts the progression of, and / or improves or alleviates the diagnosed pathological condition or disorder. Thus, those in need of treatment include those already with the disorder. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may continue after symptoms have resolved, e.g., to prevent or delay recurrence. In some embodiments, for example, after a patient has developed symptoms associated with a disease or disorder, A subject has been successfully "treated" for a disease or disorder according to the methods provided herein if they exhibit total, partial, or temporary alleviation or elimination. For example, "treating edema" can include, but is not limited to, reducing swelling, reducing inflammation, reducing fibrosis, reducing pain, increasing range of motion, reducing heaviness, reducing tightness, reducing skin thickening, and / or improving lymphatic function.

[0395] "Preventing" or "prevention" refers to prophylactic or preventative treatment that interrupts, delays, and / or slows the onset of the targeted pathological condition or disorder, or one or more symptoms of the targeted pathological condition or disorder. Accordingly, those in need of prevention include those at risk of or susceptible to developing the disorder. Subjects at risk of or susceptible to developing lymphedema include, but are not limited to, cancer patients undergoing radiation therapy, chemotherapy, and / or surgical lymph node dissection. In some embodiments, a disease or disorder has been successfully prevented in accordance with the methods provided herein if the patient develops, e.g., less severe symptoms associated with the disease or disorder, or less severe symptoms, temporarily or permanently, or shows a later onset of symptoms associated with the disease or disorder, than patients not undergoing the methods of the invention.

[0396] "Anti-T cell agents" are molecules that reduce T cell-mediated inflammation, T cell activation, T cell differentiation, and / or T cell proliferation. Classes of anti-T cell agents include calcineurin inhibitors and IL-2 inhibitors. Examples of small molecule anti-T cell agents include tacrolimus, teriflunomide, leflunomide, cyclosporine, and pimecrolimus. Examples of macromolecular anti-T cell agents include denileukin diftitox and basiliximab.

[0397] An "anti-TGF-β1 agent" is a molecule that inhibits the expression, secretion, activation, signaling, or activity of transforming growth factor beta 1. Pirfenidone and deuterium-enriched pirfenidone are examples of small molecule anti-TGF-β1 agents.

[0398] An "anti-angiotensin agent" is a molecule that inhibits the activity of AngI or AngII, or inhibits the conversion of AngI to AngII (e.g., an ACE inhibitor or ACE agonist). Examples of anti-angiotensin agents include captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE099.

[0399] The compounds of the present invention include those described generally herein and are further described by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, chemical elements are defined in accordance with the Periodic Table of the Elements, Handbook of Chemistry and Physics, 98 th Further, general principles of organic chemistry are identified in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 7 th Edition, John Wiley & Sons, 2013, the entire contents of which are incorporated herein by reference.

[0400] As used herein, the term "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable according to appropriate medical judgment. "A" refers to a salt that is within the acceptable range of toxicity, is suitable for use in contact with the tissues of humans and lower animals without causing undue toxicity, irritation, allergic responses, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups (or other basic groups) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of the salt include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0401] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0402] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the present compounds are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C enrichment or 14 Compounds having the present structures including the replacement of a carbon with a C-rich carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention.

[0403] The disclosed compounds, and pharmaceutically acceptable compositions comprising the disclosed compounds and a pharmaceutically acceptable excipient, adjuvant, diluent, or carrier, are useful for treating a variety of diseases, disorders, and conditions, including those described herein.

[0404] Those skilled in the art will recognize that each of the therapeutic agents described herein is known to be associated with the treatment of one or more diseases, disorders, or conditions. Accordingly, it will be appreciated that in certain embodiments, the present invention provides a method of treating a disease, disorder, or condition in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed compound, combination of compounds, or pharmaceutical composition thereof.

[0405] Other activators In some embodiments, the present invention provides systemic (e.g., IV or oral) or local (e.g., topical or transdermal) administration of anti-T cell agents, anti-TGF-β1 agents, and / or anti-angiotensin agents, such as tacrolimus, deuterium-enriched pirfenidone, teriflunomide, leflunomide, or captopril, or pharmaceutically acceptable salts thereof. In some embodiments, administration of such combinations improves lymphedema and lymphatic function and has various other beneficial biological effects, including stimulation of lymphangiogenesis, when administered to a mammalian subject. Furthermore, because these agents act at different steps in the fibrotic pathway, in some embodiments, combinations of anti-T cell, anti-TGF-β1, and / or anti-angiotensin agents are more effective than administration of either agent alone. In some embodiments, the combinations exhibit synergistic effects. In some embodiments, the present invention provides systemic or local administration of anti-TGF-β agents and / or anti-TNF-alpha agents, such as deuterium-enriched pirfenidone. In some embodiments, disclosed herein are methods of treating a disease, e.g., edema, comprising administering LYT-100 and pirfenidone, wherein the LYT-100 and pirfenidone together provide an effective amount of the active agent(s) to treat the disease.

[0406] Tacrolimus is FDA approved as a topical formulation for the treatment of atopic dermatitis (Ruzicka Tacrolimus is an anti-T cell agent used to treat inflammatory / fibrotic diseases of the skin, including psoriasis (Wang et al., J. Cutan. Med. Surg. 18:8-14 (2014)), and localized scleroderma (Mancuso et al., Br. J. Dermatol. 152:180-182 (2005)). Tacrolimus is a macrolide produced by the soil bacterium Streptomyces tsukubaensis that is well tolerated when used to prevent transplant rejection and treat various autoimmune diseases. Tacrolimus exerts its anti-T cell properties by binding to FK-506 binding protein 12 (FKBP-12), thereby inhibiting calcineurin and ultimately reducing IL-2 expression. Clipstone et al., Nature, 357:695-697 (1992). IL-2 mediates T cell activation and CD4 + Calcineurin inhibitors are essential for T cell differentiation, so they inhibit CD4 + It has a broad immunosuppressive effect on cells. Liao et al., Immunity, 38:13-25 (2013); Rautajoki et al., Ann. Med. 40:322-335 (2008). Teriflunomide is an immunosuppressant that reduces T-cell inflammatory responses. Oral administration of teriflunomide is FDA-approved for the treatment of multiple sclerosis. Williamson et al., J. Biol. Chem. 270:22467-22472 (1995); Davis et al., Biochem. 35:1270-1273 (1996); Iglesias-Bregna et al., J. Pharmacol. Exp. Ther. 347:203-211 (2013). Teriflunomide is the active metabolite of leflunomide and inhibits de novo pyrimidine synthesis by blocking the enzyme diribudroorotate dehydrogenase. Teriflunomide has also been shown to inhibit activation of signal transducer and activator of steroid (STAT)-6, a key regulator of Th2 differentiation. Olsan et al., Proc. Natl. Acad. Sci. USA, 108:18067-18072 (2011). As a result of these mechanisms, teriflunomide inhibits actively dividing Th2 cells, reducing the inflammatory response.

[0407] Captopril is an angiotensin-converting enzyme (ACE) inhibitor approved by the FDA for oral administration in the treatment of hypertension, certain types of heart failure, and diabetic nephropathy. ACE converts angiotensin I (AngI) to angiotensin II (AngII), causing vasoconstriction and inhibiting vasodilation, and indirectly regulates intravascular fluid volume through its effects on the renin-angiotensin system (RAS). Therefore, ACE inhibition has become the mainstay of treatment for hypertension. Furthermore, recent studies have shown that AngII is also a key regulator of fibrosis in various organ systems, including the kidney, liver, and lung. [Langham et al., Diabetes Care, 29:2670-2675 (2006); Alves de Albuquerque et al., Kidney Intl. 65:846-859 (2004); Osterreicher et al., Diabetes Care, 29:2670-2675 (2006)]. et al., Hepatology. 50:929-938 (2009); Mak et al., Mol. Ther. 23:1434-1443 (2015); Wang et al., Cell Physiol. Biochem. 36:697-711 (2015). The profibrotic effects of Ang II are mediated by multiple mechanisms, including the production of reactive oxygen species, chemokine and cytokine production, increased expression of adhesion molecules, and modulation of TGF-β expression / activity. In contrast, Ang I possesses antiproliferative and antifibrotic activity by activating its cell surface receptor. Mas. Clarke et al., Int. J. Hypertens. 2012:307-315 (2011). Consequently, inhibitors of ACE and / or Ang II, such as captopril, losartan, and other similar drugs, have been proposed as potential therapeutic options for pulmonary, renal, and hepatic fibrotic disorders.

[0408] In one aspect, the present invention provides a pharmaceutical composition comprising deuterium-enriched pirfenidone in combination with one or more anti-T cell agents, anti-TGF-β1 agents, and / or anti-angiotensin and / or anti-inflammatory agents.

[0409] In some embodiments, the anti-T cell agent is selected from tacrolimus, teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab. In some embodiments, the anti-TGF-β1 agent or anti-angiotensin agent is selected from pirfenidone, deuterium-enriched pirfenidone, captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, and fimasartan. In some embodiments, the anti-angiotensin agent is an ACE agonist, e.g., an ACE-2 agonist. The composition can be formulated for systemic or local administration. In some embodiments, the composition is formulated for topical administration.

[0410] The pharmaceutical compositions of the present invention can include any combination of anti-T cell agents, anti-TGF-β1 agents, and / or anti-angiotensin agents.

[0411] In some embodiments, a composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and one or more anti-T cell agent(s). In some embodiments, a composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab. For example, in some embodiments, a composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and tacrolimus. In another example, some In some embodiments, the composition includes deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and teriflunomide.

[0412] In some embodiments, compositions include deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and one or more anti-TGF-β1 agent(s). Non-limiting examples of anti-TGF-β1 agents include LY550410 and LY580276, SB-505124, or galunisertib (LY2157299 monohydrate), or deuterium-enriched pirfenidone other than LYT-100, e.g., as described herein. In some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and one or more anti-TGF-β1 agent(s) selected from LY550410 and LY580276, SB-505124, or galunisertib (LY2157299 monohydrate), or a deuterium-enriched pirfenidone other than LYT-100, e.g., as described herein. In some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and a second type of deuterium-enriched pirfenidone, e.g., a compound listed in Table 1, other than a compound of Formula I, e.g., LYT-100.

[0413] In some embodiments, compositions comprise deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and one or more anti-angiotensin agent(s). In some embodiments, compositions comprise deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and one or more anti-angiotensin agent(s) selected from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE099. For example, in some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and captopril.

[0414] In some embodiments, compositions include deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and one or more anti-inflammatory agent(s). Non-limiting examples of anti-inflammatory agents include etodolac, famotidine, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, and tolmetin. Anti-inflammatory agents also include Cox-2 inhibitors, including, but not limited to, celecoxib, apricoxib, robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and firocoxib. In some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., LYT-100, e.g., a compound listed in Table 1, and etodolac, famotidine, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumisole, cimicoxib, rofecoxib, mavacoxib, methadone ... and one or more anti-inflammatory agent(s) selected from the group consisting of pirfenidone, ibuprofen, and firocoxib. For example, in some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, and ibuprofen.

[0415] In some embodiments, compositions comprise deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, one or more anti-T cell agent(s), and optionally one or more anti-angiotensin agent(s). In some embodiments, compositions comprise deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab, and optionally one or more anti-angiotensin agent(s). In some embodiments, the one or more anti-angiotensin agent(s) are selected from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099. For example, in some embodiments, a composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, tacrolimus, and one or more anti-angiotensin agent(s), e.g., captopril. In another example, in some embodiments, a composition includes deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, teriflunomide, and one or more anti-angiotensin agent(s), e.g., captopril.

[0416] In some embodiments, compositions comprise deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, one or more anti-T cell agent(s), and optionally one or more anti-inflammatory agent(s). In some embodiments, compositions comprise deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, one or more anti-T cell agent(s) selected from tacrolimus, teriflunomide, leflunomide, cyclosporine, pimecrolimus, denileukin diftitox, and basiliximab, and one or more anti-inflammatory agent(s). In some embodiments, the one or more anti-inflammatory agent(s) are selected from etodolac, famotidine, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and firocoxib. For example, in some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., LYT-100, e.g., a compound listed in Table 1, including tacrolimus, and ibuprofen. In another example, in some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, teriflunomide, and ibuprofen.

[0417] In some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, one or more anti-TGF-β1 agent(s), and optionally one or more anti-angiotensin agent(s). In some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, one or more anti-TGF-β1 agent(s). Compounds of Formula I, e.g., compounds listed in Table 1, including LYT-100, one or more anti-TGF-β1 agent(s) selected from LY550410, LY580276, SB-505124, or galunisertib (LY2157299 monohydrate), e.g., deuterium-enriched pirfenidone other than LYT-100, e.g., as described herein, and optionally one or more anti-angiotensin agent(s). In some embodiments, the anti-angiotensin agent(s) are selected from captopril, zofenopril, enalapril, lisinopril, ramipril, quinapril, perindopril, benazepril, imidapril, trandolapril, cilazapril, fosinopril, losartan, irbesartan, olmesartan, candesartan, telmisartan, valsartan, fimasartan, diminazene aceturate, xanthenone, and AVE 099. For example, in some embodiments, a composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, one or more anti-TGF-β1 agent(s), e.g., deuterated pirfenidone in a second form other than LYT-100, and one or more anti-angiotensin agent(s), e.g., captopril.

[0418] In some embodiments, the compositions comprise deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, one or more TGF-β1 agent(s), and optionally one or more anti-inflammatory agent(s). In some embodiments, the compositions comprise deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including LYT-100, one or more anti-TGF-β1 agent(s) selected from LY550410, LY580276, SB-505124, (LY2157299 monohydrate), deuterium-enriched pirfenidone other than LYT-100, e.g., as described herein, and one or more anti-inflammatory agent(s). In some embodiments, the one or more anti-inflammatory agent(s) is selected from etodolac, famotidine, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lansoprazole, mefenamic acid, meloxicam, misoprostol, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, apricoxib, robenacoxib, valdecoxib, anitrazafen, tilmacoxib, flumizole, cimicoxib, rofecoxib, mavacoxib, and firocoxib. For example, in some embodiments, the composition comprises deuterium-enriched pirfenidone, e.g., a compound of Formula I, e.g., a compound listed in Table 1, including a compound of Formula 1, e.g., a compound listed in Table 1, including LYT-100, and one or more anti-...

Claims

1. 1. A method of treating edema comprising administering to a subject in need thereof: 【Chemistry 1】 or a pharma- ceutical acceptable salt thereof, In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and R １１ is selected from hydrogen and deuterium; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８、 R ９ , R １０ and R １１ At least one of R is deuterium; ７ , R ８ , R ９ , R １０ , and R １１ If is deuterium, then R １ , R ２ , R ３ , R ４ , R ５ , and R ６ at least one of is deuterium, The method wherein edema is treated in said subject.

2. The deuterium-enriched pirfenidone has the structure: 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof.

3. 3. The method of claim 1 or 2, wherein the edema is lymphedema.

4. 4. The method of claim 3, wherein the lymphedema is secondary lymphedema.

5. 13. The method of any preceding claim, wherein the subject has been treated for cancer and the lymphedema is associated with the treatment or diagnosis of said cancer.

6. 10. The method of any preceding claim, wherein the subject has breast cancer-related arm lymphedema.

7. 10. The method of any preceding claim, wherein the subject has mild to moderate breast cancer-related lymphedema.

8. 13. The method of any preceding claim, wherein the subject is undergoing or has undergone chemotherapy or radiation therapy.

9. 2. The method of any preceding claim, wherein at least one of the positions designated as D independently has a deuterium enrichment of about 95% or greater.

10. 2. The method of any preceding claim, wherein at least one of said positions designated as D independently has a deuterium enrichment of about 98% or greater.

11. 2. The method of any preceding claim, wherein at least one of said positions designated as D independently has a deuterium enrichment of about 99% or greater.

12. 13. The method of any of the preceding claims, wherein the deuterium-enriched pirfenidone is administered orally in a total daily dose of 250-2500 mg.

13. 13. The method of claim 12, wherein the deuterium-enriched pirfenidone is administered orally in a total daily dose of 500-1500 mg.

14. 14. The method of claim 13, wherein the deuterium-enriched pirfenidone is administered orally in a total daily dose of 750-1000 mg.

15. 14. The method of claim 13, wherein the deuterium-enriched pirfenidone is administered orally twice daily at a total daily dose of 1500 mg.

16. 14. The method of claim 13, wherein the deuterium-enriched pirfenidone is administered orally twice daily at a total daily dose of 1000 mg.

17. 14. The method of claim 13, wherein the deuterium-enriched pirfenidone is administered orally twice daily at a total daily dose of 500 mg.

18. 14. The method of claim 13, wherein the deuterium-enriched pirfenidone is administered orally once daily at a total daily dose of 1500 mg.

19. 14. The method of claim 13, wherein the deuterium-enriched pirfenidone is administered orally once daily at a total daily dose of 1000 mg.

20. 14. The method of claim 13, wherein the deuterium-enriched pirfenidone is administered orally once daily at a total daily dose of 750 mg.

21. 14. The method of claim 13, wherein the deuterium-enriched pirfenidone is administered orally once daily at a total daily dose of 500 mg.

22. 13. The method of any of the preceding claims, wherein the deuterium-enriched pirfenidone is administered with food.

23. 13. The method of any of the preceding claims, wherein the deuterium-enriched pirfenidone is administered without food.

24. 13. The method of any of the preceding claims, wherein the deuterium-enriched pirfenidone is in tablet form.

25. 1. A method of treating interstitial lung disease (ILD), comprising administering to a subject in need thereof a compound having the structure: 【Chemistry 3】 or a pharma- ceutical acceptable salt thereof, In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and R １１ is selected from hydrogen and deuterium; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ At least one of R is deuterium; ７ , R ８ , R ９ , R １０ , and R １１ If is deuterium, then R １ , R ２ , R ３ , R ４ , R ５ , and R ６ at least one of is deuterium, The method wherein ILD is treated in said subject.

26. The deuterium-enriched pirfenidone has the structure: 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

27. 27. The method of claim 25 or 26, wherein the ILD is idiopathic pulmonary fibrosis (IPF).

28. 28. The method of any one of claims 25 to 27, wherein at least one of the positions designated as D independently has a deuterium enrichment of about 95% or greater.

29. 29. The method of any one of claims 25 to 28, wherein at least one of said positions designated as D independently has a deuterium enrichment of about 98% or greater.

30. 30. The method of any one of claims 25 to 29, wherein at least one of said positions designated as D independently has a deuterium enrichment of about 99% or greater.

31. The method of any one of claims 25 to 30, wherein the deuterium-enriched pirfenidone is administered orally in a total daily dose of 250 to 2500 mg.

32. The method of any one of claims 25 to 30, wherein the deuterium-enriched pirfenidone is administered orally in a total daily dose of 500 to 1500 mg.

33. The method of any one of claims 25 to 30, wherein the deuterium-enriched pirfenidone is administered orally in a total daily dose of 750 to 1000 mg.

34. The deuterium-enriched pirfenidone is administered orally at a total daily dose of 1500 mg. The method according to any one of claims 25 to 30.

35. The method of any one of claims 25 to 30, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 1000 mg.

36. The method of any one of claims 25 to 30, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 500 mg.

37. The method of any one of claims 25 to 30, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 1500 mg.

38. The method of any one of claims 25 to 30, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 1000 mg.

39. The method of any one of claims 25 to 30, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 750 mg.

40. The method of any one of claims 25 to 30, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 500 mg.

41. The method of any one of claims 25 to 40, wherein the deuterium-enriched pirfenidone is administered with food.

42. The method of any one of claims 25 to 40, wherein the deuterium-enriched pirfenidone is administered without food.

43. The method of any one of claims 25 to 42, wherein the deuterium-enriched pirfenidone is in tablet form.

44. 1. A method of treating a fibrotic disorder or a collagen infiltration disorder, comprising administering to a subject in need thereof a compound having the structure: 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof, In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and R １１ is selected from hydrogen and deuterium; R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ At least one of R is deuterium; ７ , R ８ , R ９ , R １０ , and R １１ If is deuterium, then R １ , R ２ , R ３ , R ４ , R ５ , and R ６ at least one of is deuterium, The fibrotic disorder or collagen infiltration disorder is treated in the subject.

45. The deuterium-enriched pirfenidone has the structure: 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof.

46. 46. ​​The method of any one of claims 44-45, wherein at least one of the positions designated as D independently has a deuterium enrichment of about 95% or greater.

47. 47. The method of claim 46, wherein at least one of the positions designated as D independently has a deuterium enrichment of about 98% or greater.

48. 48. The method of claim 47, wherein at least one of the positions designated as D independently has a deuterium enrichment of about 99% or greater.

49. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally in a total daily dose of 250-2500 mg.

50. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally in a total daily dose of 500-1500 mg.

51. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally in a total daily dose of 750-1000 mg.

52. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 1500 mg.

53. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 1000 mg.

54. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 500 mg.

55. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 1500 mg.

56. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 1000 mg.

57. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 750 mg.

58. 49. The method of any one of claims 44-48, wherein the deuterium-enriched pirfenidone is administered orally at a total daily dose of 500 mg.

59. Any of claims 44 to 58, wherein the deuterium-enriched pirfenidone is administered with food. The method according to any one of claims 1 to 5.

60. 59. The method of any one of claims 44-58, wherein the deuterium-enriched pirfenidone is administered without food.

61. 61. The method of any one of claims 44 to 60, wherein the deuterium-enriched pirfenidone is in tablet form.

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