Compositions for achieving effective dose levels of mtor inhibitors

Abstract

Provided herein are compositions and methods for treating autoimmune, alloimmune, inflammatory, aging-related, and cancer-related conditions.

Description

COMPOSITIONS FOR ACHIEVING EFFECTIVE DOSE LEVELS OF MTOR INHIBITORSFIELD OF TECHNOLOGY

[0001] The present disclosure provides, among other things, methods of administering an mTOR inhibitor (e.g. sirolimus, which is also known as rapamycin) in combination with a cytochrome p450 enzyme inhibitor (e.g. ritonavir) to achieve a blood level correlated with effective inhibition of mTOR complexes and limited adverse effects. In some embodiments, methods and compositions described herein are useful for alleviating, slowing, or preventing the onset of autoimmune, alloimmune, inflammatory, cancer-related, or aging-related conditions.CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and benefit of U.S. Application No. 63 / 580,027, filed September 1, 2023, the entire contents of which arc hereby incorporated by reference.BACKGROUND

[0003] mTOR inhibitors are used as treatments for a variety of alloimmune, autoimmune, inflammatory, and cancer-related conditions. They have also shown promise as treatments for conditions associated with aging [Wilkinson et al. 2012], However, their use is limited by the frequency of adverse effects associated with them, as well as the frequency with which patients are required to take their doses [Sofrianadou et al., 2011].SUMMARY

[0004] mTOR inhibitors are often used as treatments for conditions related to the immune system, including, for example, rapamycin for renal transplantation [Knechtle et al., 2003] or everolimus to prevent rejection in liver transplantation [Levy et al., 2006]. These treatments, however, are limited by the adverse effects associated with mTOR inhibitors. Rapamycin, for example, is associated with dyslipidemia [Kassike et al., 2008], while everolimus is associated with diabetes mellitus [Ohyama et al., 2022]. Because mTOR inhibitors have a narrow therapeutic index, meaning that the blood level of the mTOR inhibitor needed to be effective in a given disease is close to the blood level associated with overdose and adverse effects, mTOR inhibitors are often“therapeutically dose monitored” when given to patients, meaning that patients need to have their blood levels of the mTOR inhibitor monitored through laboratory tests. Rapamycin, for example, is typically dosed at 2 mg once per day in human adults to reach an effective concentration while avoiding adverse effects.

[0005] Applicant surprisingly discovered that administration of an mTOR inhibitor (e.g., rapamycin) in combination with a cytochrome p450 inhibitor (e.g., ritonavir) provides for more effective and consistent treatment at lower doses of the mTOR inhibitor. The synergistic effect of provided combination therapies allow for less frequent administration, lower dose amounts, and reduced pharmacokinetic variability for subjects receiving an mTOR inhibitor (e.g., rapamycin).

[0006] It is currently understood that mTOR inhibitors are metabolized via cytochrome p450 enzymes. Without being bound by theory, the present disclosure encompasses an insight that inhibitors of cytochrome p450, when administered simultaneously with an mTOR inhibitor, can result in a more consistent achievement of dose levels associated with efficacy in treating certain diseases, such as the 5-15 ng / mL blood level associated with safe, effective use of rapamycin in treating vascular anomalies [Nadal et al., 2016].

[0007] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition comprising administering to a subject an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, and a cytochrome p 450 inhibitor, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the present disclosure provides a method for achieving target dose levels of mTOR inhibitors, the method comprising administering an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, and a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof, to a subject or biological sample.

[0009] In some embodiments, the disclosure provides a method of preventing adverse effects associated with the metabolism of mTOR inhibitors, the method comprising contacting mTOR with a mTOR inhibitor, or a pharmaceutically acceptable salt thereof; and contacting cytochrome p450 with a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, an mTOR inhibitor is selected from the group consisting of rapamycin (also known as sirolimus), everolimus, temsirolimus, ridaforolimus, umirolimus, zotarolimus, and analogs or derivatives thereof. In some embodiments, an mTOR inhibitor is rapamycin.

[0011] In some embodiments, an mTOR inhibitor is administered orally at a dose of about 0.6 mg per day.

[0012] In some embodiments, a cytochrome p450 inhibitor is amiodarone, chloroquine, cimetidine, clomipramine, diphenhydramine, fluoxetine, fluphenazine, haloperidol, paroxetine, perphenazine, propafenone, propoxyphene, quinacrine, quinidine, sertraline, terbinafine, thioridazine, amprenavir, clarithromycin, danazol, delavirdine, diltiazem, efavirenz, erythromycin, ethinylestradiol, fluconazole, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelflnavir, quinine, ritonavir, saquinavir, synercid, troleandomycin, verapamil, boceprevir, telithromycin, ceritinib, mibefradil, ribociclib, tucatinib, chloramphenicol, posaconazole, voriconazole, cobicistat, aprepitant, ciprofloxacin, conivaptan, crizotinib, rutin, tofisopam, miconazole, bergamottin, cyclosporine, donedarone, imatinib, berberine, buprenorphine, cafestol, cilostazol, fosaprepitant, lomitapide, orphenadrine, omeprazole, quercetin, ranitidine, ranolazine, tacrolimus, ticagrelor, valproic acid, amlodipine, azithromycin, bergaptol, cannabidiol, dithiocarbamate, mifepristone, norfloxacin, gestodene, niacin, niacinamide, isoniazid, or zafirlukast. In some embodiments, a cytochrome p450 inhibitor is ritonavir or cobicistat. In some embodiments, a cytochrome p450 inhibitor is ritonavir. In some embodiments, a cytochrome p450 inhibitor is cobicistat.

[0013] In some embodiments, a cytochrome p450 inhibitor is administered at a dose of about 20 mg / day.

[0014] In certain aspects, the present disclosure provides a method of achieving target dose levels of an mTOR inhibitor, the method consisting of identifying a subject with a condition that would benefit from mTOR inhibition; administering to said subject an mTOR inhibitor, or a pharmaceutically acceptable salt thereof; and a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments of provided methods, a cytochrome p450 inhibitor and an mTOR inhibitor are administered to a subject once daily. In some embodiments, a cytochrome p450 inhibitor and an mTOR inhibitor are administered to a subject once per week. In some embodiments, a cytochrome p450 inhibitor and an mTOR inhibitor are administered to a subject once every other week. In some embodiments, a cytochrome p450 inhibitor and an mTOR inhibitor are administered to a subject once per month.

[0016] In some embodiments of provided methods, a subject is a human. In some embodiments, a subject is a dog or a cat. In some embodiments, a subject is a dog. In some embodiments, a subject is a cat.

[0017] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a subject comprising administering to said subject an mTOR inhibitor, or a pharmaceutically acceptable salt thereof; and a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is about ten times greater in the subject relative to a subject that is administered an mTOR inhibitor alone (e.g., as measured in hrxng / mL) . In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is greater than about 150 hrxng / mL. In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is greater than about 300 hrxng / mL. In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is greater than about 500 hrxng / mL. In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is greater than about 1000 hrxng / mL.

[0018] In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a Cmax of the mTOR inhibitor that is about ten times greater in the subject relative to a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a Cmax of the mTOR inhibitor that is greater than about 5 ng / mL. In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a Cmax of the mTOR inhibitor that is greater than about 15 ng / mL. In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is greater than about 500 hrxng / mL; and / or a Cmax of the mTOR inhibitor that is greater than about 5 ng / mL.

[0019] In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a half-life of the mTOR inhibitor that is greater in the subject relative to a subject that is administered an mTOR inhibitor alone. In some embodiments,administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a half-life of the mTOR inhibitor that is between 1 to 2 times greater in the subject relative to a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a half-life of the mTOR inhibitor that is about 1.3 times to about 1.8 times greater in the subject relative to a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a half-life of the mTOR inhibitor that is about 1.0 times, about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, or about 2.0 times greater in the subject relative to a subject that is administered an mTOR inhibitor alone.

[0020] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a population of subjects, comprising administering to each subject within the population an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, and a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a population of subjects, comprising administering to each subject within the population an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, and a cytochrome p 450 inhibitor, or a pharmaceutically acceptable salt thereof, wherein pharmacokinetic variability between the subjects in the population is reduced compared to a population of subjects that is administered an mTOR inhibitor alone.BRIEF DESCRIPTION OF THE DRAWING

[0021] FIG. 1 provides a graph of the whole blood concentration of rapamycin in subjects over time treated with rapamycin alone or a combination of ritonavir + rapamycin in Period 1 of a two- part study.

[0022] FIG. 2 provides a graph of the whole blood concentration of rapamycin in subjects over time treated with rapamycin alone or a combination of ritonavir + rapamycin in Period 2 of a two- part study.DETAILED DESCRIPTION mTOR Inhibitors

[0023] mTOR inhibitors are widely used for autoimmune, alloimmune, inflammatory, and cancer- related conditions. Rapamycin (also known as sirolimus), for example, is used to prevent organ transplant rejection, an alloimmune condition, as well as to prevent restenosis, an autoimmune condition. Without being bound by theory, it is understood that the mechanism by which mTOR inhibitors are able to treat these conditions is to bind to the cytosolic protein FK-binding protein 12, inhibiting the mTOR pathway by directly binding to mTOR Complex 1. This lowers the activity of T cells, an important type of white blood cell, as well as proliferative responses caused by several cytokines. This can also have downregulating effects on the immune system at large [Seghal, 1998],

[0024] mTOR inhibitors have also been used to treat cancer. Everolimus, for example, has been used to treat advanced kidney cancer [Atkins et al., 2009], Without being bound by theory, it is understood that the mechanism by which mTOR inhibitors treat cancer is by preventing the downstream phosphorylation of S6K1 and 4EBP1, leading to a late blockage of the Gl / S cell cycle[Atkins et al., 2009],

[0025] mTOR inhibitors have also shown promise in aging-related conditions. Rapamycin, for example, has been used to slow aging in mice [Wilkinson et al., 2012], Without being bound by theory, it is understood that the mechanism by which mTOR inhibitors treat aging is by preventing the initiation of the senescence-associated secretory phenotype [Yessenkyzy et al., 2020].

[0026] High levels of mTOR inhibitors, however, can also lead to adverse effects. For example, it was found that rapamycin blood concentration of greater than 15 ng / mL can lead to adverse effects in organ transplantation, including hyperlipidemia. Unfortunately, the therapeutic window for effectiveness of rapamycin to prevent organ rejection in transplant patients is 5-15 ng / mL, which affords only a very narrow therapeutic window for rapamycin to be effective [Yatscoff et al., 1995]. Similarly narrow therapeutic windows are found with other mTOR inhibitors.

[0027] Previously, it has been found that administration of rapamycin with a 3D regimen comprising ritonavir, ombitasvir, paritaprevir, and dasabuvir resulted in an increase in rapamycin exposure, but the authors warned against co-administration if dosing could not be carefully managed. [Zha et al., 2022],

[0028] Others have attempted to improve the pharmacokinetic profile of an mTOR inhibitor by designing new mTOR inhibitors that arc derivatives (or otherwise structurally similar) to rapamycin, such as everolimus [Moes et al., 2015]. Such a solution limits the available therapies that can be used to treat patients.

[0029] The present disclosure overcomes the problems associated with the approaches summarized above, and in some embodiments, provides solutions contrary to the assumptions of this previous work by providing, among other things, therapeutic regimens comprising administration of both a cytochrome p450 inhibitor and an mTOR inhibitor deliberately for the treatment of certain diseases, disorders, and conditions. For example, in some embodiments, the present disclosure encompasses an insight that cytochrome p450 inhibitors, if administered in combination with (e.g., simultaneously or near simultaneously) with an mTOR inhibitor, the pharmacokinetics of the mTOR inhibitor can be improved, allowing for more consistent achievement of a target dose level.

[0030] The presently claimed methods and compositions are useful for alleviating a variety of diseases, disorders, and conditions, such as inflammatory, alloimmune, autoimmune, aging- related, and / or cancer-related conditions. In some embodiments, the disease is feline chronic kidney disease.

[0031] The present disclosure encompasses an insight that a combination of inhibition of mTOR and inhibition of cytochrome p450 can alleviate inflammation, alloimmunity, and autoimmunity disease, disorder, or conditions, associated with, in some embodiments, high levels of lymphocytes. The present disclosure also encompasses an insight that a combination of inhibition of mTOR and inhibition of cytochrome p450 can alleviate cancer-related conditions as well as aging-related conditions.Compositions

[0032] In some embodiments, methods described herein include the manufacture and use of pharmaceutical compositions and medicaments that include compounds identified by a method described herein as active ingredients. Also included are the pharmaceutical compositions themselves.

[0033] In one or more embodiments, an mTOR inhibitor is selected from the group consisting of rapamycin (also known as sirolimus), everolimus, temsirolimus, ridaforolimus, umirolimus, andzotarolimus, and analogs or derivatives thereof. In some embodiments, an mTOR inhibitor is rapamycin. In some embodiments, an mTOR inhibitor is cvcrolimus. In some embodiments, an mTOR inhibitor is temsirolimus. In some embodiments, an mTOR inhibitor is ridaforolimus. In some embodiments, an mTOR inhibitor is umirolimus. In some embodiments, an mTOR inhibitor is zotarolimus

[0034] In some embodiments, a cytochrome p450 inhibitor is amiodarone, chloroquine, cimetidine, clomipramine, diphenhydramine, fluoxetine, fluphenazine, haloperidol, paroxetine, perphenazine, propafenone, propoxyphene, quinacrine, quinidine, sertraline, terbinafine, thioridazine, amprenavir, clarithromycin, danazol, delavirdine, diltiazem, efavirenz, erythromycin, ethinylestradiol, fluconazole, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, quinine, ritonavir, saquinavir, synercid, troleandomycin, verapamil, boceprevir, telithromycin, ceritinib, mibefradil, ribociclib, tucatinib, chloramphenicol, posaconazole, voriconazole, cobicistat, aprepitant, ciprofloxacin, conivaptan, crizotinib, rutin, tofisopam, miconazole, bergamottin, cyclosporine, donedarone, imatinib, berberine, buprenorphine, cafestol, cilostazol, fosaprepitant, lomitapide, orphenadrine, omeprazole, quercetin, ranitidine, ranolazine, tacrolimus, ticagrelor, valproic acid, amlodipine, azithromycin, bergaptol, cannabidiol, dithiocarbamate, mifepristone, norfloxacin, gestodene, niacin, niacinamide, isoniazid, or zafirlukast. In some embodiments, a cytochrome p450 inhibitor is ritonavir. In some embodiments, a cytochrome p450 inhibitor is amiodarone. In some embodiments, a cytochrome p450 inhibitor is chloroquine. In some embodiments, a cytochrome p450 inhibitor is cimetidine. In some embodiments, a cytochrome p450 inhibitor is clomipramine. In some embodiments, a cytochrome p450 inhibitor is diphenhydramine. In some embodiments, a cytochrome p450 inhibitor is fluoxetine. In some embodiments, a cytochrome p450 inhibitor is fluphenazine. In some embodiments, a cytochrome p450 inhibitor is haloperidol. In some embodiments, a cytochrome p450 inhibitor is paroxetine. In some embodiments, a cytochrome p450 inhibitor is perphenazine. In some embodiments, a cytochrome p450 inhibitor is propafenone. In some embodiments, a cytochrome p450 inhibitor is propoxyphene. In some embodiments, a cytochrome p450 inhibitor is quinacrine. In some embodiments, a cytochrome p450 inhibitor is quinidine. In some embodiments, a cytochrome p450 inhibitor is sertraline. In some embodiments, a cytochrome p450 inhibitor is terbinafine. In some embodiments, a cytochrome p450 inhibitor is thioridazine. In some embodiments, a cytochrome p450 inhibitor isamiodarone. In some embodiments, a cytochrome p450 inhibitor is amprenavir. In some embodiments, a cytochrome p450 inhibitor is clarithromycin. In some embodiments, a cytochrome p450 inhibitor is danazol. In some embodiments, a cytochrome p450 inhibitor is delavirdine. In some embodiments, a cytochrome p450 inhibitor is diltiazem. In some embodiments, a cytochrome p450 inhibitor is efavirenz. In some embodiments, a cytochrome p450 inhibitor is erythromycin. In some embodiments, a cytochrome p450 inhibitor is ethinylestradiol. In some embodiments, a cytochrome p450 inhibitor is fluconazole. In some embodiments, a cytochrome p450 inhibitor is fluvoxamine. In some embodiments, a cytochrome p450 inhibitor is grapefruit juice. In some embodiments, a cytochrome p450 inhibitor is indinavir. In some embodiments, a cytochrome p450 inhibitor is itraconazole. In some embodiments, a cytochrome p450 inhibitor is ketoconazole. In some embodiments, a cytochrome p450 inhibitor is nefazodone. In some embodiments, a cytochrome p450 inhibitor is nelfinavir. In some embodiments, a cytochrome p450 inhibitor is quinine. In some embodiments, a cytochrome p450 inhibitor is saquinavir. In some embodiments, a cytochrome p450 inhibitor is Synercid. In some embodiments, a cytochrome p450 inhibitor is troleandomycin. In some embodiments, a cytochrome p450 inhibitor is verapamil. In some embodiments, a cytochrome p450 inhibitor is zafirlukast. In some embodiments, a cytochrome p450 inhibitor is ritonavir or cobicistat. In some embodiments, a cytochrome p450 inhibitor is cobicistat.

[0035] In some embodiments, an mTOR inhibitor is rapamycin and a cytochrome p450 inhibitor is ritonavir. In some embodiments, an mTOR inhibitor is rapamycin and a cytochrome p450 inhibitor is cobicistat.

[0036] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, and a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, pharmaceutical compositions described herein include other compounds, drugs, and / or agents used for the treatment of alloimmune, autoimmune, inflammatory, aging-related, and cancer-related conditions. For example, in some instances, compositions disclosed herein can be combined with one or more (e.g., one, two, three, four, five, or less than ten) compounds.

[0038] As described herein, a pharmaceutical composition described herein is formulated or adapted for administration to a subject via any route, e.g., any route approved by the Food andDrug Administration (FDA). Exemplary methods are described in the FDA's CDER Data Standards Manual, version number 004 (which is available at fda.give / cder / dsm / DRG / drg00301.htm). Pharmaceutical compositions described herein can be formulated for oral, parenteral, or transdermal delivery. Compounds of the present disclosure may also be combined with other pharmaceutical agents. In some embodiments, the present disclosure provides a pharmaceutical composition comprising an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner or adjuvant.

[0039] In some embodiments, the present disclosure provides kits that include one or more compositions comprising rapamycin and / or ritonavir (in separate compositions or in a single composition). The kit may also include instructions for the physician and / or patient, syringes, needles, box, bottles, vials, etc.

[0040] In some embodiments, methods described herein comprise administration of an effective amount of a composition or compositions comprising an mTOR inhibitor and a cytochrome p450 inhibitor (as part of a single composition, or as separate compositions), as described above. The terms “effective amount” and “effective to treat,” as used herein, refer to an amount or a concentration of one or more drugs for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome.

[0041] In some embodiments, therapies are administered as separate pharmaceutical compositions, for example, a first pharmaceutical composition comprising an mTOR inhibitor (e.g., rapamycin) and a pharmaceutically acceptable carrier, adjuvant and / or vehicle, and a second pharmaceutical composition comprising a cytochrome p450 inhibitor (e.g., ritonavir) and a pharmaceutically acceptable carrier, adjuvant and / or vehicle. In some embodiments, therapies are administered as a single pharmaceutical composition, for example, a pharmaceutical composition comprising an mTOR inhibitor (e.g., rapamycin), a cytochrome p450 inhibitor (e.g., ritonavir), and a pharmaceutically acceptable carrier, adjuvant and / or vehicle. In some embodiments, compositions described herein further comprise one or more additional therapeutic agents in an effective amount for achieving a modulation of disease or disease symptoms.

[0042] The term “pharmaceutically acceptable carrier or adjuvant” or “pharmaceutically acceptable carrier, adjuvant and / or vehicle” refers to a carrier, adjuvant, or vehicle that may beadministered to a patient, together with a compound of this present disclosure, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. As used herein the language “pharmaceutically acceptable carrier” includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

[0043] Compositions are typically formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.

[0044] Compositions can be in the form of a solution or powder for inhalation and / or nasal administration. Such compositions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0045] Compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions and / or emulsions arc administered orally, the active ingredient may be suspended or dissolved in an oily phase combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0046] Alternatively or in addition, pharmaceutical compositions can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0047] In some instances, therapeutic compositions disclosed herein can be formulated for sale in the US, import into the US, and / or export from the US.

[0048] Pharmaceutical compositions described herein can be included in a container, pack, or dispenser together with instructions for administration.Dosage

[0049] In some embodiments, the present disclosure provides a method of treating an autoimmune, alloimmune, inflammatory, aging-related, or cancer-related condition comprising administering to a subject an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, and a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, an mTOR inhibitor and a cytochrome p450 inhibitor are administered contemporaneously.

[0051] In some embodiments, an mTOR inhibitor and a cytochrome p450 inhibitor are administered sequentially.

[0052] In some aspects of the present disclosure, an mTOR inhibitor and a cytochrome p450 inhibitor are individually administered (i.e., separate dosage forms). In some embodiments, an mTOR inhibitor and a cytochrome p450 inhibitor are administered as a single dosage form.

[0053] In some embodiments, an mTOR inhibitor is administered in an amount that is from about 0.2 mg to about 16 mg per day. In some embodiments, an mTOR inhibitor is administered in an amount that is from about 0.2 mg to about 1 mg per day. In some embodiments, the mTOR inhibitor is administered in an amount of about 0.2 mg / day, 0.5 mg / day, about 0.6 mg / day, about 1 mg / day, about 4 mg / day, about 8 mg / day, or about 16 mg / day. In some embodiments, an mTORinhibitor is administered in an amount that is about 0.2 mg per day. In some embodiments, an mTOR inhibitor is administered in an amount that is about 0.6 mg per day. In some embodiments, an mTOR inhibitor is administered in an amount that is about 0.8 mg per day. In some embodiments, an mTOR inhibitor is administered in an amount that is about 1.0 mg per day.

[0054] In some embodiments, an mTOR inhibitor is administered in an amount that is from about 0.2 mg to about 16 mg per week. In some embodiments, an mTOR inhibitor is administered in an amount that is from about 0.2 mg to about 1 mg per week. In some embodiments, the mTOR inhibitor is administered in an amount that is about 0.2 mg / week, 0.5 mg / week, about 0.6 mg / week, about 1 mg / week, about 4 mg / week, about 8 mg / week, or about 16 mg / week. In some embodiments, an mTOR inhibitor is administered in an amount that is about 0.2 mg per week. In some embodiments, an mTOR inhibitor is administered in an amount that is about 0.6 mg per week. In some embodiments, an mTOR inhibitor is administered in an amount that is about 0.8 mg per week. In some embodiments, an mTOR inhibitor is administered in an amount that is about 1.0 mg per week.

[0055] In some embodiments, an mTOR inhibitor is administered in an amount that is from about 0.2 mg to about 16 mg every other week (i.e., biweekly). In some embodiments, an mTOR inhibitor is administered in an amount that is from about 0.2 mg to about 1 mg every other week. In some embodiments, the mTOR inhibitor is administered in an amount that is about 0.2 mg / biweekly, 0.5 mg / biweekly, about 0.6 mg / biweekly, about 1 mg / biweekly, about 4 mg / biweekly, about 8 mg / biweekly, or about 16 mg / biweekly. In some embodiments, an mTOR inhibitor is administered in an amount that is about 0.2 mg every other week. In some embodiments, an mTOR inhibitor is administered in an amount that is about 0.6 mg every other week. In some embodiments, an mTOR inhibitor is administered in an amount that is about 0.8 mg every other week. In some embodiments, an mTOR inhibitor is administered in an amount that is about 1.0 mg every other week.

[0056] In some embodiments, an mTOR inhibitor is rapamycin. In some embodiments, rapamycin is administered in an amount that is from about 0.2 mg to about 16 mg per day. In some embodiments, rapamycin is administered in an amount that is from about 0.2 mg to about 1 mg per day. In some embodiments, the mTOR inhibitor is administered in an amount of about 0.2 mg / day, 0.5 mg / day, about 0.6 mg / day, about 1 mg / day, about 4 mg / day, about 8 mg / day, or about 16 mg / day. In some embodiments, rapamycin is administered in an amount that is about 0.2 mgper day. In some embodiments, rapamycin is administered in an amount that is about 0.6 mg per day. In some embodiments, rapamycin is administered in an amount that is about 0.8 mg per day. In some embodiments, rapamycin is administered in an amount that is about 1.0 mg per day.

[0057] In some embodiments, rapamycin is administered in an amount that is from about 0.2 mg to about 16 mg per week. In some embodiments, rapamycin is administered in an amount that is from about 0.2 mg to about 1 mg per week. In some embodiments, the mTOR inhibitor is administered in an amount of that is about 0.2 mg / week, 0.5 mg / week, about 0.6 mg / week, about1 mg / week, about 4 mg / week, about 8 mg / week, or about 16 mg / week. In some embodiments, rapamycin is administered in an amount that is about 0.2 mg per week. In some embodiments, rapamycin is administered in an amount that is about 0.6 mg per week. In some embodiments, rapamycin is administered in an amount that is about 0.8 mg per week. In some embodiments, rapamycin is administered in an amount that is about 1.0 mg per week.

[0058] In some embodiments, rapamycin is administered in an amount that is from about 0.2 mg to about 16 mg every other week (i.e., biweekly). In some embodiments, rapamycin is administered in an amount that is from about 0.2 mg to about 1 mg every other week. In some embodiments, the mTOR inhibitor is administered in an amount that is about 0.2 mg / biweekly, 0.5 mg / biweekly, about 0.6 mg / biweekly, about 1 mg / biweekly, about 4 mg / biweekly, about 8 mg / biweekly, or about 16 mg / biweekly. In some embodiments, rapamycin is administered in an amount that is about 0.2 mg every other week. In some embodiments, rapamycin is administered in an amount that is about 0.6 mg every other week. In some embodiments, rapamycin is administered in an amount that is about 0.8 mg every other week. In some embodiments, rapamycin is administered in an amount that is about 1.0 mg every other week.

[0059] In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 5 mg / day to about 40 mg per day. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 10 mg per day. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 20 mg per day. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 40 mg per day. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 5 mg / day, about 10 mg / day, about 20 mg / day, or about 40 mg / day. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 5 mg per week to about 40 mg per week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 10 mgper week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 20 mg per week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 40 mg per week. In some embodiments, the cytochrome p450 inhibitor is administered in an amount that is about 5 mg / week, about 10 mg / week, about 20 mg / week, or about 40 mg / week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 5 mg every other week to about 40 mg every other week (i.e., is administered biweekly). In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 10 mg every other week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 20 mg every other week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 40 mg every other week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 5 mg every other week (i.e., is biweekly), about 10 mg every other week, about 20 mg every other week, or about 40 mg every other week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 10 mg every other week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 20 mg every other week. In some embodiments, a cytochrome p450 inhibitor is administered in an amount that is about 40 mg every other week.

[0060] In some embodiments, ritonavir is administered in an amount of that is about 5 mg / day, about 10 mg / day, about 20 mg / day, or about 40 mg / day. In some embodiments, the cytochrome p450 inhibitor is administered in an amount of that is about 5 mg / week, about 10 mg / week, about 20 mg / week, or about 40 mg / week. In some embodiments, ritonavir is administered in an amount that is about 5 mg every other week (i.e., is biweekly), about 10 mg every other week, about 20 mg every other week, or about 40 mg every other week.

[0061] As described herein, provided compounds can be administered separately or together, including as a part of a regimen of treatment.

[0062] In some embodiments, the mTOR inhibitor is rapamycin and the cytochrome p450 inhibitor is ritonavir. In some embodiments, rapamycin and ritonavir are individually administered (i.e., separate dosage forms). In some embodiments, rapamycin is administered in an amount of about 0.5 mg / day, about 0.6 mg / day, about 1 mg / day, about 4 mg / day, about 8 mg / day, or about 16 mg / day. In some embodiments, rapamycin is administered in an amount of about 0.5 mg / week, about 0.6 mg / week, about 1 mg / week, about 4 mg / week, about 8 mg / week, or about 16 mg / week.In some embodiments, ritonavir is administered in an amount of about 5 mg / day, about 10 mg / day, about 20 mg / day, or about 40 mg / day. In some embodiments, ritonavir is administered in an amount of about 5 mg / week, about 10 mg / week, about 20 mg / week, or about 40 mg / week. In some embodiments, ritonavir is administered in an amount of about 0.1 mg / kg of a subject’ s body weight per day, about 0.5 mg / kg of a subject’s body weight per day, about 1 mg / kg of a subject’s body weight per day, about 2 mg / kg of a subject’s body weight per day, or about 4 mg / kg of a subject’s body weight per day. Provided compounds can be administered separately or together, including as a part of a regimen of treatment.

[0063] The present disclosure further provides dosing regimens, such that an mTOR inhibitor and a cytochrome p450 inhibitor are administered, separately or together, as a single daily dosage, on a daily basis, a weekly basis or some other basis. Further, the patient may receive the specific dosage over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years and the like.

[0064] In some embodiments, an mTOR inhibitor and a cytochrome p450 inhibitor are administered once daily. In some embodiments, an mTOR inhibitor and a cytochrome p450 inhibitor are administered once every other day. In some embodiments, an mTOR inhibitor and a cytochrome p450 inhibitor are administered twice per week. In some embodiments, an mTOR inhibitor and a cytochrome p450 inhibitor are administered once per week. In some embodiments, an mTOR inhibitor and a cytochrome p450 inhibitor are administered once every other week. In some embodiments, an mTOR inhibitor and a cytochrome p450 inhibitor are administered once per month.

[0065] In some embodiments, the present disclosure provides a dosing regimen for treatment of a disease, disorder, or condition comprising administering to a subject an mTOR inhibitor is rapamycin and a cytochrome p450 inhibitor is ritonavir. In some embodiments, rapamycin and ritonavir are administered separately or together, as a single daily dosage, on a daily basis, a weekly basis or some other basis. In some embodiments, a subject may receive the dose of an mTOR inhibitor and a cytochrome p450 inhibitor over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years and the like.

[0066] In some embodiments, efficacy of a dosing regimen is determined by measuring AUC of a compound provided herein, such as an mTOR inhibitor, after administration to a subject. In some embodiments, efficacy of a dosing regimen is determined by measuring Cmax of a compound provided herein, such as an mTOR inhibitor, after administration to a subject. In some embodiments, efficacy of a dosing regimen is determined by measuring half-life of a compound provided herein, such as an mTOR inhibitor, after administration to a subject.

[0067] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides an AUC of the mTOR inhibitor that is about 150 hrxng / mL to about 1 00 hrxng / mL, about 150 hrxng / mL to about 1400 hrxng / mL, about 150 hrxng / mL to about 1300 hrxng / mL, about 150 hrxng / mL to about 1200 hrxng / mL, about 150 hrxng / mL to about 1100 hrxng / mL, about 150 hrxng / mL to about 1000 hrxng / mL, about 150 hrxng / mL to about 900 hrxng / mL, about 150 hrxng / mL to about 800 hrxng / mL, about 150 hrxng / mL to about 700 hrxng / mL, about 150 hrxng / mL to about 600 hrxng / mL, about 150 hrxng / mL to about 500 hrxng / mL, about 150 hrxng / mL to about 400 hrxng / mL, or about 150 hrxng / mL to about 300 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 300 hrxng / mL to about 1500 hrxng / mL, about 300 hrxng / mL to about 1400 hrxng / mL, about 300 hrxng / mL to about 1300 hrxng / mL, about 300 hrxng / mL to about 1200 hrxng / mL, about 300 hrxng / mL to about 1100 hrxng / mL, about 300 hrxng / mL to about 1000 hrxng / mL, about 300 hrxng / mL to about 900 hrxng / mL, about 300 hrxng / mL to about 800 hrxng / mL, about 300 hrxng / mL to about 700 hrxng / mL, about 300 hrxng / mL to about 600 hrxng / mL, about 300 hrxng / mL to about 500 hrxng / mL, or about 300 hrxng / mL to about 400 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 400 hrxng / mL to about 1500 hrxng / mL, about 400 hrxng / mL to about 1400 hrxng / mL, about 400 hrxng / mL to about 1300 hrxng / mL, about 400 hrxng / mL to about 1200 hrxng / mL, about 400 hrxng / mL to about 1100 hrxng / mL, about 400 hrxng / mL to about 1000 hrxng / mL, about 400 hrxng / mL to about 900 hrxng / mL, about 400 hrxng / mL to about 800 hrxng / mL, about 400 hrxng / mL to about 700 hrxng / mL, about 400 hrxng / mL to about 600 hrxng / mL, or about 400 hrxng / mL to about 500 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 500 hrxng / mL to about 1500 hrxng / mL, about 500 hrxng / mL to about 1400 hrxng / mL, about 500 hrxng / mL to about 1300 hrxng / mL, about 500 hrxng / mL to about 1200 hrxng / mL, about 500 hrxng / mL to about 1100 hrxng / mL, about 500 hrxng / mL to about 1000 hrxng / mL, about 500 hrxng / mL to about 900 hrxng / mL, about 500 hrxng / mL to about 800hrxng / mL, about 500 hrxng / mL to about 700 hrxng / mL, or about 500 hrxng / mL to about 600 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 600 hrxng / mL to about 1500 hrxng / mL, about 600 hrxng / mL to about 1400 hrxng / mL, about 600 hrxng / mL to about 1300 hrxng / mL, about 600 hrxng / mL to about 1200 hrxng / mL, about 600 hrxng / mL to about 1100 hrxng / mL, about 600 hrxng / mL to about 1000 hrxng / mL, about 600 hrxng / mL to about 900 hrxng / mL, about 600 hrxng / mL to about 800 hrxng / mL, or about 600 hrxng / mL to about 700 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 700 hrxng / mL to about 1500 hrxng / mL, about 700 hrxng / mL to about 1400 hrxng / mL, about 700 hrxng / mL to about 1300 hrxng / mL, about 700 hrxng / mL to about 1200 hrxng / mL, about 700 hrxng / mL to about 1100 hrxng / mL, about 700 hrxng / mL to about 1000 hrxng / mL, about 700 hrxng / mL to about 900 hrxng / mL, or about 700 hrxng / mL to about 800 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 800 hrxng / mL to about 1500 hrxng / mL, about 800 hrxng / mL to about 1400 hrxng / mL, about 800 hrxng / mL to about 1300 hrxng / mL, about 800 hrxng / mL to about 1200 hrxng / mL, about 800 hrxng / mL to about 1100 hrxng / mL, about 800 hrxng / mL to about 1000 hrxng / mL, or about 800 hrxng / mL to about 900 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 900 hrxng / mL to about 1500 hrxng / mL, about 900 hrxng / mL to about 1400 hrxng / mL, about 900 hrxng / mL to about 1300 hrxng / mL, about 900 hrxng / mL to about 1200 hrxng / mL, about 900 hrxng / mL to about 1100 hrxng / mL, or about 900 hrxng / mL to about 1000 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 1000 hrxng / mL to about 1500 hrxng / mL, about 1000 hrxng / mL to about 1400 hrxng / mL, about 1000 hrxng / mL to about 1300 hrxng / mL, about 1000 hrxng / mL to about 1200 hrxng / mL, or about 1000 hrxng / mL to about 1100 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 1100 hrxng / mL to about 1500 hrxng / mL, about 1100 hrxng / mL to about 1400 hrxng / mL, about 1100 hrxng / mL to about 1300 hrxng / mL, or about 1100 hrxng / mL to about 1200 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 1200 hrxng / mL to about 1500 hrxng / mL, about 1200 hrxng / mL to about 1400 hrxng / mL, or about 1200 hrxng / mL to about 1300 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 1300 hrxng / mL to about 1500 hrxng / mL, or about 1300 hrxng / mL to about 1400 hrxng / mL. In some embodiments, the AUC of the mTOR inhibitor is about 1400 hrxng / mL to about 1500 hrxng / mL.

[0068] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides an AUC of the mTOR inhibitor that is greater than about 150hrxng / mL, greater than about 300 hrxng / mL, greater than about 400 hrxng / mL, greater than about 500 hrxng / mL, greater than about 600 hrxng / mL, greater than about 700 hrxng / mL, greater than about 800 hrxng / mL, greater than about 900 hrxng / mL, greater than about 1000 hrxng / mL, greater than about 1100 hrxng / mL, greater than about 1200 hrxng / mL, greater than about 1300 hrxng / mL, greater than about 1400 hrxng / mL, or greater than about 1500 hrxng / mL. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides an AUC of the mTOR inhibitor that is about 150 hrxng / mL, about 300 hrxng / mL, about 400 hrxng / mL, about 500 hrxng / mL, about 600 hrxng / mL, about 700 hrxng / mL, about 800 hrxng / mL, about 900 hrxng / mL, about 1000 hrxng / mL, about 1100 hrxng / mL, about 1200 hrxng / mL, about 1300 hrxng / mL, about 1400 hrxng / mL, or about 1500 hrxng / mL.

[0069] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides an AUC of the mTOR inhibitor that is about two, about five, or about ten times greater in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides an AUC of the mTOR inhibitor that is about ten times greater in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides an AUC of the mTOR inhibitor that is about five times greater in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides an AUC of the mTOR inhibitor that is about two times greater in the subject than in a subject that is administered an mTOR inhibitor alone.

[0070] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a Cmax of the mTOR inhibitor that is about 5 ng / mL to about 100 ng / mL, about 5 ng / mL to about 90 ng / mL, about 5 ng / mL to about 80 ng / mL, about 5 ng / mL to about 70 ng / mL, about 5 ng / mL to about 60 ng / mL, about 5 ng / mL to about 50 ng / mL, about 5 ng / mL to about 40 ng / mL, about 5 ng / mL to about 30 ng / mL, about 5 ng / mL to about 20 ng / mL, about 5 ng / mL to about 15 ng / mL, or about 5 ng / mL to about 10 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 10 ng / mL to about 100 ng / mL, about 10 ng / mL to about 90 ng / mL, about 10 ng / mL to about 80 ng / mL, about 10 ng / mL to about 70 ng / mL, about 10 ng / mL to about 60 ng / mL, about 10 ng / mL to about 50 ng / mL, about 10 ng / mL to about 40 ng / mL, about10 ng / mL to about 30 ng / mL, about 10 ng / mL to about 20 ng / mL, or about 10 ng / mL to about 15 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 15 ng / mL to about 100 ng / mL, about 15 ng / mL to about 90 ng / mL, about 15 ng / mL to about 80 ng / mL, about 15 ng / mL to about 70 ng / mL, about 15 ng / mL to about 60 ng / mL, about 15 ng / mL to about 50 ng / mL, about 15 ng / mL to about 40 ng / mL, about 15 ng / mL to about 30 ng / mL, or about 15 ng / mL to about 20 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 20 ng / mL to about 100 ng / mL, about 20 ng / mL to about 90 ng / mL, about 20 ng / mL to about 80 ng / mL, about 20 ng / mL to about 70 ng / mL, about 20 ng / mL to about 60 ng / mL, about 20 ng / mL to about 50 ng / mL, about 20 ng / mL to about 40 ng / mL, or about 20 ng / mL to about 30 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 30 ng / mL to about 100 ng / mL, about 30 ng / mL to about 90 ng / mL, about 30 ng / mL to about 80 ng / mL, about 30 ng / mL to about 70 ng / mL, about 30 ng / mL to about 60 ng / mL, about 30 ng / mL to about 50 ng / mL, or about 30 ng / mL to about 40 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 40 ng / mL to about 100 ng / mL, about 40 ng / mL to about 90 ng / mL, about 40 ng / mL to about 80 ng / mL, about 40 ng / mL to about 70 ng / mL, about 40 ng / mL to about 60 ng / mL, or about 40 ng / mL to about 50 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 50 ng / mL to about 100 ng / mL, about 50 ng / mL to about 90 ng / mL, about 50 ng / mL to about 80 ng / mL, about 50 ng / mL to about 70 ng / mL, or about 50 ng / mL to about 60 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 60 ng / mL to about 100 ng / mL, about 60 ng / mL to about 90 ng / mL, about 60 ng / mL to about 80 ng / mL, or about 60 ng / mL to about 70 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 70 ng / mL to about 100 ng / mL, about 70 ng / mL to about 90 ng / mL, or about 70 ng / mL to about 80 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 80 ng / mL to about 100 ng / mL, or about 80 ng / mL to about 90 ng / mL. In some embodiments, the Cmax of the mTOR inhibitor is about 90 ng / mL to about 100 ng / mL.

[0071] In some embodiments administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a Cmax of the mTOR inhibitor that is greater than about 5 ng / mL, greater than about 10 ng / mL, greater than about 15 ng / mL, greater than about 20 ng / mL, greater than about 30 ng / mL ng / mL, greater than about 40 ng / mL, greater than about 50 ng / mL, greater than about 70 ng / mL, greater than about 80 ng / mL, or greater than about 90 ng / mL. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a Cmax of the mTOR inhibitor that is about 5 ng / mL, about 10 ng / mL, about 15 ng / mL,about 20 ng / mL, about 30 ng / mL ng / mL, about 40 ng / mL, about 50 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, or about 100 ng / mL.

[0072] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a Cmax of the mTOR inhibitor that is about two, about five, or about ten times greater in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a Cmax of the mTOR inhibitor that is about ten times greater in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a Cmax of the mTOR inhibitor that is about five times greater in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a Cmax of the mTOR inhibitor that is about two times greater in the subject than in a subject that is administered an mTOR inhibitor alone.

[0073] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a half-life of the mTOR inhibitor that is about 50 hours to about 100 hours, about 50 hours to about 95 hours, about 50 hours to about 90 hours, about 50 hours to about 85 hours, about 50 hours to about 80 hours, about 50 hours to about 75 hours, about 50 hours to about 70 hours, about 50 hours to about 65 hours, about 50 hours to about 60 hours, or about 50 hours to about 55 hours. In some embodiments, the half-life is about 55 hours to about 100 hours, about 55 hours to about 95 hours, about 55 hours to about 90 hours, about 55 hours to about 85 hours, about 55 hours to about 80 hours, about 55 hours to about 75 hours, about 55 hours to about 70 hours, about 55 hours to about 65 hours, or about 55 hours to about 60 hours. In some embodiments, the half-life is about 60 hours to about 100 hours, about 60 hours to about 95 hours, about 60 hours to about 90 hours, about 60 hours to about 85 hours, about 60 hours to about 80 hours, about 60 hours to about 75 hours, about 60 hours to about 70 hours, or about 60 hours to about 65 hours. In some embodiments, the half-life is about 65 hours to about 100 hours, about 65 hours to about 95 hours, about 65 hours to about 90 hours, about 65 hours to about 85 hours, about 65 hours to about 80 hours, about 65 hours to about 75 hours, or about 65 hours to about 70 hours. In some embodiments, the half-life is about 70 hours to about 100 hours, about 70 hours to about 95 hours, about 70 hours to about 90 hours, about 70 hours to about 85 hours, about 70 hours to about 80 hours, or about 70 hours to about 75 hours. In some embodiments, the half-life isabout 75 hours to about 100 hours, about 75 hours to about 95 hours, about 75 hours to about 90 hours, about 75 hours to about 85 hours, or about 75 hours to about 80 hours. In some embodiments, the half-life is about 80 hours to about 100 hours, about 80 hours to about 95 hours, about 80 hours to about 90 hours, or about 80 hours to about 85 hours. In some embodiments, the half-life is about 85 hours to about 100, about 85 hours to about 95, or about 85 hours to about 90 hours. In some embodiments, the half-life is about 90 hours to about 100, or about 90 hours to about 95 hours. In some embodiments, the half-life is about 95 hours to about 100 hours.

[0074] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a half-life of the mTOR inhibitor that is greater than about 50 hours, greater than about 55 hours, greater than about 60 hours, greater than about 65 hours, greater than about 70 hours, greater than about 75 hours, greater than about 80 hours, greater than about 85 hours, greater than about 90 hours, greater than about 95 hours, or greater than about 100 hours. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a half-life of the mTOR inhibitor that is about 50 hours, about 55 hours, about 60 hours, about 65 hours, about 67 hours, about 70 hours, about 75 hours, about 80 hours, about 85 hours, about 88 hours, about 90 hours, about 95 hours, or about 100 hours.

[0075] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a half-life of the mTOR inhibitor that is about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2.0 times, about 2.1 times, about 2.2 times, about 2.3 times, about 2.4 times, or about 2.5 times greater in the subject relative to a subject that is administered an mTOR inhibitor alone.

[0076] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for greater than about two, greater than about three, greater than about four, greater than about five, greater than about six, greater than about seven, greater than about eight, greater than about nine, or greater than about ten times longer in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about two, about three, about four, aboutfive, about six, about seven, about eight, about nine, or about ten times longer in the subject than in a subject that is administered an mTOR inhibitor alone.

[0077] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about two times longer in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about three times longer in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about four times longer in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about five times longer in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about six times longer in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about seven times longer in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about eight times longer in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about nine times longer in the subject than in a subject that is administered an mTOR inhibitor alone. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for about ten times longer in the subject than in a subject that is administered an mTOR inhibitor alone.

[0078] In some embodiments, a dose or dosing regimen of the present disclosure is useful for treating a subject or a population of subjects. The present disclosure encompasses an insight that provided dosing regimens surprisingly provide for consistent dosing among populations of subjects (e.g., populations of humans, populations of cats, populations of dogs), and reduce pharmacokinetic variability such that the same dose can be applied across each subject in a provided population. Pharmacokinetic variability (sometimes represented as CV%, which is determined by dividing the standard deviation of values measured from a population of patients by the mean and multiplying by 100) is defined as inter-subject variations of a drug’s pharmacokinetic parameters, which may result in different plasma concentration-time profiles after administration of the same dose to different subjects.

[0079] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a population of subjects, comprising administering to each subject within the population an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, and a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a population of subjects, comprising administering to each subject within the population an mTOR inhibitor, or a pharmaceutically acceptable salt thereof, and a cytochrome p450 inhibitor, or a pharmaceutically acceptable salt thereof, wherein pharmacokinetic variability between the subjects in the population is reduced compared to a population of subjects that is administered an mTOR inhibitor alone.

[0080] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a population of subjects provides an AUC CV% of the mTOR inhibitor in the population of subjects of less than about 75%, less than about 70%, 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, or less than about 25%. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a population of subjects provides an AUC CV% of the mTOR inhibitor in the population of subjects of about 75%, about 70%, 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, or about 25%.

[0081] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a population of subjects provides an AUC CV% of the mTOR inhibitor that is about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2.0 times, about 2.1 times, about 2.2 times, about2.3 times, about 2.4 times, or about 2.5 times greater in the population of subjects relative to a population of subjects that is administered an mTOR inhibitor alone.

[0082] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a population of subjects provides a Cmax CV% of the mTOR inhibitor in the population of subjects of less than about 75%, less than about 70%, 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, or less than about 25%. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a population of subjects provides a Cmax CV% of the mTOR inhibitor in the population of subjects of about 75%, about 70%, 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, or about 25%.

[0083] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a population of subjects provides a Cmax CV% of the mTOR inhibitor that is about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2.0 times, about 2.1 times, about 2.2 times, about2.3 times, about 2.4 times, or about 2.5 times greater in the population of subjects relative to a population of subjects that is administered an mTOR inhibitor alone.

[0084] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a population of subjects provides half-life CV% of the mTOR inhibitor in the population of subjects of less than about 75%, less than about 70%, 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, or less than about 25%. In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a population of subjects provides a half-life CV% of the mTOR inhibitor in the population of subjects of about 75%, about 70%, 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, or about 25%.

[0085] In some embodiments, administration of an mTOR inhibitor and a cytochrome p450 inhibitor to a population of subjects provides a half-life CV% of the mTOR inhibitor that is about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2.0 times, about 2.1 times, about 2.2 times, about2.3 times, about 2.4 times, about 2.5 times, about 2.6 times, about 2.7 times, about 2.8 times, about 2.9 times, about 3.0 times, about 3.1 times, about 3.2 times, about 3.3 times, about 3.4 times, orabout 3.5 times greater in the population of subjects relative to a population of subjects that is administered an mTOR inhibitor alone.

[0086] As generally described herein, the present application encompasses the surprising discovery that administration of an mTOR inhibitor with a cytochrome p450 inhibitor provides for improved pharmacokinetic properties of the mTOR inhibitor upon administration to a subject in need thereof. For example, RapaVet®, a composition comprising rapamycin for treating hypertrophic cardiomyopathy in cats, exhibits, at a dose of 0.75 mg / kg, a Cmax of about 8.07 ng / mL. See U.S. Patent Publication No. 2022 / 0401421. Provided dosing regimens, by combining administration of an mTOR inhibitor and a cytochrome p450 inhibitor, provide improved Cmax, clearance, half-life, and AUC relative, among other things, to RapaVet®.Methods of Treatment

[0087] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition, such as a disease, disorder, or condition described herein. In some embodiments, methods described herein include methods for the treatment of disorders associated with elevated levels of lymphocytes (e.g., organ transplant rejection), cancer-related conditions (e.g., pTEN hamartoma) or aging-related conditions (e.g., sarcopenia). Generally, the methods include administering a therapeutically effective amount of an mTOR inhibitor (e.g., rapamycin) in combination with a cytochrome p450 inhibitor (e.g., ritonavir) as described herein, to a subject (e.g., a mammalian subject, e.g., a human subject) who is in need of, or who has been determined to be in need of, such treatment.

[0088] In some embodiments, provided methods can include selection of a human subject who has or had a disease, disorder, or condition. In some instances, suitable subjects include, for example, subjects who have or had a condition or disease but that resolved the disease or an aspect thereof, present reduced symptoms of disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), and / or that survive for extended periods of time with the condition or disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), e.g., in an asymptomatic state (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease).

[0089] The methods disclosed herein can be applied to a wide range of species, e.g., humans, nonhuman primates (e.g., monkeys), horses, cattle, pigs, sheep, deer, elk, goats, dogs, cats, rabbits,guinea pigs, hamsters, rats, and mice. In some embodiments, a subject is a human. In some embodiments, a subject is a cat. In some embodiments, a subject is a dog. In some embodiments, a subject is a horse. In some embodiments, a subject is a primate (e.g., a cynomolgus monkey; a marmoset). In some embodiments, a subject is a rat. In some embodiments, a subject is a mouse.

[0090] The terms “treat”, “treating”, “treatment”, etc., as applied to an isolated cell, include subjecting the cell to any kind of process or condition or performing any kind of manipulation or procedure on the cell. As applied to a subject, the term “treating” refer to providing medical or surgical attention, care, or management to an individual. The individual is usually ill or injured, or at increased risk of becoming ill relative to an average member of the population and in need of such attention, care, or management.

[0091] In some embodiments, the terms “treating” and “treatment” refer to administering to a subject an effective amount of a composition, e.g., a composition comprising an mTOR inhibitor and a composition comprising a cytochrome p450 inhibitor, so that the subject has a reduction in at least one symptom of the disease or an improvement in the disease, for example, beneficial or desired clinical results. For purposes of the present disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. Treating can refer to prolonging survival as compared to expected survival if not receiving treatment. Thus, one of skill in the art realizes that a treatment may improve the disease condition, but may not be a complete cure for the disease. In some embodiments, treatment can be prophylactic treatment, where the subject is administered a composition as disclosed herein to a subject at risk of developing inflammation as disclosed herein. In some embodiments, treatment is “effective” if the progression of a disease is reduced or halted.

[0092] The term “subject,” as used herein, refers to any animal. In some instances, the subject is a mammal. In some instances, the term “subject”, as used herein, refers to a human (e.g., a man, a woman, or a child).

[0093] In some instances, subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection. In some instances, the subject can be confirmed or identified, e.g., by a healthcare professional, as having had or having a condition or disease. In some instances, exhibition of a positive immuneresponse towards a condition or disease can be made from patient records, family history, and / or detecting an indication of a positive immune response. In some instances, multiple parties can be included in subject selection. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample. In some instances, subjects can be selected and / or referred by a medical practitioner (e.g., a general practitioner). In some instances, subject selection can include obtaining a sample from a selected subject and storing the sample and / or using the methods disclosed herein. Samples can include, for example, cells or populations of cells.

[0094] In some instances, treatment methods can include a single administration, multiple administrations, and repeating administration as required for the prophylaxis or treatment of the disease or condition from which the subject is suffering. In some instances, treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and / or after treatment. In some instances, treatment can continue until a decrease in the level of disease in the subject is detected.

[0095] The terms “administer,” “administering,” or “administration,” as used herein refer to implanting, absorbing, ingesting, injecting, or inhaling, the inventive drug, regardless of form. In some instances, one or more of the compounds disclosed herein can be administered to a subject topically (e.g., nasally) and / or orally. For example, the methods herein include administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0096] Following administration, the subject can be evaluated to detect, assess, or determine their level of disease. In some instances, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected.

[0097] Upon improvement of a patient's condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, composition or combination of this present disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which theimproved condition is retained. Patients may, however, require intermittent treatment on a longterm basis upon any recurrence of disease symptoms.Definitions

[0098] “Neurodegeneration” refers to any condition that results in the progressive death of nerve cells.

[0099] “Cancer-related condition” refers to any condition that results from cancer or cancer- related dysfunction.

[0100] “Aging-related condition” refers to any condition that results from aging or is associated with or worsened by aging.

[0101] Inhibitory agent: As used herein, the term “inhibitory agent” refers to an entity, condition, or event whose presence, level, or degree correlates with decreased level or activity of a target. In some embodiments, an inhibitory agent may be act directly (in which case it exerts its influence directly upon its target, for example by binding to the target); in some embodiments, an inhibitory agent may act indirectly (in which case it exerts its influence by interacting with and / or otherwise altering a regulator of the target, so that level and / or activity of the target is reduced). In some embodiments, an inhibitory agent is one whose presence or level correlates with a target level or activity that is reduced relative to a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known inhibitory agent, or absence of the inhibitory agent in question, etc.).

[0102] An inhibitor, as used herein, refers to an inhibitory agent, while inhibition refers to the activity of an inhibitor agent.

[0103] Regulating: “regulating” refers to altering, enhancing, or diminishing the activities or an organelle or cell.

[0104] Antagonist: Those skilled in the art will appreciate that the term “antagonist”, as used herein, may be used to refer to an agent, condition, or event whose presence, level, degree, type, or form correlates with decreased level or activity of another agent (i.e., the inhibited agent, or target). In general, an antagonist may be or include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that shows the relevant inhibitory activity. In some embodiments, an antagonist may be direct (in which case it exerts its influence directly upon its target); in some embodiments, anantagonist may be indirect (in which case it exerts its influence by other than binding to its target; c.g., by interacting with a regulator of the target, so that level or activity of the target is altered).

[0105] Agonist: Those skilled in the art will appreciate that the term “agonist” may be used to refer to an agent, condition, or event whose presence, level, degree, type, or form correlates with increased level or activity of another agent (i.e., the agonized agent or the target agent). In general, an agonist may be or include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and / or any other entity that shows the relevant activating activity. In some embodiments, an agonist may be direct (in which case it exerts its influence directly upon its target); in some embodiments, an agonist may be indirect (in which case it exerts its influence by other than binding to its target; e.g., by interacting with a regulator of the target, so that level or activity of the target is altered).

[0106] Administration: As used herein, the term “administration,” typically refers to application or delivery to a subject or system. Those of ordinary skill in the art, reading the present disclosure, will appreciate, for example, that a variety of routes are available for administration of compositions; for example, some compositions may be administered by one or more routes such as ocular, oral, parenteral, topical, etc.. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc.), enteral, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e. g. intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. Furthermore, the present disclosure, in some embodiments, describes administration of behavioral therapy, for example via interaction with a counselor (e.g., a therapist) and / or with a device or computing system as described herein. In some embodiments, administration may involve dosing, application, or interaction that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion), application or interaction for at least a selected period of time.

[0107] Subject or patient: As used herein, the terms “subject” or “patient” refer to an organism, for example, a mammal (e.g., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, a dog). In some embodiments a humansubject is an adult, adolescent, or pediatric subject. In some embodiments, a subject is suffering from a disease, disorder or condition, c.g., a disease, disorder or condition that can be treated as provided herein. In some embodiments, a subject is susceptible to a disease, disorder, or condition; in some embodiments, a susceptible subject is predisposed to and / or shows an increased risk (as compared to the average risk observed in a reference subject or population) of developing the disease, disorder or condition. In some embodiments, a subject displays one or more symptoms of a disease, disorder or condition. In some embodiments, a subject does not display a particular symptom (e.g,. clinical manifestation of disease) or characteristic of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0108] Rapamycin is a chemical compound with the following structure:

[0109] Ritonavir is a chemical compound with the following structure:

[0110] About: The term “about”, when used herein in reference to a value, refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0111] Pharmaceutically Acceptable Salts: The term “pharmaceutically acceptable salt” or “pharmaceutically acceptable salts” refers to a salt formed from an acid and a basic group of a pharmaceutically active compounds. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0112] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the ait to which this present disclosure belongs. Methods and materials are described herein for use in the present disclosure; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0113] Other features and advantages of the present disclosure will be apparent from the following detailed description and figures, and from the claims.

[0114] The present disclosure is further described in the following examples, which do not limit the scope of the present disclosure described in the claims.EXEMPLIFICATION

[0115] The present disclosure is further described in the following examples, which do not limit the scope of the present disclosure described in the claims.Example 1Materials and Methods

[0116] Compounds are tested in a rising dose study as described herein.

[0117] Rapamycin and ritonavir are obtained.

[0118] 12 dogs are screened for inclusion to the rising dose study. Inclusion criteria are 3-6 years of age and a body weight of 8-12 kg. Exclusion criteria are the evidence of any clinically significant (in the opinion of the Investigator) acute or chronic disease following a detailed medical and surgical history and a complete physical examination; as well as poor metabolization of Cytochrome P450 3A4-metabolized substances based on genotyping.

[0119] Following admittance, each dog will receive a single dose of 2 mg rapamycin, and will then be followed for 7 days. Following a 7 day washout, each dog will receive a single dose of 2 mg rapamycin and 20 mg ritonavir, and followed for 7 days.

[0120] Each cohort will be sampled at 0, 2, 4, 8, 12, 24 hours and then once daily for 7 days following oral dose of rapamycin and oral dose of co-administered rapmycin and ritonavir.Results

[0121] Whole blood rapamycin concentrations will be determined for each sample. Also, for each sample, whole blood PK parameters will be estimated using noncompartmental analysis, as appropriate: Cmax, tmax, kel, 11 / 2, AUCO-last, AUCO-inf, CL / F, and Vz / F. Also, plasma ritonavir concentrations will be measured to confirm its presence after Day 4 dosing.

[0122] Descriptive statistics for all relevant PK parameters will be calculated: n, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation.

[0123] PK parameters — Cmax, AUCO-last, AUCO-inf — will be compared between Day 1 and Day 4 using an analysis of variance (ANOVA) model with subject as a random effect and day as a fixed effect, using the natural logarithms of the parameters uncorrected for dose. Confidence intervals (CI) (90%) will be constructed for the geometric mean ratios (GMR) of rapamycin on Day 4 to Day 1 for all three parameters using the log transformed data and the two one-sided t- tests procedure. The GMRs and 90% Cis will be exponentiated back to the original scale. The effects of coadministration of ritonavir on rapamycin will be evaluated from the GMRs and Cis.

[0124] This analysis will show a statistically significant effect for the decrease in pharmacokinetic variability of rapamycin and more consistent achievement of target dose level.Example 2Materials and Methods

[0125] A two-period, two-treatment crossover study was conducted in 12 cats to evaluate the pharmacokinetics of rapamycin alone and in combination with ritonavir. The study design was as follows:

[0126] A 7-day washout period was observed between treatments. Blood samples were collected at multiple time points over 7 days following each dose administration for pharmacokinetic analysis.Results

[0127] Pharmacokinetic parameters were determined based on the blood samples of Group A and Group B subjects after each treatment period. Results are shown below in Table 1.Table 1 : Summary of Pharmacokinetic Parametersreported.

[0128] As shown in FIG. 1, subjects that received a combination of ritonavir and rapamycin in Period 1 experienced higher concentration levels of rapamycin within the blood and for extended periods of time. Particularly, these subjects experienced concentration levels of rapamycin within the 5 ng / mL to 15 ng / mL therapeutic range for an extended period of time (e.g., 3-fold longer) as compared to the subjects receiving solely rapamycin. As shown in FIG. 2, these results are replicated in Period 2 for the cohort of subjects that received the rapamycin and ritonavir combination.

[0129] As shown in Table 1, the AUC and elimination half-life of ritonavir alone in Group B Period 2 cohort, which previously received the combination treatment, was greater than the values seen in the Group A Period 1 cohort that had not previously received the combination treatment. Additionally, the co-administration of ritonavir with rapamycin resulted in an AUC(O-inf) increase from 85.8 hrxng / mL (rapamycin alone) to 1170 hrxng / mL (rapamycin + ritonavir) in Period 1, representing a 13 .6-fold increase. In contrast, a 2-3-fold increase is typically observed with coadministration of CYP3A4 inhibitors.

[0130] Still further, results showed that the elimination half-life of rapamycin increased from 49.5 hours (rapamycin alone) to 66.8 hours (rapamycin + ritonavir). In Group B, Period 2 (rapamycin alone after previous ritonavir exposure), the half-life was 88.6 hours, an 80% increase over thebaseline rapamycin alone condition. Notably, the co-administration of ritonavir with rapamycin led to a marked reduction in pharmacokinetic variability for several key parameters, including:- Two weeks after administration of ritonavir, AUC(inf) CV% decreased from 64.5% to 35.4% (Period 1 Group A to Period 2 Group B),- Cmax CV% decreased from 75.6% to 49.4%, and half life CV% decreased from 46.7% to 15.2%

[0131] These data suggest that once-weekly dosing of the rapamycin / ritonavir combination could maintain therapeutic levels (5-15 ng / mL) for a significantly longer duration compared to rapamycin alone. Similarly, the 16.6-fold increase in AUC with co-administration suggests that the rapamycin dose could potentially be reduced by up to 94% while maintaining similar exposure.References

[0001] Wilkinson, John E., et al. "Rapamycin slows aging in mice." Aging cell 11.4 (2012): 675-682.[2] Yessenkyzy A, Saliev T, Zhanaliyeva M, Masoud AR, Umbayev B, Sergazy S, Krivykh E,Gulyayev A, Nurgozhin T. Polyphenols as Caloric-Restriction Mimetics and AutophagyInducers in Aging Research. Nutrients. 2020 May 8; 12(5): 1344. doi: 10.3390 / nul2051344.PMID: 32397145; PMCID: PMC7285205.[3] Sofroniadou, Sofia, and David Goldsmith. "Mammalian target of rapamycin (mTOR) inhibitors: potential uses and a review of haematological adverse effects." Drug Safety 34.2 (2011): 97-115.[4] Knechtle, Stuart J., et al. "Campath-IH induction plus rapamycin monotherapy for renal transplantation: results of a pilot study." American Journal of Transplantation 3.6 (2003): 722- 730.[5] Levy, Gary, et al. "Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12-and 36-month results." Liver transplantation 12.11 (2006): 1640-1648.[6] Kasiske, B. L., et al. "Mammalian target of rapamycin inhibitor dyslipidemia in kidney transplant recipients." American Journal of Transplantation 8.7 (2008): 1384-1392.[7] Ohyama, Katsuhiro, Hiroyuki Tanaka, and Yusuke Hori. "Effect of concomitant drug use on the onset and exacerbation of diabetes mcllitus in cvcrolimus-trcatcd cancer." Journal of Pharmacy & Pharmaceutical Sciences 25 (2022): 245-252.[8] Nadal, Marion, et al. "Efficacy and safety of mammalian target of rapamycin inhibitors in vascular- anomalies: a systematic review." Acta dermato-venereologica 96.4 (2016): 448-452.[9] Sehgal, Suren N. "Rapamune®(RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression." Clinical biochemistry 31.5 (1998): 335-340.

[0010] Atkins, Michael B., Uma Yasothan, and Peter Kirkpatrick. "Everolimus." Nature reviews Drug discovery 8.7 (2009).

[0011] Yatscoff, Randall W., et al. "Consensus guidelines for therapeutic drug monitoring of rapamycin: report of the consensus panel." Therapeutic drug monitoring 17.6 (1995): 676-680.

[0012] Zha, Jiuhong, et al. "Effects of a ritonavir-containing regimen on the pharmacokinetics of sirolimus or everolimus in healthy adult subjects." Pharmacology Research & Perspectives 10.6 (2022): eO 1024.

[0013] Moes, Dirk Jan AR, Henk-Jan Guchelaar, and Johan W. de Fijter. "Sirolimus and everolimus in kidney transplantation." Drug discovery today 20.10 (2015): 1243-1249.

Claims

CL IMS1. A method of treating an alloimmune, autoimmune, inflammatory, aging-related, or cancer- related condition in a subject, the method comprising: administering to the subject an mTOR inhibitor and a cytochrome p450 inhibitor.

2. The method of claim 1, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered contemporaneously.

3. The method of claim 1, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered near contemporaneously but sequentially.

4. The method of any one of claims 1-3, wherein the mTOR inhibitor is selected from: rapamycin, everolimus, temsirolimus, ridaforolimus, umirolimus, zotarolimus, and analogs or derivatives thereof.

5. The method of any one of claims 1-4, wherein the cytochrome p450 inhibitor is selected from: amiodarone, chloroquine, cimetidine, clomipramine, diphenhydramine, fluoxetine, fluphenazine, haloperidol, paroxetine, perphenazine, propafenone, propoxyphene, quinacrine, quinidine, sertraline, terbinafine, thioridazine, amprenavir, clarithromycin, danazol, delavirdine, diltiazem, efavirenz, erythromycin, ethinylestradiol, fluconazole, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, quinine, ritonavir, saquinavir, synercid, troleandomycin, verapamil, boceprevir, telithromycin, ceritinib, mibefradil, ribociclib, tucatinib, chloramphenicol, posaconazole, voriconazole, cobicistat, aprepitant, ciprofloxacin, conivaptan, crizotinib, rutin, tofisopam, miconazole, bergamottin, cyclosporine, donedarone, imatinib, berberine, buprenorphine, cafestol, cilostazol, fosaprepitant, lomitapide, orphenadrine, omeprazole, quercetin, ranitidine, ranolazine, tacrolimus, ticagrelor, valproic acid, amlodipine, azithromycin, bergaptol, cannabidiol, dithiocarbamate, mifepristone, norfloxacin, gestodene, niacin, niacinamide, isoniazid, zafirlukast, and analogs or derivatives thereof.

6. The method of any one of claims 1-5, wherein the mTOR inhibitor is rapamycin.

7. The method of any one of claims 1 -6, wherein the cytochrome p450 inhibitor is ritonavir.

8. The method of any one of claims 1-6, wherein the cytochrome p450 inhibitor is cobicistat.

9. The method of any one of claims 1-8, wherein the mTOR inhibitor is administered in an amount that is about 0.2 mg / day, about 0.6 mg / day, about 1 mg / day, about 4 mg / day, about 8 mg / day, or about 16 mg / day.

10. The method of any one of claims 1-8, wherein the mTOR inhibitor is administered in an amount that is about 0.2 mg / week, about 0.6 mg / week, about 1 mg / week, about 4 mg / week, about 8 mg / week, or about 16 mg / week.

11. The method of any one of claims 1-8, wherein the mTOR inhibitor is administered in an amount that is about 0.6 mg / week.

12. The method of any one of claims 1-11, wherein the cytochrome p450 inhibitor is administered in an amount that is about 0.1 mg / kg of a subject’s body weight per day, about 0.5 mg / kg of a subject’s body weight per day, about 1 mg / kg of a subject’s body weight per day, about 2 mg / kg of a subject’s body weight per day, or about 4 mg / kg of a subject’s body weight per day.

13. The method of any one of claims 1-11, wherein the cytochrome p450 inhibitor is administered in an amount that is about 5 mg / day, about 10 mg / day, about 20 mg / day, or about 40 mg / day.

14. The method of any one of claims 1-11, wherein the cytochrome p450 inhibitor is administered in an amount that is about 5 mg / week, about 10 mg / week, about 20 mg / week, or about 40 mg / week.

15. The method of any one of claims 1-11, wherein the cytochrome p450 inhibitor is administered in an amount that is about 20 mg / week.

16. The method of any one of claims 1 -15, wherein the autoimmune, alloimmune, or inflammatory condition is associated with elevated levels of lymphocytes.

17. The method of any one of claims 1-15, wherein the cancer-related condition is associated with the mTOR complex.

18. The method of any one of claims 1-15, wherein the aging-related condition is associated with the mTOR complex.

19. The method of claim 16, wherein the autoimmune, alloimmune, or inflammatory condition is organ transplant rejection, lupus, sclerosis or heart failure.

20. The method of claim 17, wherein the cancer-related condition is breast, prostate, lung, melanoma, bladder, brain, or renal carcinoma.

21. The method of claim 18, wherein the aging-related condition is neurodegenerative, cardiac- related, or musculoskeletal.

22. The method of any one of claims 1-21, wherein the mTOR inhibitor is administered as an oral dosage form.

23. The method of any one of claims 1-21, wherein the cytochrome p450 inhibitor is administered as an oral dosage form.

24. A method of mediating a disease, disorder, or condition associated with elevated levels of lymphocytes in a subject, the method comprising administering to the subject an mTOR inhibitor and a cytochrome p450 inhibitor.

25. A method of mediating a disease, disorder, or condition associated with the mTOR complex in a subject, the method comprising administering to the subject an mTOR inhibitor and a cytochrome p450 inhibitor.

26. The method of any one of claims 19-21, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered contemporaneously.

27. The method of any one of claims 19-21, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered near contemporaneously sequentially.

28. The method of any one of claims 24-27, wherein the mTOR inhibitor is selected from: rapamycin (also known as sirolimus), everolimus, temsirolimus, ridaforolimus, umirolimus, zotarolimus, and analogs or derivatives thereof, or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 24-27, wherein the cytochrome p450 inhibitor is selected from: amiodarone, chloroquine, cimetidine, clomipramine, diphenhydramine, fluoxetine, fluphenazine, haloperidol, paroxetine, perphenazine, propafenone, propoxyphene, quinacrine, quinidine, sertraline, terbinafine, thioridazine, amprenavir, clarithromycin, danazol, delavirdine, diltiazem, efavirenz, erythromycin, ethinylestradiol, fluconazole, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, quinine, ritonavir, saquinavir, synercid, troleandomycin, verapamil, boceprevir, telithromycin, ceritinib, mibefradil, ribociclib, tucatinib, chloramphenicol, posaconazole, voriconazole, cobicistat, aprepitant, ciprofloxacin, conivaptan, crizotinib, rutin, tofisopam, miconazole, bergamottin, cyclosporine, donedarone, imatinib, berberine, buprenorphine, cafestol, cilostazol, fosaprepitant, lomitapide, orphenadrine, omeprazole, quercetin, ranitidine, ranolazine, tacrolimus, ticagrelor, valproic acid, amlodipine, azithromycin, bergaptol, cannabidiol, dithiocarbamate, mifepristone, norfloxacin, gestodene, niacin, niacinamide, isoniazid, zafirlukast, and analogs or derivatives thereof, or a pharmaceutically acceptable salt thereof.

30. The method of any one of claims 1-29, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is about ten times greater in the subject than in a subject that is administered an mTOR inhibitor alone.31 . The method of any one of claims 1 -29, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is greater than about 150 hrxng / mL.

32. The method of any one of claims 1-29, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is greater than about 300 hrxng / mL.

33. The method of any one of claims 1-29, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is greater than about 500 hrxng / mL.

34. The method of any one of claims 1-29, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides an AUC of the mTOR inhibitor that is greater than about 1000 hrxng / mL.

35. The method of any one of claims 1-34, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a Cmax of the mTOR inhibitor that is about ten times greater in the subject than in a subject that is administered an mTOR inhibitor alone.

36. The method of any one of claims 1-34, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a Cmax of the mTOR inhibitor that is greater than about 5 ng / mL.

37. The method of any one of claims 1-34, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a Cmax of the mTOR inhibitor that is greater than about 15 ng / mL.

38. The method of any one of claims 1-34, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides: an AUC of the mTOR inhibitor that is greater than about 500 hrxng / mL; and / ora Cmax of the mTOR inhibitor that is greater than about 5 ng / mL.

39. The method of any one of claims 1-38, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a half-life that is greater than about 60 hours.

40. The method of any one of claims 1-38, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a half-life that is greater than about 80 hours.

41. The method of any one of claims 1-40, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for greater than about two times longer in the subject than in a subject that is administered an mTOR inhibitor alone.

42. The method of any one of claims 1-40, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to the subject provides a concentration of the mTOR inhibitor in the subject between 5 ng / mL to 15 ng / mL for greater than about three times longer in the subject than in a subject that is administered an mTOR inhibitor alone.

43. The method of any one of claims 1-42, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered to the subject once daily.

44. The method of any one of claims 1-42, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered to the subject once per week.

45. The method of any one of claims 1-42, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered to the subject once every other week.

46. The method of any one of claims 1-42, wherein the mTOR inhibitor and the cytochrome p450 inhibitor are administered to the subject once per month.

47. The method of any one of claims 1-46, wherein the subject is a human.

48. The method of any one of claims 1-46, wherein the subject is a cat.

49. The method of any one of claims 1-46, wherein the subject is a dog.

50. A method of treating an alloimmune, autoimmune, inflammatory, aging-related, or cancer-related condition in a population of subjects, the method comprising: administering to each subject within the population an mTOR inhibitor and a cytochrome p450 inhibitor.

51. The method of claim 50, wherein the mTOR inhibitor is selected from: rapamycin, everolimus, temsirolimus, ridaforolimus, umirolimus, zotarolimus, and analogs or derivatives thereof.

52. The method of any one of claims 50-51, wherein the cytochrome p450 inhibitor is selected from: amiodarone, chloroquine, cimetidine, clomipramine, diphenhydramine, fluoxetine, fluphenazine, haloperidol, paroxetine, perphenazine, propafenone, propoxyphene, quinacrine, quinidine, sertraline, terbinafine, thioridazine, amprenavir, clarithromycin, danazol, delavirdine, diltiazem, efavirenz, erythromycin, ethinylestradiol, fluconazole, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, quinine, ritonavir, saquinavir, synercid, troleandomycin, verapamil, boceprevir, telithromycin, ceritinib, mibefradil, ribociclib, tucatinib, chloramphenicol, posaconazole, voriconazole, cobicistat, aprepitant, ciprofloxacin, conivaptan, crizotinib, rutin, tofisopam, miconazole, bergamottin, cyclosporine, donedarone, imatinib, berberine, buprenorphine, cafestol, cilostazol, fosaprepitant, lomitapide, orphenadrine, omeprazole, quercetin, ranitidine, ranolazine, tacrolimus, ticagrelor, valproic acid, amlodipine, azithromycin, bergaptol, cannabidiol, dithiocarbamate, mifepristone, norfloxacin, gestodene, niacin, niacinamide, isoniazid, zafirlukast, and analogs or derivatives thereof.

53. The method of any one of claims 50-52, wherein the mTOR inhibitor is rapamycin.

54. The method of any one of claims 50-53, wherein the cytochrome p450 inhibitor is ritonavir.

55. The method of any one of claims 50-53, wherein the cytochrome p450 inhibitor is cobicistat.

56. The method of any one of claims 50-55, wherein the mTOR inhibitor is administered in an amount that is about 0.2 mg / day, about 0.6 mg / day, about 1 mg / day, about 4 mg / day, about 8 mg / day, or about 16 mg / day.

57. The method of any one of claims 50-55, wherein the mTOR inhibitor is administered in an amount that is about 0.2 mg / week, about 0.6 mg / week, about 1 mg / week, about 4 mg / week, about 8 mg / week, or about 16 mg / week.

58. The method of any one of claims 50-55, wherein the mTOR inhibitor is administered in an amount that is about 0.6 mg / week.

59. The method of any one of claims 50-55, wherein the mTOR inhibitor is administered in an amount that is about 0.2 mg every other week, about 0.6 mg every other week, about 1 mg every other week, about 4 mg every other week, about 8 mg every other week, or about 16 mg every other week .

60. The method of any one of claims 50-59, wherein the cytochrome p450 inhibitor is administered in an amount that is about 5 mg / day, about 10 mg / day, about 20 mg / day, or about 40 mg / day.

61. The method of any one of claims 50-58, wherein the cytochrome p450 inhibitor is administered in an amount that is about 5 mg / week, about 10 mg / week, about 20 mg / week, or about 40 mg / week.

62. The method of any one of claims 50-58, wherein the cytochrome p450 inhibitor is administered in an amount that is about 5 mg every other week, about 10 mg every other week, about 20 mg every other week, or about 40 mg every other week..

63. The method of any one of claims 50-62, wherein the cytochrome p450 inhibitor is administered as an oral dosage form.

64. The method of any one of claims 50-63, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides an AUC of the mTOR inhibitor that is about ten times greater in each subject than in a subject that is administered an mTOR inhibitor alone.

65. The method of any one of claims 50-63, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides an AUC of the mTOR inhibitor that is greater than about 150 hrxng / mL.

66. The method of any one of claims 50-63, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides an AUC of the mTOR inhibitor that is greater than about 300 hrxng / mL.

67. The method of any one of claims 50-63, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides an AUC of the mTOR inhibitor that is greater than about 500 hrxng / mL.

68. The method of any one of claims 50-63, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides an AUC of the mTOR inhibitor that is greater than about 1000 hrxng / mL.

69. The method of any one of claims 50-68, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides a Cmax of the mTOR inhibitor that is about ten times greater in each subject than in a subject that is administered an mTOR inhibitor alone.

70. The method of any one of claims 50-68, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides a Cmax of the mTOR inhibitor that is greater than about 5 ng / mL.

71. The method of any one of claims 50-68, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides a Cmax of the mTOR inhibitor that is greater than about 15 ng / mL.

72. The method of any one of claims 50-68, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides: an AUC of the mTOR inhibitor that is greater than about 500 hrxng / mL; and / or a Cmax of the mTOR inhibitor that is greater than about 5 ng / mL.

73. The method of any one of claims 50-72, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides a half-life that is greater than about 60 hours.

74. The method of any one of claims 50-72, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides a half-life that is greater than about 80 hours.

75. The method of any one of claims 50-74, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides a concentration of the mTOR inhibitor in each subject between 5 ng / mL to 15 ng / mL for greater than about two times longer in each subject than in a subject that is administered an mTOR inhibitor alone.

76. The method of any one of claims 50-74, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides a concentration of the mTOR inhibitor in each subject between 5 ng / mL to 15 ng / mL for greater than about three times longer in the subject than in a subject that is administered an mTOR inhibitor alone.

77. The method of any one of claims 50-76, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides an AUC CV% of the mTOR inhibitor that is about 1.8 times greater in the population of subjects than in a population of subjects that is administered an mTOR inhibitor alone.

78. The method of any one of claims 50-77, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides a Cmax CV% of the mTOR inhibitor that is about 1.5 times greater in the population of subjects than in a population of subjects that is administered an mTOR inhibitor alone.

79. The method of any one of claims 50-78, wherein administration of the mTOR inhibitor and the cytochrome p450 inhibitor to each subject in the population provides a half-life CV% of the mTOR inhibitor that is about 3.1 times greater in the population of subjects than in a population of subjects that is administered an mTOR inhibitor alone.

80. The method of any one of claims 50-79, wherein each subject in the population is a human.

81. The method of any one of claims 50-79, wherein each subject in the population is a cat.

82. The method of any one of claims 50-79, wherein each subject in the population is a dog.

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