Dosage regimens for treating metal-induced diseases

Abstract

A safe and effective dosing regimen for metal chelators as a treatment for metal overload disorders, particularly iron overload and iron-related conditions, is provided. The method includes orally administering to a subject multiple doses of a metal chelator, each dose administered more than 24 hours after the previous dose, and / or no more than five doses per week, preferably by intravenous or subcutaneous administration of less than five weekly doses of the metal chelator.

Description

[Technical Field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Application No. 62 / 371,274, filed August 5, 2016, and and claims priority to the specification of U.S. Patent Application No. 62 / 371,280 filed August 5, 2016, which No. 6,239,999, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] 2.Background Iron and other metals are essential nutrients for health. Metals are synthesized in a number of processes known as metalloenzymes. They form cofactors for enzymes that are involved in the synthesis of other metal-containing proteins, e.g., cytochromes, hemoglobins, and Many of these metal-containing proteins are normally Metal deficiency is usually caused by inadequate gastrointestinal absorption (e.g., ceria). calcium in rheumatoid arthritis) or due to diseases affecting the gastrointestinal tract, kidneys, or skin Losses (e.g., magnesium in the kidneys with diarrhea or diuretic use) It has a well-defined clinical syndrome of characteristic signs and symptoms. Storage disorders also occur when excessive amounts of metal accumulate in the body's tissues, usually followed by excessive absorption (e.g. iron in hereditary hemochromatosis), or when they impair secretory mechanisms (e.g. , copper in Wilson's disease) and similarly well-defined characteristic signs and pathology. causes a distinct clinical syndrome.

[0003] Iron is a good example for other metals. Iron is abundant in nature but difficult to absorb from the diet. Inadequate absorption of iron from the diet or loss through bleeding (e.g., menstruation) can lead to deficiency. Approximately 11% of people in the United States are iron deficient, and 1-2% of deficiencies lead to anemia. Iron overload is less common and can be severe enough to cause Anemia due to abnormally increased iron absorption, such as in erythrocytes, or due to abnormal red blood cell (RBC) production Anemia occurs most frequently in association with an overexpression of hepatic hepcidin, a key regulator of iron absorption. The decrease in blood hepcidin suppresses the expression of enterocyte ferroportin (iron transporter). Iron overload can lead to excessive iron absorption by intestinal enterocytes, which can lead to the need for blood transfusions to treat anemia. This severely deteriorates a subpopulation of patients in need. The average unit of concentrated RBCs is 200-25 0 mg of iron. To put this in perspective, the average person's body contains 3 grams of iron. There is no mechanism for iron excretion, so iron overload occurs quickly with RBC transfusion. These disorders include thalassemia, sickle cell disease, Diamond-Blackfriars disease, and Anemia, congenital sideroblastic anemia, congenital dyserythropoietic anemia, myelodysplastic syndrome (MDS) and aplastic anemia.

[0004] Iron is normally transported through the body bound to the protein transferrin. The transferrin receptor binds to and internalizes the transferrin-iron complex, transporting iron into the cell. Circulating transferrin complexed with iron The percentage of iron in the blood, transferrin saturation, is used clinically as an indicator of the body's iron status. Normal transferrin saturation is in the range of approximately 20-50%. Values ​​below this range are A value above 0.05 indicates iron deficiency, whereas a value above 0.05 indicates iron overload or excess. Inside the cell, iron is transported by the Ferritin is stored in spheres of proteins known as ferritin. It can leak from the blood and is used as an indicator of iron status in the body. ~200ng / mL, and values ​​below this range, similar to transferrin saturation and above suggests iron deficiency or iron overload. Iron is normally transported via transferrin Bound to transferrin in the circulation or stored in ferritin Non-transferrin-bound iron (NTBI), which is unbound iron, is a low molecular weight substance, e.g. Some NTBIs catalyze reactive oxygen species (i.e., biosynthesis). Reactive oxygen species are sometimes called "free radicals." It is called "cal" and contains lipids, proteins, deoxyribonucleic acid (DNA), and intracellular organelles. Iron overload symptoms and diseases Symptoms include fatigue, joint pain, impotence, osteoporosis, diabetes, heart failure and cirrhosis of the liver. It can be obtained.

[0005] Before there were effective drugs to chelate iron and remove it from the body, blood transfusions were Patients with β-thalassemia, a severe form of iron overload, can develop heart failure as early as the second decade of life. After the introduction of iron chelators in the early 1970s, progressive life expectancy extension However, according to data from the United Kingdom (UK) Thalassemia Registry, Approximately 50% of patients are reported to die before the age of 35, primarily from heart disease. An important predictor of iron intake is body iron load. Patients who maintained their iron levels (a marker of body iron content) below 2500 ng / mL were more likely to live without heart disease. The 15-year survival rate was 91%, whereas patients with ferritin levels above 2500 ng / mL The rate was 20% for those with diabetes.

[0006] Iron chelators are small molecules that complex with iron and promote its excretion. Before starting treatment, the body's iron load should be increased by 100% in the liver and / or kidney. It is determined by measuring the iron content of the liver (LIC) and the iron content of the heart. is measured by magnetic resonance imaging, or MRI. Cardiac iron is also determined by MRI. and T2 * It is reported as a score. The lower the score, the higher the iron content of the heart. The goal of iron chelation depends on the degree of iron overload. >7 or T2 * <10), the goal is to create a negative iron balance in the body. Tolerable iron overload (LIC 3-7 and T2 * >10) In patients with CKD, the goal is to balance iron intake (from diet and transfusion) with iron excretion from chelators. The idea is to create a lance.

[0007] Three iron chelator compounds, deferoxamine (e.g., Desferal®) ), deferiprone (e.g., Ferriprox®), and deferasirox (e.g., Exjade®, Jadenu®) are marketed in the United States and other countries. All three chelating agents are effective to varying degrees, It is associated with serious dose-related and iron-status-related toxic side effects. It results in an LIC <3. Excessive iron chelation has been shown to be extremely dangerous and in some cases fatal. do.

[0008] Deferoxamine, the first approved iron chelator, is used to treat iron overload and improve life expectancy. Deferoxamine was a major success in the substantial expansion of It is indicated in the United States for the treatment of acute iron toxicity and chronic iron overload. Loxamine has poor oral bioavailability, a short half-life, and should be taken 8-10 hours a day. Requires continuous parenteral administration (intravenous [IV] or subcutaneous [SC]) 5 to 7 days per week for Side effects include local inflammatory and allergic reactions, systemic allergic reactions, and visual disturbances. disability and hearing impairment, increased serum creatinine, renal failure, renal tubular damage, growth retardation, Non-compliance is a significant problem, resulting in suboptimal efficacy. Half of patients using deferoxamine may have iron overload levels associated with premature cardiac death Survival is closely related to medication adherence. In one study, survival at age 30 was 60% in adherent patients but only 10% in non-adherent patients.

[0009] The burdensome nature of deferoxamine treatment and the strong association between survival and compliance are important considerations. This motivated the search for alternative treatments. Deferiprone was the first approved orally active iron inhibitor. It is a therapeutic agent for the treatment of patients with thalassemia syndromes when current chelation therapy is inadequate. Deferiprone has a low iron chelating efficiency and a short elimination half-life (t 1 / 2 = 1.9 hours), resulting in a dose of 75-99 mg / kg / day divided into three daily doses. Side effects include nausea, vomiting, and abdominal pain. Increased ALT, joint pain, neutropenia, and potentially fatal Frequent monitoring is required to avoid infections that may be causing agranulocytosis. Furthermore, deferiprone has been shown to be effective in the pregnancy category, where fetal death and malformations have occurred in non-clinical studies. Of the three available chelating agents, deferiprone chelates cardiac iron. It may be most effective in saturating liver iron but is least effective in removing liver iron. As a result of this safety and efficacy profile, deferiprone is one of the least used It is an iron chelator and is primarily used as an adjunct to deferoxamine.

[0010] Deferasirox is a recently developed oral iron chelator that can be administered once daily. Deferasirox has a more potent and pharmacokinetic profile than deferoxamine. Non-inferiority of defecib was demonstrated in the subgroup of patients with elevated LIC. The approval of Lasirox represents a major advance in the treatment of iron overload, and it is now available for patients 2 years of age and older. It is indicated for the treatment of chronic iron overload caused by blood transfusion in patients. Loxacin can cause kidney and liver damage, including organ failure and gastrointestinal bleeding. In some cases, these reactions can be fatal. As a result, kidney function may be impaired. Close monitoring with frequent testing of liver function is required during treatment. The drug is classified as creatinine clearance <40 mL / min or serum creatinine >normal. Twice the upper limit of the value, poor performance status, high-risk MDS, advanced malignancy, or hematologic It is contraindicated in patients with very low platelet counts. Approximately one-third of patients have serum platelet counts of 33% or higher. experience a persistent increase in creatinine, necessitating dose reduction, interruption, or discontinuation Abdominal pain, diarrhea, nausea, vomiting, and rash can lead to noncompliance or underdosing. Deferasirox is a common side effect. Disperse thoroughly in the juice and avoid food effects on bioavailability. It is available as a wafer-like tablet that must be taken 30 minutes before the event. Jadenu tablets allow oral administration of deferasirox doses without the need for dispersion Jadenu and Exjade contain the same active ingredient, so the side effect profile is similar. Despite these limitations, deferasirox is available in the United States. It has become the most widely used iron chelator.

[0011] Considering the limitations of the three approved iron chelators, there are many options for safe and effective iron chelators. There is a significant unmet medical need to provide iron chelators that can be administered orally to provide high iron levels. Chelation efficiency, all organs adversely affected by iron overload (e.g., liver, heart, pancreas, and kidney) and minimal toxicity, especially to the kidneys, liver, and gastrointestinal system This has been made clear by the past failures of products that have been in clinical development. As is clear, this was not easy to achieve. The development of (hydroxybenzyl)ethylenediamine-N,N8-diacetic acid (N,N8-diacetic acid) is a sufficient oral bioavailability It was discontinued after Phase 1 due to poor oral bioavailability. Deferitrin (4,5-dihydro-2- (2,4-dihydroxyphenyl)-4-methylthiazole-4(S)-carboxylic acid) It was discontinued after a Phase 2 trial in which kidney damage was demonstrated. SPD602 ((S)-2-(2-hydroxy-3-(2-(2-methoxyethoxy)-2-methylpropional) (ethoxy)ethoxy)ethoxy)phenyl)-4-methyl-4,5-dihydrothiazole- 4-carboxylic acid) has completed a phase 2 trial and has not demonstrated efficacy in LIC in patients with β-thalassemia. SP-420 ((S)-4,5-dihydro-2 -[2-hydroxy-4-(3,6-dioxaheptyloxy)phenyl]-4-methyl -4-thiazolecarboxylic acid) has completed phase 1 and 2 trials, but The treatment was terminated early due to renal toxicity. Summary of the Invention [Problem to be solved by the invention]

[0012] Therefore, there is a need for improved chelator therapies for metal-induced diseases. [Means for solving the problem]

[0013] 3. Overview The present disclosure provides, for example, a method for treating a metal-induced disorder in a subject having one of the metal-induced disorders described herein. The present disclosure further relates to a method for treating metal-induced diseases using a compound comprising: In one aspect, the present disclosure relates to reducing the toxicity associated with metal chelators used in SP-420 ((S)-4,5-dihydro-2-[2-hydroxybenzoate]) in the treatment of iron-induced diseases hydroxy-4-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4-thia carboxylic acids) and their pharmaceutically acceptable salts, solvates and hydrates (Summary and reducing toxicity associated with the SP-420 compound.

[0014] There appears to be a strong correlation between effective chelation and toxicity. SPD602 was not effective, and both drugs had significant toxicity. For most small molecule drugs, exposure and efficacy increased with increasing dose. It is not surprising that side effects and adverse reactions increase. Side effects can be caused by a variety of factors, including the mechanism of action of the drug, other receptors, and Off-target effects on receptors or pathways, or idiosyncratic effects such as allergic reactions In the case of iron chelators, the side effects may be mechanistically related. Iron chelators remove iron from cells, but this is the intended effect and the reason for this is unclear. The reason is that iron overload is harmful to cells, especially in the heart, liver, and pancreas. However, iron chelators often have toxicity in other organs, such as the kidney and intestine, which are the target organs. The cells of these organs also remove iron, which is essential for normal cell functions such as respiration. Because cellular processes require available (unchelated) intracellular iron, Iron-containing proteins are abundant in mitochondria and can affect cellular function and function. are most likely to be affected because their survival and survival depend on abundant energy supplies. The most metabolically active cells are the most metabolically active cells. This makes iron particularly effective at high doses or when iron stores are low. Explain why side effects can be severe or fatal with iron chelators if depleted As a class, iron chelators have a low therapeutic index, but alternatives exist. In the absence of these, chelating agents are widely prescribed for transfusion-associated iron overload.

[0015] The present disclosure provides chelating agents, such as approved iron chelators and SP-420 compounds. By modifying the dose or dosing regimen of Without being bound by theory, the present inventors have discovered that the without compromising the goal of removing the metal from sensitive tissues or from the intended target organs. Dosing frequency can be modified to minimize metal (e.g., iron) removal from tissue. Specifically, we do not necessarily measure total chelator dose or total body metal clearance. or reducing the duration or frequency of exposure without significantly reducing Cells of sensitive organs (e.g., kidney, intestine) recover from the effects of chelation due to the reduction It is expected that the "off" chelator period (also provides a period of cell recovery, allowing these cells to perform important metabolic functions, such as respiration and The administration regimens described herein can maintain energy production, etc. , reducing the duration and / or frequency of metal chelator administration results in cell recovery in sensitive organs. This regimen is briefly referred to as the "cell restoration regimen" because it is based on the premise that " or "Cellular Restoration Regimen." [Brief explanation of the drawings]

[0016] [Figure 1-1] FIG. 1A shows representative KIM-1 data for rats from Example 2 administered SP-420 daily (FIG. 1A). [Figure 1-2] FIG. 1B shows representative KIM-1 data for rats from Example 2 administered SP-420 every other day (FIG. 1B). [Figure 2] FIG. 1 shows KIM-1 strips for rats of Example 2 after administration of a cumulative dose of 2600 mg / kg SP-420. [Figure 3]FIG. 1 shows KIM-1 test strips at the end of the administration period (left) and 5 days after administration (right) for rats of Example 2 administered 162.5 mg / kg of SP-420 daily for 16 days. [Figure 4] FIG. 1 shows 24-hour urine samples from rats administered SP-420 daily at a dose of 200 mg / kg / day. [Figure 5] FIG. 1 shows mean KIM-1 data for rats from Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0017] 5. Detailed Description 5.1 Metal-induced diseases Metal ions are important for the proper functioning of biological systems. Ions include, to name just a few: For example, Fe 3+ , Zn 2+ , Cu 2+ , Ca 2+ and Co 3+ etc., more than one-third Known enzymes and other functional proteins, such as RNA polymerases, DNA transcription factors, Enzymes such as cytochrome P450, hemoglobin, myoglobin, and vitamin B12 These metals are then found in the active sites of the metals, which are involved in oxidation and reduction reactions. They act to promote the original reaction, stabilize or protect the charge distribution, and orient the substrates of the reaction.

[0018] However, the body has a limited ability to absorb and excrete metals, and excess metals can be toxic. The underlying principle of this disclosure is that any excess metal is a causative agent of a health condition. can be applied to the situation.

[0019] An example is the chronic transfusion required in such conditions as β-thalassemia major. inherited from infected red blood cells or caused by mutations in genes such as HFE Excess iron due to increased dietary iron absorption, such as in chronic hemochromatosis, can lead to the formation of HO and H It can be toxic through iron-induced generation of reactive oxygen species such as OO·. 2+ In the presence of H2O2 is reduced to the hydroxyl radical (HO·), a highly reactive species, and this process The process is known as the Fenton reaction. Hydroxyl groups react very closely with various cellular components. Free radicals and radicals mediate reactions that react rapidly, damaging DNA and membranes and generating carcinogens The clinical outcome is that without effective treatment, total body iron The iron in the blood gradually increases and is deposited in the liver, heart, pancreas, and other parts of the body. Accumulation of iron contributes to (i) liver disease that can progress to cirrhosis, and (ii) iron-induced reduction of pancreatic β-cell secretion. (iii) diabetes, which is associated with both hypoglycemia and increased hepatic insulin resistance; as a major cause of death in beta-thalassemia major and other anemias associated with transfusional iron overload It can also cause heart disease.

[0020] As another example, relative iron excess is associated with an increased risk of cardiovascular disease (e.g., heart disease). Serum ferritin levels and inflammatory biomarkers, such as C-reactive protein, There is a strong correlation between vasopressin and interleukin-1, and peripheral arterial disease is the leading cause of death. This is a subpopulation of patients with rheumatoid arthritis, for which phlebotomy and iron chelation are used to mitigate the risk. Treatment with iron chelators reduces iron stores and decreases serum ferritin. This may reduce the risk of heart disease and stroke.

[0021] As another example, ions that have little or no endogenous function may enter the body and cause damage. Hg2+ Heavy metal ions such as Zn in metal-binding proteins 2+ Io and others This can displace and inactivate the steroids, resulting in the death of the patient or their children. This results in severe acute or chronic toxicity that can result in birth defects. More significantly, radioactive isotopes of the lanthanide and actinide series are released into the atmosphere through the mouth, air, and or skin contact can cause serious illness in exposed individuals. Such exposures can occur not only from the explosion of a nuclear bomb or a "dirty bomb" made up of nuclear waste, but also from It could also be caused by the destruction of a nuclear power plant.

[0022] Any of the foregoing metal-induced diseases, as well as embodiments 46 and 89 to 105 Conditions identified as being susceptible to the cell restoration dosing regimen disclosed herein may benefit from the cell restoration dosing regimen. Thus, the present disclosure provides methods for treating rheumatoid arthritis using the regimens described in Section 5.3. or such metals as identified using the assays specified in Section 5.4. The present invention also encompasses methods of treating induced diseases.

[0023] 5.2 Metal chelating agents The disclosed cell-restorative dosing regimens involve metal chelators, e.g., SP-420 compounds. As used herein, "SP-420 compound" refers to SP-420 ((S)-4 ,5-Dihydro-2-[2-hydroxy-4-(3,6-dioxaheptyloxy)phenyl]

[0023] [4-methyl-4-thiazolecarboxylic acid] and their pharmaceutically acceptable salts Salts, solvates and hydrates are meant.

[0024] Various drugs related to the chelation and desorption of metal ions in vivo are in clinical use. , and others have been disclosed, but neither has been clinically tested or is in clinical trials due to toxicity. No progress was made in the study. Any metal chelator derived from a cell restoration regimen identified using an assay similar to Treatment based on this approach may be beneficial in reducing toxicity.

[0025] Exemplary metal chelators to which the regimen may be applied include, but are not limited to, In Sections 1 and 3, embodiments 48, 70, 73, 76, 79, 86, and 106 and those identified in PCT publications, the contents of which are incorporated herein by reference. According to formulas (I) to (IX) described in WO 2006 / 107626 These compounds are included.

[0026] Some metal chelators of the present disclosure, such as those described in the previous paragraph, are pharmaceutical The compound can be administered in the form of a pharmaceutically acceptable salt. Alkaline and alkaline earth metals (e.g., sodium, potassium, magnesium, calcium, Further pharmaceutically acceptable salts include amine salts. Preferably, the pharmaceutically acceptable salt is a metal-free (e.g., iron-free) salt. As used herein, "metal-free salts" refers to alkali metal salts and alkaline earth metal salts. This does not include metal salts.

[0027] 5.3 Dosing regimen The disclosed cell restoration dosing regimen maintains efficacy while minimizing toxicity. , which appears to have the net effect of increasing the therapeutic index of metal chelator therapy.

[0028] The regimen generally provides chelates at concentrations high enough to effectively chelate metal ions. The period between doses (dose interval) is set to allow a period during which the drug is not present in the body's cells. By expanding the cells, the frequency of administration can be reduced. This allows the cells to produce functional metal-containing proteins. Proteins can be present in amounts sufficient for normal cell function. The dose and frequency of the agent should be adjusted to create a state of metal balance depending on the therapeutic goal of chelation therapy. or sufficient to nullify the metal balance.

[0029] For chelating agents currently approved for therapy, in some embodiments, The interval is increased by approximately 30% to 300% (approximately 4 to 72 hours for once-daily administration at 24-hour intervals) For example, chelating agents such as deferasirox are typically administered before breakfast. It is administered once daily on an empty stomach or with a light, low-fat breakfast. In one scenario, the second dose is given at mealtime the next day at noon, The interval is extended to about 28 hours. The third dose is given the next day, such as at dinner time. In Rio, the second dose will be administered at dinner the following day, extending the interval to about 32 hours. In this scenario, the second dose would be given two days later with the morning meal, extending the interval to approximately 48 hours. The predicted benefit of extending the dosing interval may be adversely affected by iron chelation. This allows the cells necessary time to recover during the effective chelator-free period. Some chelating agent may be present, but enough so as not to interfere with cellular function. Deferasirox causes substantially less kidney and gastrointestinal damage. More generally, the dose-related toxicity observed with any chelating agent is expected to be variable. This is expected to be reduced or eliminated with the modified dosing regimen.

[0030] In certain embodiments, the doses administered in the new regimen compensate for the reduced frequency of administration. Therefore, the dose of chelating agent administered at each administration should be increased to the intended amount. The dose is increased so that metal clearance is maintained with the new regimen. The amount can be increased by adding 10% to 300% of the above. For example, 20 mg The deferasirox dose is increased to a range of 22 to 60 mg / kg at each dose. All ranges set forth in this disclosure are inclusive (e.g., 22-60 mg / kg range includes a dose of 22 mg / kg and a dose of 60 mg / kg).

[0031] In some embodiments, the total weekly dose or total monthly dose (administered in a week or month) For example, if deferasirox is initially administered at 20 mg / kg daily, the total dose (sum of all doses administered) is maintained at 20 mg / kg daily. g and the dosing interval is changed to every other day, the dose administered will be every other day The dose is increased to 40 mg / kg.

[0032] In the dosing regimens described herein, the phrase "weekly dose" when preceded by an integer means: means the number of doses administered per week. For example, a dosing regimen that includes "fewer than 5 weekly doses" Men should be administered to subjects less than 5 times per week (e.g., 1, 2, 3, or 4 times per week) of the dose. Similarly, the phrase when preceded by an integer includes a dosing regimen in which a metal chelator is administered. "Daily dose" means the number of doses administered per day. For example, "one or two daily doses" The dosing regimen, including the "amount" of the metal chelator, is administered to the subject once daily or twice daily. When a specific dose of a metal chelator is provided, Unless otherwise required by context, dose refers to the amount of metal chelator administered in a single dose. The aforementioned weekly dose, daily dose and specific doses should be taken for at least one week, at least one month, ... month, at least one month, at least for a period of at least three months, at least six months, at least one year, or indefinitely (e.g., Unless the context requires otherwise, the duration of administration is the period between the first and last administration of a metal chelator, rather than the period of a single administration. It means between.

[0033] Modify your dosing regimen to improve convenience, compliance, and adherence For example, alternate-day dosing can be intensified to three days a week, with a weekend break, for example. In areas where the weekend is Saturday and Sunday, such The dosing schedule consisted of administering the chelating agent on Mondays, Wednesdays, and Fridays. This helps patients remember to take their doses and thereby adhere to the recommended regimen. In addition, as shown in Example 2, A brief interruption of administration is expected to minimize the toxicity of the chelating agent.

[0034] Metal chelation efficiency (the percentage of administered drug that is excreted from the body chelated with metals) This can be determined by metal balance studies in animals, human clinical trial subjects, or patients, or For example, in animals by using atomic absorption spectroscopy of tissue or in humans by MR imaging. It can be determined by measuring tissue metal content by I.

[0035] Side effects from chelating agents can be predicted or predicted based on screening tests. This allows for monitoring for side effects such as abdominal pain or kidney damage or failure. The dosing interval can be adjusted over time while confirmatory urine or blood tests are performed.

[0036] For metal chelators without established doses, the administration schedule may be as described herein. Using the principles that have been established, for example using the assay described in Section 5.4 It is possible.

[0037] In certain embodiments, the metal chelator is a compound as defined in any one of embodiments 1 to 106. The compound may be administered according to any of the methods described in Section 5.4.

[0038] The chelating agents used in the cell restoration regimens of the present disclosure are preferably immediate release In oral formulations, but may also be in delayed release oral dosage forms or parenteral preparations. The disclosed cell restoration regimens are effective in humans (including both adults and children) and non-human animals. It can be used to administer.

[0039] 5.4 Assays for Optimizing Dosing Regimen Various cell and animal models can be used to evaluate the optimal dosing interval of metal chelators. These models allow the investigation of the toxic effects of metal chelators on cells of sensitive organs. Determine dose toxicity and cell recovery time between doses.

[0040] The cell types tested in cell culture are those that are adversely affected in humans, e.g., liver One may choose to study cells such as granulocyte progenitor cells.

[0041] To evaluate the effect of metal chelators on nephrotoxicity, primary renal proximal tubule cells or Immortalized proximal tubule cell lines were grown in tissue culture (in vitro) using defined culture media. The metabolic status of these cells (e.g., MTTP assay), proliferation, Assays for quantifying cell viability (e.g., cell count) and viability (e.g., trypan blue exclusion) Metal (e.g., iron) chelators are used to model in vivo exposure of the kidney. For example, the antibody can be added to the culture medium for a defined period of time to maintain steady-state activity in a human patient. Following daily oral administration of deferasirox in this condition, peak serum concentrations were achieved approximately 2 hours after administration. Deferasirox is highly bound to albumin and has a mean elimination half-life of approximately 12 hours. To model this, cells in culture were incubated in a medium containing albumin. The culture medium can be exposed to high peak serum concentrations in the soil for 2 hours. (2-hour initial high concentration + 12-hour decreasing concentration) so that the final concentration is approximately half of the initial concentration. The medium can be replaced every 2 hours with fresh medium containing a low concentration of deferasirox. This 2-hourly decline in deferasirox concentrations continued through the end of the 24-hour period. The trough concentrations observed in patients receiving chronic deferasirox once daily were Approximately equivalent concentrations result. This administration scheme may be repeated for several days, for example, 4 days. A cell recovery regimen incorporating a chelator-free period during which cells can regain metabolic function. To confirm that toxicity can be reduced using metal chelators, Cytotoxicity observed using a dose-based exposure schedule followed by cell recovery doses Compare with the toxicity observed using a schedule-based exposure schedule, e.g. For deferasirox, the cell assay described above can be performed, for example, by culturing cells every other day for the same number of days. Reduced dosing strategies include exposure to twice the concentration of deferasirox to achieve the same total dose. This can be done using a schedule.

[0042] For other chelators, the assay should be tailored to the typical pharmacokinetic profile of that chelator. to compare the change profile incorporating a chelator-free period for cell recovery. Deferiprone is designed to be taken three times a day, typically once in the morning after waking. It is given once in the day and once in the evening. Thus, a typical regimen involves giving the doses approximately 5 hours apart. , peak serum concentrations are achieved after 1 hour and the half-life is 2 hours. High initial deferiprone concentrations in vitro, followed by a 50% concentration decline over 2 hours, This cycle can be simulated by a further drop of 50% for 2 hours. The treatment is repeated three times a day, mimicking the three times daily administration in patients. To reduce toxicity, a cell recovery regimen incorporating a chelator-free period is used. To confirm that this is possible, exposure studies based on standard doses of metal chelators were then performed. The cytotoxicity observed using this schedule will be compared to the cell recovery dosing schedule. For ferriprone, toxicity was assessed using an exposure schedule based on the standard dosing schedule. The effect is to obtain the same total dose administered in two divided doses of higher concentration, 10 hours apart, or is compared to an exposure schedule resulting in single doses spaced 24 hours apart.

[0043] Renal proximal tubule cells and other cells, such as hepatocytes, can also be used in microfluidic kidneys. model ("kidney-on-a-chip") or liver model ("liver-on-a-chip") , can be exposed to the chelating agent in a manner that mimics the pharmacokinetics of various dosing regimens. In one embodiment, it is used to assess the toxicity of metal chelators and cell recovery time. The "kidney-on-a-chip" model was described by Kim and Takayama. (Kim et al., 2015, Biofabrication. Volume 8, Number 1 015021, dx.doi.or g / 10.1088 / 1758-5090 / 8 / 1 / 015021). As with simpler cell culture models, metabolic status and The survival rates were compared between patients receiving standard dosing regimens (e.g., daily deferasirox or deferasirox). Cell recovery dosing regimens (e.g., Defe) compared with Ripulon (three times daily). Lasirox given every other day, or deferiprone given twice daily or once daily ) can be evaluated according to

[0044] The frequency of the dosing regimen can also be tested in animals. For example, A group of animals was given 10 mg / kg of a chelating agent (e.g., 30 mg / kg / day) three times a day. while another group of animals can be given 15 mg / kg twice daily. A third group of animals can be administered 30 mg / kg once daily. In extension, another group of animals can receive 60 mg / kg once every other day, and Another group of animals can be administered 90 mg / kg every three days. evidence of overt toxicity and organ dysfunction (e.g., elevated serum creatinine or urinalysis) abnormalities in blood tests or elevated liver enzymes), or changes in tissues (e.g., renal proximal tubule cells) The liver is monitored for signs of liver cirrhosis (vacuolation of liver cells or fat accumulation in liver cells).

[0045] Information from these assays can be used to guide standard chelator dosing regimens. To compare modified regimens incorporating a period of cell recovery from drug therapy, Modified regimens can also be tested alone, e.g., to guide dose selection. Comparisons with historical control data are available from studies using [Example]

[0046] 6. Working Example [Example 1] 6.1 Example 1: Comparison of Daily and Alternate Day Administration of SP-420 This test measures the levels of kidney injury molecule-1 (KIM-1) and the presence of glucose in the urine. (diabetes) by assessing the daily administration of SP-420 (administered as the sodium salt) This study was conducted to compare the toxicity of KIM-1 with that of KIM-1 administered every other day. are sensitive and specific urinary biomarkers of kidney injury in both humans and animals (e.g., Sa (See Bbisetti et al., 2014, J Am Soc Nephrol. 25(10):2177-2186). M-1 is minimally expressed in normal rat kidneys, but is significantly expressed in kidney injury. (See, e.g., Vaidya et al., 2010, Nat Biotechnol. 28(5): 478-485) ) Glucose filtered by the renal glomerulus is normally completely absorbed by the renal proximal tubule cells. Because glucose is reabsorbed, it is extremely abnormal to detect glucose in the urine. Glycosuria is a condition in which too much glucose is filtered through the glomerulus, destroying the absorption mechanism. Commonly in diabetes mellitus secondary to hyperglycemia or in conditions such as renal Fanconi syndrome Renal Fanconi syndrome is only detected when the renal proximal tubule cells malfunction. The cluster has been reported to be caused by iron chelator treatment. The absorption of urea and other filtered substances (e.g., amino acids, phosphorus, uric acid) is highly energy-dependent and requires renally Chelation of iron in proximal tubule cells leads to a decrease in mitochondrial energy production, This leads to cellular dysfunction with reduced absorption capacity.

[0047] 6.1.1. Method Male Sprague-Dawley rats (n=5 per group) were given 1 dose per day. at a dose of 162.5 mg / kg once daily (SID) or 325 mg / kg every other day (EOD) Each group of rats was administered SP-420 orally by gavage at a dose of The rats received a cumulative dose of 2600 mg / kg of 0.0. Urine was collected from metabolic cages EOD during dosing. The patients were collected 5 or 6 days after the last dose, and again 11 or 12 days after the last dose. were evaluated for KIM-1 content and subjected to 10-parameter urine dipstick analysis. Urine samples from animals treated with SP-420 EOD were collected immediately after drug administration for 24 hours. It was recovered.

[0048] 6.1.2. Results All SID- and EOD-treated rats survived the drug exposure. One rat in the 162.5 mg / kg SID group continued to lose weight and showed signs of deterioration. The rats were euthanized 3 days after drug administration due to hypertension. Urinary KIM-1 levels were elevated in both groups. However, the increase was less significant in animals treated with the drug EOD. Changes in M-1 levels were generally at baseline levels by 5 or 6 days after drug administration. Back to Bell. Glycosuria was observed in 4 / 5 rats treated with SP-420 SID. However, this was not observed in rats administered SP-420 EOD.

[0049] This study demonstrated that alternate-day administration of SP-420 reduced toxicity compared with daily administration. It is clear.

[0050] [Example 2] 6.2 Example 2: Replicate of Example 1 In Example 1, "recovery" KIM-1 levels were measured 5 or 6 days after the last dose. It was clear that KIM-1 levels were significantly reduced during this period. However, the study in Example 1 did not demonstrate how quickly the parameters returned to baseline levels. Furthermore, in Example 1, urine was analyzed to determine whether the drug The chelating agent EOD was administered to rats within 24 hours after administration, but SP-420 was not. Data were not collected on urine produced in the 24-48 hours leading up to the next dose of acetaminophen. We determined what happened during this "rest" day and whether urinary KIM-1 levels declined between doses. To determine whether this is the case, the test of Example 1 was repeated with some modifications.

[0051] 6.2.1. Method Ten male Sprague-Dawley rats were randomly divided into two groups of five and administered the test compound described in Example 1. Unlike Example 1, in which the rats were housed in metabolic cages EOD, this repeated Animals in the study were housed individually in metabolic cages throughout the course of the dosing regimen and for six days thereafter. The animals were housed and urine was collected during the recovery period. Urine was collected at 24-hour intervals throughout the course of the study. The KIM-1 content was evaluated. KIM-1 data were collected from 0 to 24 hours immediately after drug administration, as well as on a "rest" day (2 days after drug administration). The rats were weighed once daily. The changes in body weight were monitored during the daytime and nighttime. The weights were calculated from the subjects' baseline weights versus their weights on the day the last dose of drug was administered.

[0052] 6.2.2.Results All rats survived exposure to the test drug. One rat died 4 days after the last dose due to weight loss and a worsening of its overall condition. He was put to death mercifully.

[0053] Representative KIM-1 data for rats in each group are shown in Figures 1A-1B. shows that SP-420 induced an increase in KIM-1 levels in both groups of animals. The values ​​rapidly returned to near baseline. The increase in KIM-1 levels in SP-420 SID-treated animals was not observed in the SP-420 SID-treated animals. This is depicted on the KIM-1 test strip shown in Figure 2. Test strips 1 to 5 were taken from rats administered SP-420 SID at 162.5 mg / kg / day. Test strips numbered 6 to 10 were from SP at 325 mg / kg EOD. Line "C" is the internal standard, while line " "T" indicates the results for the test animals. The "T" lines on test strips 3-5 are very clear. However, very little KIM-1 was observed in test papers 6 to 10 except for test paper 7. As shown in Figure 3, KIM-1 levels decreased from the last dose up to 5 days after administration. Figure 3 shows the results of SP-420 SI at the end of the administration period (left) and 5 days after administration (right). The KIM-1 test strips from rats administered KD were shown. Five days after drug administration, only a small amount of K IM-1 was observed in test strips #4 and #5. The rats corresponding to test strip #3 showed a significant increase after administration. They were euthanized before obtaining the day 5 sample.

[0054] Under the conditions tested, KIM-1 levels were elevated in the "resting" state (as shown in representative Figure 1B). On the day of withdrawal, the EOD treatment did not reduce the serotonin level. This was also observed in the recovery data from treated rats, where KIM-1 levels increased significantly on the last day of treatment. There was no substantial change in the amount of KIM-1 detected in urine 24 hours after drug administration. However, there was no significant difference between doses in EOD animals or between drugs in SID rodents. The lack of a decrease in KIM-1 within 24 hours of cessation is not surprising. Rats generally excrete less than 10-15 ml of urine per day. Since a large amount of KIM-1, glucose, etc. is produced from one day to the next, For example, the photograph in Figure 4 shows the 200 mg 24-hour urine samples from rats treated with SID at a dose of 1 / kg / day of SP-420 are shown. The amount of urine produced that day was only 14.6 mL. The lower half of the tube appeared normal. The upper half contained a clear layer of blood. The "layering effect" between normal and blood-containing urine observed in the intervening sample Based on this, the amount of KIM-1 or glucose present at the end of a 24-hour collection period It is not inappropriate to expect that some will continue to be excreted in the next day's urine sample.

[0055] The average KIM-1 data for all rats in each group is shown in Figure 5. showed that induced an increase in the mean KIM-1 levels in both groups of animals. The mean values ​​rapidly returned to near baseline. The increase in mean KIM-1 levels in animals treated with SP-420 SID was The difference was not very significant.

[0056] Glycosuria was observed in 3 / 5 rats administered SP-420 SID. Glycosuria was observed in all three rats one day after drug administration and in one-third of the rats two days after drug administration. Observation continued, and no rats were affected by the three days after the final administration. g of SP-420 EOD was not observed in any of the rats administered.

[0057] Summary Example 2 demonstrates that alternate-day administration of SP-420 reduces toxicity compared to once-daily administration. This was done both in terms of urinary KIM-1 excretion and in terms of the presence or absence of glucose in the urine of the test animals. The rapid decline in urinary KIM-1 levels 2-6 days after drug administration was reflected in the weekend rest period. A three-day-a-week dosing schedule, such as Monday, Wednesday, and Friday, is recommended. I strongly support the idea of ​​administering chelating agents. For a schedule, weekend breaks may be required to allow kidney replacement before dosing resumes on Monday, if necessary. You can adjust the recovery time.

[0058] [Example 3] 6.2.4. Example 3: Comparison of daily and alternate-day administration of different doses of SP-420 Similar tests to those described in Examples 1 and 2 were performed with 250 mg / kg of SP-420. EOD, 250mg / kg SID, 500mg / kg EOD, 200mg / kg S The results of the study were compared with those in Examples 1 and 2. The results of the studies described in 2 are summarized in Table 1 below. As shown in Table 1, and KIM-1 levels were significantly higher with EOD administration compared with the SID regimen for the same cumulative dose. The data were consistently low for the regimen. Patients will be given SP-420 on a dosing schedule (e.g., Monday, Wednesday, Friday). It supports the idea.

[0059] [Table 1]

[0060] 7. Specific Embodiments, Citation of References While various specific embodiments have been shown and described, various modifications may be made within the spirit and scope of the present disclosure(s). It will be understood that this disclosure may be modified without departing from the scope of the present disclosure. This is exemplified by the numbered embodiments set forth in

[0061] 1. Treating (a) a metal-induced disease in a subject, and / or (b) a metal chelator 2. A method for reducing the renal, gastrointestinal, hepatic, hematologic, visual, and / or cutaneous toxicity of and orally administering to said subject multiple doses of a metal chelator, each dose being more than 24 hours after a single dose and / or administered no more than five times per week. 2. Treating (a) a metal-induced disease in a subject, and / or (b) a metal chelator and reducing the renal, visual, auditory, neurological, respiratory and / or musculoskeletal toxicity of administering to said subject less than five weekly doses of a metal chelator intravenously or subcutaneously, nothing, method. 3. The method of embodiment 1, wherein said metal chelator is administered five times per week. 4. The method of claim 1 or 2, wherein the metal chelator is administered four times per week. method. 5. The method of claim 1 or 2, wherein the metal chelator is administered three times a week. method. 6. The method of embodiment 1, wherein the metal chelator is administered 15 to 25 times per month. 7. The method of embodiment 1, wherein the metal chelator is administered 20 to 25 times per month. 8. Embodiment 1 or Embodiment 2, wherein the metal chelator is administered 12 to 18 times per month. The method described below. 9. Embodiment 1 or Embodiment 2, wherein the metal chelator is administered 15 to 20 times per month. The method described below. 10. Any of embodiments 1 to 9, wherein the metal chelator is administered every 28 to 72 hours. The method according to any one of the preceding claims. 11. The method of embodiment 10, wherein said metal chelator is administered every 28 hours. 12. The method of embodiment 10, wherein said metal chelator is administered every 32 hours. 13. The method of embodiment 10, wherein said metal chelator is administered every 36 hours. 14. The method of embodiment 10, wherein said metal chelator is administered every 42 hours. 15. The method of embodiment 10, wherein the metal chelator is administered every 48 hours. 16. The method of embodiment 10, wherein the metal chelator is administered every two days. 17. The method of embodiment 10, wherein the metal chelator is administered every 60 hours. 18. The method of embodiment 10, wherein the metal chelator is administered every 72 hours. 19. The method of embodiment 10, wherein the metal chelator is administered every three days. 20. The method of embodiment 10, wherein the metal chelator is administered every 28 to 36 hours. method. 21. The method of embodiment 10, wherein the metal chelator is administered every 32 to 48 hours. method. 22. The method of embodiment 10, wherein the metal chelator is administered every 36 to 48 hours. method. 23. The method of embodiment 10, wherein the metal chelator is administered every 32 to 60 hours. method. 24. The method of embodiment 10, wherein the metal chelator is administered every 36 to 60 hours. method. 25. The method of embodiment 10, wherein the metal chelator is administered every 48 to 60 hours. method. 26. The method of embodiment 10, wherein the metal chelator is administered every 32 to 72 hours. method. 27. The method of embodiment 10, wherein the metal chelator is administered every 36 to 72 hours. method. 28. The method of embodiment 10, wherein the metal chelator is administered every 48 to 72 hours. method. 29. (a) Treating a metal-induced disease and / or (b) metal chelation in a subject 1. A method for reducing the hematological, gastrointestinal, hepatic and / or musculoskeletal toxicity of an agent, said method comprising: orally administering one or two daily doses of the metal chelator to the subject; The metal chelating agent is deferiprone or a pharmaceutically acceptable salt, solvate or is a hydrate, 30. As described in embodiment 29, comprising administering two daily doses of the metal chelator. How to do it. 31. The method of embodiment 29, wherein the daily doses are administered at 6, 9, or 12 hour intervals. method. 32. The method of embodiment 29, wherein said metal chelator is administered 14 times per week. 33. Embodiments 1 to 32, wherein the metal chelator is administered for a period of at least 1 week. 10. The method according to claim 9, wherein 34. Embodiments 1 to 32, wherein the metal chelator is administered for a period of at least one month. 10. The method according to claim 9, wherein 35. Embodiments 1 to 32, wherein the metal chelator is administered for a period of at least 3 months. 10. The method according to claim 9, wherein 36. Embodiments 1 to 32, wherein the metal chelator is administered for a period of at least 6 months. 10. The method according to claim 9, wherein 37. Embodiments 1 to 32, wherein the metal chelator is administered for a period of at least 1 year. 10. The method according to claim 9, wherein 38. Any one of embodiments 1 to 32, wherein the metal chelator is administered indefinitely. The method described below. 39. Any of embodiments 1 to 38, wherein a dose greater than the standard daily dose is administered at each administration. or one of the methods described above. 40. Any one of embodiments 1 to 39, wherein the total weekly dose administered is equal to the standard total weekly dose. The method described in the first paragraph. 41. The method of any one of embodiments 1 to 39, wherein the total weekly dose administered is less than the standard total weekly dose. The method according to any one of the preceding claims. 42. The total weekly dose administered is 0.75 to 0.9 times the standard total weekly dose. 42. The method of claim 41. 43. The standard daily dose is administered at each administration time and / or the total weekly dose is administered. The method of any one of embodiments 1 to 38, wherein the amount is equal to said standard total weekly dose. 44. Any of embodiments 1 to 39, wherein the total weekly dose administered is greater than the standard total weekly dose. The method according to any one of the preceding claims. 45. Embodiments in which the total weekly dose administered is 1.25 to 2 times the standard total weekly dose. 44. The method according to claim 44. 46. ​​The method of any one of embodiments 1 to 45, wherein the metal is iron. 47. The method of embodiment 46, wherein the metal chelator is an iron chelator. 48. Embodiments 1 to 4, wherein the metal chelator is other than an SP-420 compound. 7. The method according to any one of claims 1 to 7. 49. Directly or indirectly to any one of embodiments 29 to 32 or 39 to 45 Embodiment 47. Except as otherwise dependent on the patient, the iron chelator is an SP-420 compound. The method described below. 50. The SP-420 compound is administered at a dose of 18 to 100 mg / kg. 49. The method according to claim 49. 51. In embodiments, the SP-420 compound is administered at a dose of 18-30 mg / kg. 49. The method according to claim 49. 52. The method of embodiment 49, wherein the SP-420 compound is administered at a dose of 24 mg / kg. The method described. 53. In embodiments, the SP-420 compound is administered at a dose of 40-60 mg / kg. 49. The method according to claim 49. 54. In embodiments, the SP-420 compound is administered at a dose of 60-84 mg / kg. 49. The method according to claim 49. 55. The method of embodiment 49, wherein the SP-420 compound is administered at a dose of 72 mg / kg. The method described. 56. The SP-420 compound is administered in a dose ranging from 500 mg to 10 g. 49. The method of claim 49, 57. Embodiment 49, wherein the SP-420 compound is administered at a dose ranging from 1 g to 5 g. The method described below. 58. A method for treating a patient in which the SP-420 compound is administered at a total weekly dose of 54 to 400 mg / kg. 58. The method according to any one of embodiments 49 to 57. 59. A method for treating a patient in which the SP-420 compound is administered at a total weekly dose of 54 to 100 mg / kg. 59. The method of embodiment 58. 60. The SP-420 compound is administered at a total weekly dose of 100 to 200 mg / kg. The method of embodiment 58. 61. The SP-420 compound is administered at a total weekly dose of 200 to 300 mg / kg. The method of embodiment 58. 62. The SP-420 compound is administered at a total weekly dose of 300 to 400 mg / kg. The method of embodiment 58. 63. The SP-420 compound is administered in a total weekly dose ranging between 1.5 g and 30 g. 58. The method of any one of embodiments 49 to 57, wherein 64. The SP-420 compound is administered in a total weekly dose ranging between 3 g and 30 g. 64. The method of embodiment 63. 65. The SP-420 compound is administered in a total weekly dose ranging between 5 g and 20 g. 64. The method of embodiment 63. 66. The SP-420 compound is SP-420 ((S)-4,5-dihydro-2-[2 -hydroxy-4-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4- 66. The method of any one of claims 49 to 65, wherein the compound is a thiazole carboxylic acid. 67. The SP-420 compound is a pharmaceutically acceptable salt of SP-420. 66. The method according to any one of aspects 49 to 65. 68. The SP-420 compound is a pharmaceutically acceptable solvate of SP-420. 66. The method of any one of embodiments 49 to 65. 69. The SP-420 compound is a pharmaceutically acceptable hydrate of SP-420. 66. The method according to any one of embodiments 49 to 65. 70. The iron chelator is deferiprone or a pharmaceutically acceptable salt or solvate thereof. or a hydrate. 71. The standard dose of deferiprone is 25-33 mg / kg orally three times a day. The method of embodiment 70, wherein 72. The dose of deferiprone administered to the subject is 37.5 to 49.5 mg twice daily. 71. The method of embodiment 70, wherein the dose is 66 to 99 mg / kg once daily. 73. Except where directly or indirectly dependent on any one of embodiments 29 to 33 and wherein the iron chelator is deferoxamine or a pharmaceutically acceptable salt, solvate or 48. The method of embodiment 47, wherein the compound is a hydrate. 74. The standard dose of deferoxamine is 20-50 mg / kg, 5-7 days a week. It is administered as a slow subcutaneous or intravenous infusion over 8 to 12 hours, or The method of embodiment 73, wherein the dose is 1000 mg or less and is administered as a daily injection. 75. The dose of deloxamine administered to the subject is 20 to 50 mg / kg. Administered as a slow subcutaneous infusion over 4-6 hours, 5-7 days a week, or 40-100 mg / kg as a slow subcutaneous or intravenous infusion over 8-12 hours, 2-3 days per week or 1000-2000 mg administered as an every other day injection, The method according to claim 73. 76. Unless directly or indirectly dependent on any one of embodiments 29 to 33 wherein the iron chelator is deferasirox, a pharmaceutically acceptable salt, solvate or water thereof. 48. The method of embodiment 47, wherein the compound is a solvate. 77. The standard dose of deferasirox is 20-40 mg / kg, orally once daily. 77. The method of embodiment 76, wherein the patient is administered 78. The dose of deferasirox administered to the subject is 40 to 80 mg / kg. 77. The method of embodiment 76, wherein said compound is orally administered once every other day. 79. Except where directly or indirectly dependent on any one of embodiments 29 to 33 wherein the iron chelator is deferithrin, a pharmaceutically acceptable salt, solvate or water thereof. 48. The method of embodiment 47, wherein the compound is a solvate. 80. The standard dose of deferithrin is 10 to 80 mg / kg, administered orally once daily. 80. The method of embodiment 79, wherein the 81. The standard dose of deferithrin is 10-60 mg / kg, administered orally once daily. 80. The method of embodiment 79, wherein the 82. The standard dose of deferithrin is 10-40 mg / kg, administered orally once daily. 80. The method of embodiment 79, wherein the 83. The dose of deferithrin administered to the subject is 20 to 160 mg / kg. 80. The method of embodiment 79, wherein said compound is orally administered once every other day. 84. The dose of deferithrin administered to the subject is 20 to 120 mg / kg. 80. The method of embodiment 79, wherein said compound is orally administered once every other day. 85. The dose of deferithrin administered to the subject is 20 to 80 mg / kg. 80. The method of embodiment 79, wherein the compound is orally administered once every other day. 86. Except where directly or indirectly dependent on any one of embodiments 29 to 33 wherein the iron chelator is SPD602 (FBS0701) or a pharmaceutically acceptable salt thereof 48. The method of embodiment 47, wherein the compound is a salt, solvate or hydrate. 87. The standard dose of SPD602 is 10-60 mg / kg, administered orally once daily. 87. The method of embodiment 86, wherein 88. The dose of SPD602 administered to the subject is 20 to 120 mg / kg. 87. The method of embodiment 86, wherein the compound is orally administered once every other day. 89. The method of any one of embodiments 46 to 88, wherein the metal-induced disease is iron overload. How to post. 90. The metal-induced disease is the result of unequal distribution or redistribution of iron in the body. 89. The method according to claim 89. 91. The metal-induced disease is atransferrinemia, aceruloplasminemia, or The method of embodiment 89, wherein the disease is Fredreich's ataxia. 92. The method of embodiment 89, wherein said metal-induced disease is the result of transfusional iron overload. 93. The method of embodiment 89, wherein the metal-induced disease is β-thalassemia. 94. The method of embodiment 93, wherein the metal-induced disease is β-thalassemia major. . 95. The method of embodiment 93, wherein the metal-induced disease is β-thalassemia intermedia. . 96. The metal-induced disease is sickle cell anemia, Diamond-Blackfan anemia, iron Blastic anemia, chronic hemolytic anemia, off-therapy leukemia, bone marrow transplantation or 90. The method of embodiment 89, wherein the is a myelodysplastic syndrome. 97. The metal-induced disease is a genetic disease that results in excessive absorption of dietary iron. 89. The method of claim 89. 98. The metal-induced disease is hereditary hemochromatosis or porphyria cutanea tarda. 98. The method of embodiment 97, wherein the disease is 99. The metal-induced disease is an acquired disease that results in excessive dietary iron absorption. 90. The method of embodiment 89. 100. The method of embodiment 99, wherein the metal-induced disease is a liver disease. 101. The method of embodiment 100, wherein the liver disease is hepatitis. 102. Embodiments 33 to 45 may be directly or indirectly connected to any one of embodiments 29 to 33. Unless indirectly dependent, the metal-induced disease is due to lanthanide or actinide excess. 46. ​​The method of any one of embodiments 1 to 28 and 33 to 45. 103. The metal chelating agent is diethylenetriaminepentaacetic acid (DTPA). 103. The method of claim 102. 104. Embodiments 33 to 45 may be directly or indirectly combined with any one of embodiments 29 to 33. 28. Except where indirectly dependent, the metal is lead or mercury. and any one of methods 33 to 45. 105. The method of embodiment 104, wherein the metal-induced disease is lead or mercury poisoning. . 106. The metal chelating agent is edetate calcium disodium or ethylenediamine 106. The method of embodiment 105, wherein the hydroxybenzoate is ethylenediaminetetraacetic acid (EDTA).

[0062] The present disclosure is further exemplified by numbered embodiment 2 described below. 1. A method for (a) treating a metal-induced disease and / or (b) reducing the renal, gastrointestinal, hepatic, hematologic, auditory, visual, and / or cutaneous toxicity of a metal chelator in a subject, comprising orally administering multiple doses of a metal chelator to the subject, each dose being administered more than 24 hours after the previous dose and / or not more than five times per week. 2. A method for (a) treating a metal-induced disease and / or (b) reducing the renal, visual, auditory, neurological, respiratory and / or musculoskeletal toxicity of a metal chelator in a subject, comprising administering to said subject intravenously or subcutaneously fewer than five weekly doses of a metal chelator. 3. The method of claim 1, wherein the metal chelator is administered 5 times per week, 15 to 25 times per month, or 20 to 25 times per month. 4. The method according to claim 1 or 2, wherein the metal chelator is administered (a) four times per week, (b) three times per week, (c) 12 to 18 times per month, or (d) 15 to 25 times per month. 5. The method according to claim 1 or 2, wherein the metal chelating agent is administered every 36 to 72 hours. 6. The method of claim 1 or 2, wherein the metal chelator is administered for a period of at least one week, at least one month, at least three months, at least six months, at least one year, or indefinitely. 7. (a) a dose greater than the standard daily dose is administered at each administration time, optionally, the total weekly dose administered is equal to or less than the standard total weekly dose, optionally, the total weekly dose administered is 0.75 to 0.9 times the standard total weekly dose; (b) the standard daily dose is administered at each administration time and / or the total weekly dose administered is equal to the standard total weekly dose; or (c) the total weekly dose administered is greater than the standard total weekly dose, and optionally, the total weekly dose administered is 1.25 to 2 times the standard total weekly dose; The method according to 1 or 2 above. 8. The method of claim 1 or 2, wherein the metal is iron, and optionally the metal chelator is an iron chelator. 9. The method according to claim 1 or 2, wherein the metal chelating agent is an SP-420 compound. 10. The metal chelator is an SP-420 compound, and optionally: (a) the SP-420 compound is administered at a dose of 18 to 100 mg / kg; (b) the SP-420 compound is administered at a total weekly dose of 54 to 400 mg / kg; (c) the SP-420 compound is SP-420 ((S)-4,5-dihydro-2-[2-hydroxy-4-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid) or a pharmaceutically acceptable salt thereof; or (d) Any combination of (a) to (c), The method according to item 9 above. 11. The method according to claim 1 or 2, wherein the metal chelating agent is not an SP-420 compound. 12. The method of claim 11, wherein the metal chelator is deferiprone or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and optionally, the dose of deferiprone administered to the subject is 37.5 to 49.5 mg / kg twice daily or 66 to 99 mg / kg once daily. 13. The method of claim 11, wherein the metal chelator is deferoxamine or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and optionally the dose of deferoxamine administered to the subject is (a) 20-50 mg / kg administered as a slow subcutaneous infusion over 4-6 hours, 5-7 days a week, or (b) 40-100 mg / kg administered as a slow subcutaneous or intravenous infusion over 8-12 hours, 2-3 days a week, or (c) 1000-2000 mg administered as an injection every other day or 3 days a week. 14. The method of claim 11, wherein the metal chelator is deferasirox or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and optionally, the dose of deferasirox administered to the subject is 40 to 80 mg / kg, administered orally once every other day or three days a week. 15. The method of claim 11, wherein the metal chelator is deferithrin or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and optionally, the dose of deferithrin administered to the subject is 20 to 160 mg / kg and is administered orally once every other day or three days a week. 16. The method of claim 11, wherein the metal chelator is SPD602 (FBS0701) or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and optionally, the dose of SPD602 administered to the subject is 20 to 120 mg / kg and is administered orally once every other day or three days a week. 17. The method according to claim 1 or 2, wherein the metal-induced disease is iron overload. 18. The method according to claim 1 or 2, wherein the metal-induced disease is lanthanide or actinide excess, and optionally the metal chelator is diethylenetriaminepentaacetic acid (DTPA). 19. The method of claim 1 or 2, wherein the metal is lead or mercury, and optionally the metal-induced disease is lead or mercury poisoning, and optionally the metal chelator is calcium disodium edetate or ethylenediaminetetraacetic acid (EDTA). 20. A method for (a) treating a metal-induced disease and / or (b) reducing the hematologic, gastrointestinal, hepatic, and / or musculoskeletal toxicity of a metal chelator in a subject, said method comprising orally administering one or two daily doses of said metal chelator to said subject, wherein said metal chelator is deferiprone or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and optionally: (a) the method comprises administering two daily doses of the metal chelator; (b) the daily doses are administered at intervals of 6 to 12 hours; or (c) the metal chelator is administered 14 times per week; method. All publications, patents, patent applications, and other documents cited herein are incorporated by reference for all purposes to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated by reference for all purposes. In the event of a conflict between the teachings of one or more references incorporated herein and the present disclosure, the teachings of the present disclosure are intended to control.

Claims

1. 1. A pharmaceutical composition comprising (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6-dioxaheptyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid ("SP-420"), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in a method for treating iron overload in a subject, said method comprising orally administering to said subject multiple doses of said SP-420, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein said SP-420, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dose of 18-100 mg / kg three or four times a week, but every other day or less frequently.

2. The SP-420 or a pharmaceutically acceptable salt, solvate or hydrate thereof (i) every other day; (ii) three times a week, or (iii) four times a week; The pharmaceutical composition according to claim 1,

3. 10. The pharmaceutical composition of claim 1, wherein the SP-420 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered every other day with a weekend break.

4. 10. The pharmaceutical composition of claim 1, wherein the SP-420 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered every 48 to 72 hours.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein the SP-420 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered for a period of at least one week, at least one month, at least three months, at least six months, at least one year, or indefinitely.

6. (a) administering the SP-420 or a pharmaceutically acceptable salt, solvate, or hydrate thereof at a total weekly dose of 54 to 400 mg / kg; and / or (b) The SP-420 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is SP-420 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 5.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein the SP-420 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered at a dose of 18 to 30 mg / kg, 30 to 40 mg / kg, 40 to 60 mg / kg, or 60 to 84 mg / kg, 3 or 4 times a week, but every other day or less frequently.

8. 8. The pharmaceutical composition of claim 7, wherein the SP-420 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered at a dose of 18-30 mg / kg, 40-60 mg / kg, or 60-84 mg / kg, 3 or 4 times a week, but every other day or less frequently.

9. 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the SP-420 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered at a weekly total dose of 54 to 100 mg / kg, 100 to 200 mg / kg, or 200 to 300 mg / kg.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the SP-420 or a pharmaceutically acceptable salt, solvate or hydrate thereof exhibits nephrotoxicity when administered daily at the same total weekly dose.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the nephrotoxicity of the SP-420 or its pharmaceutically acceptable salt, solvate or hydrate is reduced.

12. 10. The pharmaceutical composition of claim 1, wherein the SP-420 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered at a dose of 18-30 mg / kg, 3 or 4 times a week, but every other day or less frequently.

13. 13. The pharmaceutical composition of claim 1 or claim 12, wherein the SP-420 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered at 40-60 mg / kg three or four times a week, but every other day or less frequently.

14. 14. The pharmaceutical composition of claim 13, wherein the SP-420 or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered at 60-84 mg / kg, three or four times a week, but every other day or less frequently.

15. 2. The pharmaceutical composition of claim 1, wherein the SP-420 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered at a total weekly dose of 54-100 mg / kg.

16. 16. The pharmaceutical composition of any one of claims 1 to 15, wherein the SP-420 or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered every other day with a weekend break.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the iron overload is transfusional iron overload.

18. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein the subject has beta thalassemia, sickle cell anemia, Diamond-Blackfan anemia, sideroblastic anemia, or chronic hemolytic anemia.

19. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein the subject has treatment-withdrawal leukemia, bone marrow transplant, or myelodysplastic syndrome.

20. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein the subject has β-thalassemia major, sickle cell anemia, or myelodysplastic syndrome.

21. The pharmaceutical composition of any one of claims 1 to 17, wherein the subject has thalassemia.

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