Modulation of vadadustat drug-drug interactions

Abstract

Provided herein are methods for reducing, minimizing, or controlling drug-drug interactions resulting from administration of a drug (e.g., a first drug) that is vadadustat (i.e., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1)) and another (e.g., a second) drug (e.g., a drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of certain proteins, receptors, and / or transporters (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir)).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 155,022, filed March 1, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (vadadustat, code: AKB-6548, compound 1), having the following chemical formula: [ka] is a prolyl hydroxylase inhibitor and may be administered to a subject to treat or prevent diseases that are ameliorated by the modulation of hypoxia inducible factor (HIF) prolyl hydroxylase (e.g., peripheral vascular disease (PVD), coronary artery disease (CAD), heart failure, ischemia, hypoxia, and anemia). For some subjects receiving Compound 1, the compound may be administered as part of a treatment regimen that includes other drugs and therapeutic agents. For example, some subjects receiving Compound 1 also require therapeutic agents, such as phosphate binders (e.g., polymeric amines that bind phosphate), or inhibitors and / or substrates of certain proteins, receptors, and / or transporters (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir). When Compound 1 and / or other drugs and therapeutic agents (e.g., phosphate binders, probenecid, cyclosporine, rifampin, digoxin, or adefovir) are co-administered to a subject, their bioavailability may be affected. For example, some subjects receiving Compound 1 also require a phosphate binder (e.g., a polymeric amine that binds phosphate) to control serum phosphorus levels. The phosphate binder can potentially reduce the bioavailability of Compound 1. Thus, new methods are needed to control any such drug-drug interactions when administering Compound 1 with other drugs and therapeutic agents, so as not to adversely affect the therapeutic effect of the administered drug or to adversely affect the subject. Summary of the Invention

[0003] The present invention is based in part on the surprising discovery of new therapeutic regimens that provide for modulation of (e.g., prevent, control, reduce, or minimize) drug-drug interactions between a first drug, which is vadadustat, and a second drug, such as a drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of certain proteins, receptors, and / or transporters (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir). Such regimens may have beneficial outcomes for patients, including those described herein.

[0004] In one aspect, the invention provides a method of preventing, controlling, reducing, or minimizing a drug-drug interaction between a first drug and a second drug, comprising administering to a subject: (a) an effective amount of the first drug, the first drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharmaceutical composition comprising an effective amount of the first drug; (b) administering an effective amount of the second drug, the second drug comprising a polymeric amine that binds phosphate; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), Methods are provided herein, wherein (a) is administered at least 2 hours prior to and / or at least 2 hours after administration of (b).

[0005] In another aspect, the invention provides a method of preventing, controlling, reducing, or minimizing a drug-drug interaction between a first drug and a second drug, comprising administering to a subject: (a) an effective amount of the first drug, the first drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharmaceutical composition comprising an effective amount of the first drug; (b) administering an effective amount of the second drug, the second drug comprising a polymeric amine that binds phosphate; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), Methods are provided herein, wherein (a) is administered at least one hour prior to and / or at least one hour after administration of (b).

[0006] In another aspect, the invention provides a method for increasing or maintaining the bioavailability of a drug, comprising administering to a subject: (a) an effective amount of a drug, the drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharmaceutical composition comprising the drug in an effective amount; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein (a) is administered at least 2 hours before and / or at least 2 hours after administration of (b).

[0007] In another aspect, the invention provides a method for increasing or maintaining the bioavailability of a drug, comprising administering to a subject: (a) an effective amount of the drug, the drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharmaceutical composition comprising an effective amount of the drug; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein (a) is administered at least one hour before and / or at least one hour after administration of (b).

[0008] In another aspect, the invention provides a method for minimizing, controlling, or preventing decreased absorption of a drug, comprising administering to a subject: (a) an effective amount of a drug, the drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharmaceutical composition comprising the drug in an effective amount; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein (a) is administered at least 2 hours before and / or at least 2 hours after administration of (b).

[0009] In another aspect, the invention provides a method for minimizing, controlling, or preventing decreased absorption of a drug, comprising administering to a subject: (a) an effective amount of the drug, the drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharmaceutical composition comprising an effective amount of the drug; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein (a) is administered at least one hour before and / or at least one hour after administration of (b).

[0010] In some embodiments, (b) is sevelamer hydrochloride or sevelamer carbonate.

[0011] In embodiments, (b) is sevelamer hydrochloride.

[0012] In embodiments, (b) is sevelamer carbonate.

[0013] In some embodiments, (b) is administered as a tablet.

[0014] In some embodiments, (b) is administered as a powder.

[0015] In some embodiments, the first drug is administered at least one hour before the second drug is administered.

[0016] In some embodiments, the first drug is administered at least 2 hours after taking the second drug.

[0017] In some embodiments, (a) is administered at least 1 hour prior to taking (b), and (b) is sevelamer hydrochloride or sevelamer carbonate.

[0018] In some embodiments, (a) is administered at least 2 hours after taking (b), and (b) is sevelamer hydrochloride or sevelamer carbonate.

[0019] In another aspect, the invention provides a method of reducing or minimizing a drug-drug interaction between a first drug and a second drug, comprising administering to a subject: (a) an effective amount of the first drug, the first drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharmaceutical composition comprising an effective amount of the first drug; (b) administering an effective amount of the second drug, wherein the second drug is an OAT1 / OAT3 inhibitor; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

[0020] In another aspect, the invention provides a method for preventing a drug-drug interaction between a first drug and a second drug, comprising administering to a subject: (a) an effective amount of the first drug, the first drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharmaceutical composition comprising an effective amount of the first drug; (b) administering an effective amount of the second drug, wherein the second drug is an OAT1 / OAT3 inhibitor; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

[0021] In another aspect, the invention provides a method of controlling a drug-drug interaction between a first drug and a second drug, comprising administering to a subject: (a) an effective amount of the first drug, the first drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharmaceutical composition comprising an effective amount of the first drug; (b) administering an effective amount of the second drug, wherein the second drug is an OAT1 / OAT3 inhibitor; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

[0022] In another aspect, the invention provides a method for maintaining bioavailability of a drug, comprising administering to a subject: (a) an effective amount of a drug, the drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharmaceutical composition comprising an effective amount of the drug; (b) administering an effective amount of a second drug, the second drug being an OAT1 / OAT3 inhibitor; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

[0023] In another aspect, the present invention provides a method of minimizing increased exposure to a drug, comprising administering to a subject: (a) an effective amount of a drug, the drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharmaceutical composition comprising an effective amount of the drug; (b) administering an effective amount of a second drug, the second drug being an OAT1 / OAT3 inhibitor; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

[0024] In another aspect, the present invention provides a method for preventing increased exposure to a drug, comprising administering to a subject: (a) an effective amount of a drug, the drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharmaceutical composition comprising an effective amount of the drug; (b) administering an effective amount of a second drug, the second drug being an OAT1 / OAT3 inhibitor; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

[0025] In another aspect, the present invention provides a method for controlling increased exposure to a drug, comprising administering to a subject: (a) an effective amount of a drug, the drug being {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharmaceutical composition comprising an effective amount of the drug; (b) administering an effective amount of a second drug, the second drug being an OAT1 / OAT3 inhibitor; The subject has renal anemia (anemia secondary to or associated with chronic kidney disease), wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

[0026] In embodiments, the subject is at risk for or has gout or gouty arthritis.

[0027] In some embodiments, (b) is probenecid.

[0028] In some embodiments, (b) is administered as a tablet.

[0029] In some embodiments, the amount of (a) is decreased compared to the amount administered in the absence of (b) or as a monotherapy.

[0030] In embodiments, the amount of (a) is reduced by about 20% to about 80% compared to the amount administered in the absence of (b) or as a monotherapy.

[0031] In some embodiments, the amount of (b) is reduced by about 40% to about 60% compared to the amount administered in the absence of (a) or as a monotherapy.

[0032] In another aspect, the invention provides a method of treating renal anemia (anemia secondary to or associated with chronic kidney disease), comprising administering to a subject having renal anemia an effective amount of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; The compound is for administration in combination with a composition comprising a polymeric amine selected from sevelamer hydrochloride and sevelamer carbonate.

[0033] In embodiments, the compound which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, is administered at least 1 hour prior to administration of the composition comprising a polymeric amine selected from sevelamer hydrochloride or sevelamer carbonate.

[0034] In embodiments, the compound which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, is administered at least 2 hours after administration of the composition comprising a polymeric amine selected from sevelamer hydrochloride or sevelamer carbonate.

[0035] In another aspect, the invention provides a method of treating renal anemia (anemia secondary to or associated with chronic kidney disease), comprising administering to a subject having renal anemia an effective amount of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; The method is provided wherein the compound is for administration in combination with an OAT1 / OAT3 inhibitor that is probenecid.

[0036] In some embodiments, the amount of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, is reduced compared to the amount administered in the absence of the probenecid OAT1 / OAT3 inhibitor or in monotherapy. [Brief description of the drawings]

[0037] [Figure 1] Shown are the mean (standard deviation) plasma concentrations of vadadustat 1) when administered alone, 2) when administered in combination with sevelamer carbonate (day 3), and 3) when administered 1 hour before sevelamer carbonate (day 5) and 2 hours after sevelamer carbonate (day 7).

[0038] [Diagram 2]Figure 1 shows the effect of a single dose of a phosphate binder, sevelamer carbonate, on the PK of vadadustat (300 mg). Values ​​shown are geometric least squares mean ratios and error bars represent 90% geometric confidence intervals. AUC0-∞: area under the plasma concentration-time curve from time 0 to infinity, AUC0-last: area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, Cmax: maximum observed plasma concentration, PK: pharmacokinetics.

[0039] [Diagram 3] Figures 3a-3b show the mean (standard deviation) vadadustat plasma concentrations (days 1 and 5) (ng / mL) versus time when 1) 300 mg vadadustat was administered alone, and 2) 300 mg vadadustat was administered with 500 mg cyclosporine (pharmacokinetic populations).

[0040] [Figure 4] 4a-4b show the mean (standard deviation) vadadustat-O-glucuronide plasma concentrations (Days 1 and 5) (ng / mL) versus time for 1) 300 mg vadadustat administered alone, and 2) 300 mg vadadustat administered with 500 mg cyclosporine (pharmacokinetic populations).

[0041] [Diagram 5] 5a-5b show the mean (standard deviation) vadadustat plasma concentrations (Days 1 and 8) (μg / ml) versus time (pharmacokinetic populations) for 1) 300 mg vadadustat administered alone, and 2) 300 mg vadadustat administered with 500 mg probenecid.

[0042] [Figure 6] 6a-6b show the mean (standard deviation) vadadustat-O-glucuronide plasma concentrations (Days 1 and 8) (μg / ml) versus time (pharmacokinetic populations) for 1) 300 mg vadadustat administered alone, and 2) 300 mg vadadustat administered with 500 mg probenecid.

[0043] [Figure 7] 7a-7b show the mean (standard deviation) digoxin plasma concentrations (Days 1 and 16) following 1) 0.5 mg digoxin administered alone, and 2) 0.5 mg digoxin administered with 600 mg vadadustat (pharmacokinetic populations).

[0044] [Figure 8] 8a-8b show the mean (standard deviation) adefovir plasma concentrations (days 1 and 7) following 1) 10 mg of adefovir administered alone, and 2) 10 mg of adefovir administered with 600 mg of vadadustat (pharmacokinetic populations). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Vadadustat ({[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, (Compound 1)) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PH inhibitor). [ka]

[0046] Compound 1 has emerged as a highly useful new drug for the treatment or prevention of renal anemia (anemia secondary to or associated with chronic kidney disease).

[0047] A subject with renal anemia (anemia secondary to or associated with chronic kidney disease) may be receiving other therapeutic agents concurrently with a vadadustat treatment regimen (e.g., to treat a coexisting condition or to treat a complication associated with chronic kidney disease or renal anemia (anemia secondary to or associated with chronic kidney disease)). In particular, drug-drug interactions may occur when a patient is administered Compound 1 in combination with another drug (e.g., a drug that contains a polymeric amine that binds phosphate (e.g., a sevelamer-based binder such as sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of certain proteins, receptors, and / or transporters (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir)). For example, administering Compound 1 with a composition that contains a polymeric amine may cause a drug-drug interaction between Compound 1 and the polymeric amine.

[0048] Drug-drug interactions can manifest in a variety of ways, including pharmaceutical interactions, pharmacokinetic interactions, pharmacodynamic interactions, effects on absorption, distribution, metabolism, or excretion. For example, drug-drug interactions can adversely affect the bioavailability and / or absorption of Compound 1 and / or other therapeutic agents, such as drugs that contain polymeric amines that bind phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or inhibitors and / or substrates of certain proteins, receptors, and / or transporters (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir). In other embodiments, still other side effects may result. Thus, modulation of drug-drug interactions is highly beneficial in achieving successful treatment of subjects with chronic kidney disease or renal anemia (anemia secondary to or associated with chronic kidney disease).

[0049] Provided herein are methods for reducing, minimizing, or controlling drug-drug interactions resulting from administration of Compound 1 and another therapeutic agent (e.g., a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate)), or an inhibitor and / or substrate of a certain protein, receptor, and / or transporter (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir) to a subject. Also provided herein are methods for increasing the bioavailability of Compound 1, where a subject is administered Compound 1 and a certain drug (e.g., a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of a certain protein, receptor, and / or transporter (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir).

[0050] Specifically, provided herein are methods for reducing, minimizing, or controlling drug-drug interactions resulting from administration to a subject of Compound 1 and other therapeutic agents that include a drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). Also provided herein are methods for increasing the bioavailability of Compound 1, where Compound 1 and certain drugs that include a polymeric amine (e.g., sevelamer hydrochloride or sevelamer carbonate) are administered to a subject.

[0051] definition In order that the present invention may be more readily understood, certain terms are first defined below. Additional definitions of the following terms and other terms are set forth throughout the specification. Publications and other reference materials referred to herein to describe the background of the invention and to provide further details regarding its practice are incorporated herein by reference for all purposes.

[0052] Animal: As used herein, the term "animal" refers to any member of the animal kingdom. In some embodiments, "animal" refers to humans at any stage of development. In some embodiments, "animal" refers to non-human animals at any stage of development. In some embodiments, the non-human animals are mammals (e.g., rodents, mice, rats, rabbits, monkeys, dogs, cats, sheep, cows, primates, and / or pigs). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, insects, and / or parasites. In some embodiments, animals may be transgenic animals, genetically engineered animals, and / or clones.

[0053] Approximately or about: As used herein, the term "approximately" or "about" as applied to one or more values ​​of interest refers to a value similar to a stated reference value. In embodiments, the term "approximately" or "about" refers to a range of values ​​that includes 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater or less) of the stated reference value (except where such number exceeds 100% of possible values), unless otherwise specified or otherwise clear from the context.

[0054] Dose: As used herein, the term "dose" refers to the amount of a compound, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, administered at one time. A dose may comprise a single unit dosage form, or alternatively, may comprise more than a single unit dosage form (e.g., a single dose may comprise two tablets), or less than a single unit dosage form (e.g., a single dose may comprise half a tablet).

[0055] Daily dose: As used herein, the term "daily dose" refers to the amount of a compound, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, administered in a 24-hour period. Thus, the daily dose may be administered all at once (i.e., once daily), or alternatively, the daily dose may be divided so that the compound is administered two times a day, three times a day, or even four times a day.

[0056] Improve, increase, or decrease: As used herein, the terms "improve," "increase," or "decrease," or grammatical equivalents, refer to a value compared to a baseline measurement, such as a measurement in the same individual prior to the initiation of a treatment described herein, or a measurement in a control sample or subject (or control samples or subjects) in the absence of a treatment described herein. A "control subject" is a subject suffering from the same form of disease as the subject being treated and who is approximately the same age as the subject being treated.

[0057] In vitro: As used herein, the term "in vitro" refers to events that take place not in a multicellular organism but in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, etc.

[0058] In vivo: As used herein, the term "in vivo" refers to events that occur within a multicellular organism, such as humans and non-human animals. In the context of cell-based systems, the term can be used to refer to events that occur within a living cell (as opposed to, for example, in vitro systems).

[0059] Patient: As used herein, the term "patient" or "subject" refers to any organism to which provided compositions can be administered, for example, for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Humans include prenatal and postnatal forms.

[0060] Pharmaceutically acceptable: The term "pharmacologically acceptable," as used herein, refers to materials which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0061] Pharmaceutically acceptable salts: Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. provide a detailed description of pharma-ceutically acceptable salts in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharma-ceutically acceptable non-toxic acid addition salts are the salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-terminated salts. + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium cations, quaternary ammonium cations, and amine cations, where appropriate, formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates, and arylsulfonates. Further pharmaceutically acceptable salts include salts formed from the quaternization of amines using suitable electrophiles, e.g., alkyl halides to form quaternary alkylated amino salts.

[0062] Preventing: As used herein, the terms "prevent", "preventing", or "prevention" refer to the effect of reducing an undesirable effect, e.g., an undesirable drug interaction. Prevention does not require 100% elimination of the likelihood of the event. Rather, prevention indicates that the likelihood of the occurrence of an event has been reduced by the compound or method.

[0063] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes prenatal and postnatal forms. In many embodiments, the subject is a human. A subject may be a patient, which refers to a human who visits a health care provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may be afflicted with or susceptible to a disease or disorder, but may or may not exhibit symptoms of the disease or disorder.

[0064] Substantially: As used herein, the term "substantially" refers to the qualitative state of exhibiting the full or nearly full extent or degree of a desired characteristic or property. Those skilled in the art of biology will understand that biological and chemical phenomena rarely, if ever, go to completion and / or reach completion, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of completion inherent in many biological and chemical phenomena.

[0065] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount sufficient to treat, diagnose, prevent, and / or delay the onset of symptoms of a disease, disorder, and / or condition when administered to a subject suffering from or susceptible to the disease, disorder, and / or condition. One of skill in the art will appreciate that a therapeutically effective amount is typically administered in a dosing regimen comprising at least one unit dose.

[0066] Treating: As used herein, the terms "treat", "treatment", or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, delay the onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who do not exhibit signs of the disease and / or who exhibit only early signs of the disease for the purpose of reducing the risk of developing conditions associated with the disease.

[0067] As used herein, the term "HIF prolyl hydroxylase" is art-recognized and may be abbreviated as "PHD." HIF prolyl hydroxylases are also known as "prolyl hydroxylase domain-containing proteins," which may be abbreviated as "PHD." In this regard, there are three distinct PHD isoforms, PHD1, PHD2, and PHD3, which are also referred to as EGLN2, EGLN1, and EGLN3, or HPH3, HPH2, and HPH1, respectively.

[0068] As used herein, the term "unit dosage form" includes tablets; caplets; capsules, such as soft elastic gelatin capsules; sachets; cachets; troches; lozenges; dispersions; powders; solutions; gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions), emulsions (e.g., oil-in-water emulsions or water-in-oil liquid emulsions), solutions, and elixirs; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for oral or parenteral administration to a patient. A unit dosage form does not necessarily have to be administered as a single dose, nor does a single unit dosage form necessarily constitute an entire dose.

[0069] Further abbreviations and acronyms are provided in the table below. [Table 1] TIFF2024510926000005.tif231170TIFF2024510926000006.tif185170

[0070] Methods of the Invention The methods described herein can modulate drug-drug interactions between one drug (e.g., a first drug) and another drug (e.g., a second drug) in a subject with renal anemia (anemia secondary to or associated with chronic kidney disease), where one drug (e.g., the first drug) is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1)) and the other drug (e.g., the second drug) includes, but is not limited to, drugs that contain polymeric amines that bind phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), and inhibitors and / or substrates of certain proteins, receptors, and / or transporters (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir).

[0071] Treatment of patients with anemia (e.g., renal anemia (anemia secondary to or associated with chronic kidney disease)) that includes administration of a HIF-PH inhibitor (e.g., vadadustat) may also include administration of one or more additional therapeutic agents. Such additional therapeutic agents may be useful in treating one or more co-morbid conditions, e.g., co-morbid conditions present prior to the initiation of anemia therapy and / or co-morbid conditions that arise during the course of anemia treatment.

[0072] For example, comorbid conditions and / or complications may include (but are not limited to) hyperphosphatemia due to impaired phosphorus excretion due to increasingly dysregulated calcium-phosphorus homeostasis. Such comorbid conditions also include, but are not limited to, thrombosis, sleep disorders, somnolence, retinal hemorrhage, vertigo, hypertension, palpitations, diarrhea, nausea, abdominal discomfort, vomiting, loose stools, gastroenteritis, stomatitis, liver dysfunction, elevated AST, rash, pruritus, eczema, erythema, alopecia, cold sweat, frequent urination, decreased serum ferritin, desaturated transferritin, fatigue, chest pain, elevated bilirubin, and / or elevated ALT. Other comorbid conditions include, but are not limited to, gout, gouty arthritis, hyperuricemia, high cholesterol, triglyceride levels, hypervolemia, edema, and / or other swellings associated with, for example, congestive heart failure, liver disease, and kidney disease.

[0073] In embodiments, administration of one or more additional therapeutic agents may be useful for gout, gouty arthritis, prevention of organ rejection in kidney, liver, and cardiac allografts, rheumatoid arthritis, psoriasis, tuberculosis, meningococcal carriage, heart failure (e.g., increasing myocardial contractility and / or controlling resting heart rate), atrial fibrillation, and / or chronic hepatitis B.

[0074] However, significant challenges can arise when a patient receives multiple therapeutic agents and the therapeutic agents may interact with each other in the patient's body in a manner that can adversely affect the intended therapeutic effect. As described herein, such drug-drug interactions can manifest themselves in the form of pharmaceutical interactions, pharmacokinetic interactions, pharmacodynamic interactions, affecting absorption, distribution, metabolism, and / or excretion. For example, drug-drug interactions can adversely affect the bioavailability and / or absorption of Compound 1 and / or another drug (e.g., a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of a certain protein, receptor, and / or transporter (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir). Specifically, drug-drug interactions can adversely affect the bioavailability and / or absorption of Compound 1 and / or a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate).

[0075] In some embodiments, the methods described herein prevent drug-drug interactions between a drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1) and another drug (e.g., a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or severomine carbonate), or an inhibitor and / or substrate of a certain protein, receptor, or transporter (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir)). In some embodiments, the methods described herein prevent drug-drug interactions between a drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1) and another drug (e.g., a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or severomine carbonate), or an inhibitor and / or substrate of a certain protein, receptor, or transporter (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir). In some embodiments, the methods described herein prevent a drug-drug interaction between a first drug, which is 1,4-dihydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), and a second drug, such as a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of a certain protein, receptor, or transporter (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir). In some embodiments, the methods described herein control a drug-drug interaction. In some embodiments, the methods described herein reduce a drug-drug interaction. In some embodiments, the methods described herein minimize a drug-drug interaction.

[0076] In embodiments, the methods described herein prevent a drug-drug interaction between a drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1) and a drug that comprises a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In embodiments, the methods described herein prevent a drug-drug interaction between a first drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1) and a second drug that comprises a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In embodiments, the methods described herein control a drug-drug interaction. In embodiments, the methods described herein reduce a drug-drug interaction. In embodiments, the methods described herein minimize a drug-drug interaction.

[0077] In embodiments, the drug-drug interaction relates to pharmaceutical interactions, pharmacokinetic interactions, pharmacodynamic interactions, absorption, distribution, metabolism, and / or excretion. In embodiments, the methods described herein increase the bioavailability of a drug. In embodiments, the methods described herein maintain the bioavailability of a drug. In embodiments, the methods described herein reduce (e.g., minimize) the decrease in absorption of a drug. In embodiments, the methods described herein prevent the decrease in absorption of a drug. In embodiments, the methods described herein control the decrease in absorption of a drug.

[0078] Dose adjustment In some embodiments, drug interactions (e.g., as described herein) are modulated by adjusting the dosage of a therapeutic agent administered to a patient (e.g., as compared to the amount administered in monotherapy). In some embodiments, drug interactions (e.g., as described herein) are modulated by adjusting the dosage of at least one therapeutic agent administered to a patient.

[0079] In some embodiments, dose adjustments occur independently of timing adjustments.

[0080] In some embodiments, both dose adjustment and timing adjustment are performed.

[0081] In some embodiments, only dose adjustments or only timing adjustments are made. In some embodiments, only dose adjustments are made.

[0082] In some embodiments, a drug-drug interaction (e.g., as described herein) is modulated by adjusting the dosage of at least one therapeutic agent administered to a patient. In some embodiments, the dosage of a drug (e.g., a first drug) that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof) is adjusted. In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of another drug (e.g., a second drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein) is adjusted. In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of both drugs (e.g., a HIF-PH inhibitor, e.g., a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, and a drug that includes a polymeric amine that binds phosphate, probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein) is adjusted. In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased.

[0083] In some embodiments, the dosage is increased. In some embodiments, the dosage is not increased by more than about 100%, 200%, or 300%. In some embodiments, the dosage is increased by more than about 300%. In some embodiments, the dosage is increased by about 20%, 40%, 60%, 80%, 100%, 120%, 140%, 160%, 180%, 200%, 220%, 240%, 260%, 280%, or 300%. In some embodiments, the dosage is increased by 0 to about 50%, about 50% to about 100%, about 100% to about 150%, about 150% to about 200%, about 200% to about 250%, or about 250% to about 300%. In some embodiments, the dosage is decreased. In some embodiments, the dosage is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or 100%. In some embodiments, the dosage is reduced by at least 0 to about 25%, at least about 25% to about 50%, at least about 50% to about 75%, or at least about 75% to about 100%. In some embodiments, the dosage is reduced by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or 100%. In some embodiments, the dosage is reduced by 0 to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to about 100%. In some embodiments, the dosage is not reduced by more than about 25%, 50%, 75%, or 100%.

[0084] In some embodiments, the dosage of at least one therapeutic agent is adjusted, and the adjustment is as described herein. In some embodiments, the dosage is increased, and the amount is as described herein. In some embodiments, the dosage is decreased, and the amount is as described herein.

[0085] In some embodiments, the dosage of a drug (e.g., a first drug) that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof) is adjusted, where the adjustment is as described herein. In some embodiments, the dosage is increased, where the amount is as described herein. In some embodiments, the dosage is decreased, where the amount is as described herein.

[0086] In embodiments, the dosage of another (e.g., second) drug (e.g., a therapeutic agent such as a drug that comprises a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein) is adjusted, where the adjustment is as described herein. In some embodiments, the dosage is increased, where the amount is as described herein. In some embodiments, the dosage is decreased, where the amount is as described herein.

[0087] In some embodiments, the dosage of both the drug (e.g., a first drug that is a HIF-PH inhibitor such as {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) and another (e.g., a second) drug (e.g., a drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein) is adjusted, where the adjustment is as described herein. In some embodiments, the dosage is increased, where the amount is as described herein. In some embodiments, the dosage is decreased, where the amount is as described herein.

[0088] In some embodiments, the drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) is the first drug administered to the patient. In some embodiments, the drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) is not the first drug administered to the patient. In some embodiments, the drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) is the second drug administered to the patient.

[0089] Provided herein are methods for reducing or minimizing drug-drug interactions between one drug (e.g., a first drug) and another (e.g., a second) drug (or a metabolite thereof) in a subject. In some embodiments, the amount of the other (e.g., second) drug (e.g., a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein) is adjusted compared to the amount administered in the absence of the first drug or in monotherapy. Also provided herein are methods for preventing and controlling drug-drug interactions between one drug (e.g., a first drug) and another (e.g., a second) drug (or a metabolite thereof) in a subject, where the amount of the other (e.g., second) drug (e.g., a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein) is adjusted compared to the amount when administered in the absence of the first drug or in monotherapy. In some embodiments, the subject is administered an effective amount of one drug (e.g., a first drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) and an effective amount of another (e.g., second) drug (e.g., a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or severine), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein).

[0090] Also provided herein is a method of maintaining the bioavailability of one or more therapeutic agents (including their metabolites) administered to a patient. For example, if a patient receives two different therapeutic agents, the methods described herein can maintain the bioavailability of one or both therapeutic agents (including their metabolites). Thus, in some embodiments, provided herein is a method of maintaining the bioavailability of a drug (or its metabolites), comprising administering to a subject an effective amount of a drug (e.g., a first drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) and an effective amount of another (e.g., a second) drug (e.g., a drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or severine), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein). In some embodiments, the bioavailability of one drug (e.g., a first drug, or a metabolite thereof) is maintained. In some embodiments, the bioavailability of another (e.g., a second) drug (or a metabolite thereof) is maintained. In some embodiments, the bioavailability of both drugs (or their metabolites) is maintained.

[0091] Also provided herein are methods of minimizing, preventing, and controlling increased exposure to one or more therapeutic agents (including their metabolites) administered to a patient. For example, if a patient receives two different therapeutic agents, the methods described herein can minimize, prevent, and / or control increased exposure to one or both therapeutic agents (including their metabolites). Thus, in some embodiments, provided herein are methods of minimizing, preventing, and controlling increased exposure to a drug (or its metabolites), comprising administering to a subject an effective amount of a drug (e.g., a first drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) and an effective amount of another (e.g., a second) drug (e.g., a drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or severine), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein). In some embodiments, the increase in exposure to one drug (e.g., a first drug, or a metabolite thereof) is controlled (e.g., there is no change in exposure or the change in exposure is less than about 25%, about 20%, about 15%, about 10%, or about 5%). In some embodiments, the increase in exposure to the other (e.g., a second) drug (or a metabolite thereof) is controlled (e.g., there is no change in exposure or the change in exposure is less than about 25%, about 20%, about 15%, about 10%, or about 5%). In some embodiments, the increase in exposure to both drugs (or their metabolites) is controlled (e.g., there is no change in exposure or the change in exposure is less than about 25%, about 20%, about 15%, about 10%, or about 5%).

[0092] Also provided herein are methods for minimizing, preventing, and controlling the reduced absorption of one or more therapeutic agents (including metabolites thereof) administered to a patient. For example, if a patient receives two different therapeutic agents, the methods described herein can control the reduced absorption of one or both therapeutic agents. Thus, in some embodiments, provided herein are methods for controlling the reduced absorption of a drug, comprising administering to a subject an effective amount of a drug (e.g., a first drug) comprising an effective amount of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, and an effective amount of another (e.g., a second) drug (e.g., a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or severine), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another therapeutic agent described herein). In some embodiments, the decrease in absorption of one drug (e.g., a first drug, or a metabolite thereof) is controlled (e.g., there is no change in absorption or the change in absorption is less than about 25%, about 20%, about 15%, about 10%, or about 5%). In some embodiments, the decrease in absorption of the other (e.g., a second) drug (or a metabolite thereof) is controlled (e.g., there is no change in absorption or the change in absorption is less than about 25%, about 20%, about 15%, about 10%, or about 5%). In some embodiments, the decrease in absorption of both drugs (or their metabolites) is controlled (e.g., there is no change in absorption or the change in absorption is less than about 25%, about 20%, about 15%, about 10%, or about 5%).

[0093] Timing Adjustment In some embodiments, drug interactions (eg, as described herein) are modulated by adjusting the timing of administration of each therapeutic agent administered to a patient.

[0094] In some embodiments, the administration of one drug (e.g., a first drug) and the other (e.g., a second) drug occurs concomitantly (co-administration). In some embodiments, the co-administration of one drug (e.g., a first drug) and the other (e.g., a second) drug occurs within a time period of about 1 hour or less (e.g., about 1, 5, 10, 15, 20, 25, or 30 minutes or less). In some embodiments, the co-administration of one drug (e.g., a first drug) and the other (e.g., a second) drug occurs simultaneously (co-administration), where both compounds are administered at the same time.

[0095] In some embodiments, the administration of a drug (e.g., a first drug) that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) and another (e.g., a second) drug (e.g., a therapeutic agent such as a drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein) occurs sequentially (sequential administration). In some embodiments, the administration of a drug (e.g., a first drug) that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) and another drug (e.g., a second drug) that is a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate) occurs sequentially (sequential administration).

[0096] In some embodiments, timing adjustments occur independently of dose adjustments.

[0097] In some embodiments, both dose adjustment and timing adjustment are performed.

[0098] In some embodiments, only timing adjustments or only dose adjustments are made. In some embodiments, only timing adjustments are made.

[0099] In some embodiments, administration of one drug (e.g., a first drug) and another (e.g., a second) drug occurs sequentially (sequential administration). In some embodiments, administration of the two drugs (e.g., a first drug and a second drug) is separated by at least about 1 hour to about 6 hours, at least about 2 hours to about 6 hours, at least about 2 hours to about 4 hours, at least about 3 hours to about 6 hours, at least about 4 hours to about 6 hours, at least about 1 hour to about 12 hours, at least about 2 hours to about 12 hours, at least about 3 hours to about 12 hours, at least about 4 hours to about 12 hours, or at least about 6 hours to about 12 hours.

[0100] In several embodiments, administration of two drugs (e.g., a first drug and a second drug) is separated by at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours.

[0101] In some embodiments, the administration of two drugs (eg, a first drug and a second drug) is separated by no more than about 12 hours or no more than about 22 hours.

[0102] In several embodiments, administration of two drugs (e.g., a first drug and a second drug) is separated by about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, or 22 hours or less.

[0103] In several embodiments, administration of the two drugs (e.g., a first drug and a second drug) is separated by about 1 hour to about 6 hours, about 2 hours to about 6 hours, about 2 hours to about 4 hours, about 3 hours to about 6 hours, about 4 hours to about 6 hours, about 1 hour to about 12 hours, about 2 hours to about 12 hours, about 3 hours to about 12 hours, about 4 hours to about 12 hours, or about 6 hours to about 12 hours.

[0104] In several embodiments, administration of two drugs (e.g., a first drug and a second drug) is separated by at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours.

[0105] In some embodiments, the administration of the two drugs (e.g., a first drug and a second drug) is separated by at least about 2 hours. In some embodiments, the administration of the two drugs (e.g., a first drug and a second drug) is separated by at least about 1 hour.

[0106] In some embodiments, one drug (e.g., a first drug) is administered at least 1 hour before the other drug (e.g., a second drug). In some embodiments, the drug (e.g., a first drug) is administered at least 2 hours after the other drug (e.g., a second drug).

[0107] In some embodiments, the drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) is the first drug administered to the patient. In some embodiments, the drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) is not the first drug administered to the patient. In some embodiments, the drug that is a HIF-PH inhibitor (e.g., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof) is the second drug administered to the patient.

[0108] Provided herein are methods of reducing or minimizing drug-drug interactions between a drug (e.g., a first drug) and another drug (e.g., a second drug) in a subject. Also provided herein are methods of preventing or controlling drug-drug interactions between a drug (e.g., a first drug) and another drug (e.g., a second drug) in a subject. In some embodiments, one drug (e.g., a first drug) is administered at least 2 hours before and / or at least 2 hours after the administration of the other drug (e.g., a second drug). In some embodiments, one drug (e.g., a first drug) is administered at least 1 hour before and / or at least 1 hour after the administration of the other drug (e.g., a second drug). In some embodiments, the subject is administered an effective amount of one drug (e.g., a first drug) that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharmaceutical composition comprising an effective amount of the drug, and an effective amount of another drug (e.g., a second drug) that is a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another drug described herein. In some embodiments, the other drug (e.g., the second drug) is a composition comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate).

[0109] Also provided herein is a method for increasing the bioavailability of one or more therapeutic agents administered to a patient. For example, if a patient receives two different therapeutic agents, the methods described herein can increase the bioavailability of one or both therapeutic agents. Thus, in some embodiments, provided herein is a method for increasing the bioavailability of a drug, comprising administering to a subject an effective amount of a drug (e.g., a first drug) comprising an effective amount of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, and an effective amount of another (e.g., a second) drug (e.g., a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another therapeutic agent described herein). In some embodiments, one drug (e.g., the first drug) is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof. In some embodiments, the other drug (e.g., the second drug) is a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein. In some embodiments, the other drug (e.g., the second drug) is a composition comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In some embodiments, one drug (e.g., the first drug) is administered at least 2 hours before and / or at least 2 hours after the other drug (e.g., the second drug). In some embodiments, one drug (e.g., the first drug) is administered at least one hour before and / or at least one hour after the other drug (e.g., the second drug). In some embodiments, the bioavailability of one of the two drugs (e.g., the first drug or the second drug) is increased. In some embodiments, the bioavailability of both drugs is increased.

[0110] Also provided herein is a method of maintaining the bioavailability of one or more therapeutic agents administered to a patient. For example, if a patient receives two different therapeutic agents, the methods described herein can maintain the bioavailability of one or both therapeutic agents. Thus, in some embodiments, provided herein is a method of maintaining the bioavailability of a drug, comprising administering to a subject an effective amount of a drug (e.g., a first drug) comprising an effective amount of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, and an effective amount of another (e.g., a second) drug (e.g., a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another therapeutic agent described herein). In some embodiments, one drug (e.g., the first drug) is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof. In some embodiments, the other drug (e.g., the second drug) is a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein. In some embodiments, the other drug (e.g., the second drug) is a composition comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In some embodiments, one drug (e.g., the first drug) is administered at least 2 hours before and / or at least 2 hours after the other drug (e.g., the second drug). In some embodiments, one drug (e.g., the first drug) is administered at least one hour before and / or at least one hour after the other drug (e.g., the second drug). In some embodiments, the bioavailability of one of the two drugs (e.g., the first drug or the second drug) is maintained. In some embodiments, the bioavailability of both drugs is maintained.

[0111] Also provided herein are methods of minimizing, preventing, and controlling the reduced absorption of one or more therapeutic agents administered to a patient. For example, when a patient receives two different therapeutic agents, the methods described herein can control the reduced absorption of one or both therapeutic agents. Thus, in some embodiments, provided herein are methods of controlling the reduced absorption of a drug, comprising administering to a subject an effective amount of a drug (e.g., a first drug) comprising an effective amount of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, and an effective amount of another (e.g., a second) drug (e.g., a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or severine), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another therapeutic agent described herein). In some embodiments, one drug (e.g., the first drug) is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof. In some embodiments, the other drug (e.g., the second drug) is a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), probenecid, cyclosporine, rifampin, digoxin, adefovir, or another described herein. In some embodiments, the other drug (e.g., the second drug) is a composition comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In some embodiments, one drug (e.g., the first drug) is administered at least 2 hours before and / or at least 2 hours after the other drug (e.g., the second drug). In some embodiments, one drug (e.g., a first drug) is administered at least one hour before and / or at least one hour after the other drug (e.g., a second drug). In some embodiments, decreased absorption of one of the two drugs (e.g., the first drug or the second drug) is minimized, prevented, and / or controlled (e.g., no change in absorption or a change in absorption of less than about 25%, about 20%, about 15%, about 10%, or about 5%).In embodiments, the decrease in absorption of both drugs is minimized, prevented, and / or controlled (e.g., no change in absorption or a change in absorption of less than about 25%, about 20%, about 15%, about 10%, or about 5% for each drug independently).

[0112] In some embodiments of the methods provided herein, the administration of the other (e.g., second) drug is associated with medical treatment. For example, a drug containing a polymeric amine (e.g., sevelamer hydrochloride or sevelamer carbonate) can be administered to reduce phosphorus intake and lower serum phosphorus levels to the normal range, the administration of probenecid can be useful for the treatment or prevention of gout or gouty arthritis, the administration of cyclosporine can be useful for the treatment or prevention of organ rejection in kidney, liver, and heart allografts, and the treatment or prevention of rheumatoid arthritis and / or psoriasis, the administration of rifampin can be useful for the treatment or prevention of tuberculosis and / or meningococcal carriage, the administration of digoxin can be useful for the treatment or prevention of heart failure (e.g., increasing myocardial contractility and / or controlling resting heart rate) and / or atrial fibrillation, and the administration of adefovir can be useful for the treatment or prevention of chronic hepatitis B. In some embodiments, the administration of the polymeric amine-containing composition is associated with the management of hyperphosphatemia.

[0113] In some embodiments of the methods provided herein, Compound 1, or a pharmaceutical composition thereof, is administered at least about 2 hours before and / or at least about 2 hours after a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In some embodiments, Compound 1, or a pharmaceutical composition thereof, is administered at least about 1 hour before and / or at least about 1 hour after a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In some embodiments, Compound 1, or a pharmaceutical composition thereof, is administered at least about 1 hour before a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In some embodiments, Compound 1, or a pharmaceutical composition thereof, is administered at least about 2 hours after a drug comprising a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate).

[0114] In certain embodiments, Compound 1, or a pharmaceutical composition thereof, is administered about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours prior to the polymeric amine-containing composition. In other embodiments, Compound 1, or a pharmaceutical composition thereof, is administered about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after the polymeric amine-containing composition.

[0115] The methods described herein may be useful for subjects with anemia. Anemia may be characterized by a hemoglobin threshold as follows: [Table 2]

[0116] In some embodiments, the subject has renal anemia (anemia secondary to or associated with chronic kidney disease).

[0117] Dialysis status The methods described herein may be beneficial for patients with different dialysis conditions, including those conditions described herein.

[0118] In some embodiments, the patient is non-dialysis dependent. For example, in some embodiments, the patient with chronic kidney disease is non-dialysis dependent (NDD-CKD patient).

[0119] In some embodiments, the patient is dialysis dependent, for example, in some embodiments, the patient with chronic kidney disease is dialysis dependent (DD-CKD patient).

[0120] In some embodiments, the patient is undergoing or has previously undergone dialysis. In some embodiments, the patient is undergoing dialysis. In some embodiments, the patient has previously undergone dialysis.

[0121] In some embodiments, the dialysis is hemodialysis (HD). In some embodiments, the patient with chronic kidney disease is undergoing or has previously undergone hemodialysis. In some embodiments, the patient with chronic kidney disease is undergoing hemodialysis. In some embodiments, the patient with chronic kidney disease has previously undergone hemodialysis.

[0122] In some embodiments, the dialysis is peritoneal dialysis (PD). In some embodiments, the patient with chronic kidney disease is undergoing or has previously undergone peritoneal dialysis. In some embodiments, the patient with chronic kidney disease is undergoing peritoneal dialysis. In some embodiments, the patient with chronic kidney disease has previously undergone peritoneal dialysis.

[0123] Formulations of Compound 1 (Pharmaceutical Compositions) In certain embodiments, Compound 1 may be provided as a formulation (pharmaceutical composition). In some embodiments, Compound 1 is provided as a pharmaceutical formulation suitable for oral administration. Such pharmaceutical compositions suitable for oral administration may be provided as individual dosage forms, including, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of active ingredient and may be prepared by methods of pharmacy well known to those skilled in the art.

[0124] Exemplary formulations of Compound 1 are described in WO2014 / 200773 and WO2016 / 161094, which are incorporated by reference in their entireties. Still further exemplary formulations are described herein.

[0125] The oral dosage forms provided herein are prepared by combining the active ingredient with at least one excipient in an intimate mixture according to conventional pharmaceutical compounding techniques. The excipients can take a wide variety of forms, depending on the preparation form desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohol, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0126] In some embodiments, the oral dosage form is a tablet or capsule, in which case solid excipients are used. In another embodiment, the tablet can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation.

[0127] For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.

[0128] Examples of excipients that can be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropylmethylcellulose (e.g., No. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0129] Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA) and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM. Other suitable forms of microcrystalline cellulose include, but are not limited to, silicified microcrystalline cellulose, e.g., materials sold as PROSOLV 50, PROSOLV 90, PROSOLV HD 90, PROSOLV 90LM, and mixtures thereof.

[0130] Examples of fillers suitable for use in pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in a pharmaceutical composition, in one embodiment, is present in about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[0131] In embodiments, the filler may include, but is not limited to, block copolymers of ethylene oxide and propylene oxide, which may be sold as POLOXAMER or PLURONIC, including, but not limited to, POLOXAMER 188NF, POLOXAMER 237NF, POLOXAMER 338NF, POLOXAMER 437NF, and mixtures thereof.

[0132] In embodiments, bulking agents can include, but are not limited to, isomalt, lactose, lactitol, mannitol, sorbitol xylitol, erythritol, and mixtures thereof.

[0133] Disintegrants can be used in the composition to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate during storage, while tablets that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to adversely alter the release of the active ingredient can be used to form a solid oral dosage form. The amount of disintegrant used varies based on the type of formulation and is readily discernible to one of skill in the art. In one embodiment, the pharmaceutical composition comprises about 0.5 weight percent to about 15 weight percent of disintegrant, or about 1 weight percent to about 5 weight percent of disintegrant.

[0134] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0135] Lubricants that may be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, for example, syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co., Baltimore, MD), coagulated aerosol of synthetic silica (sold by Degussa Co., Plano, TX), CAB-O-SIL (a pyrogenic colloidal silicon dioxide product sold by Cabot Co., Boston, MA), and mixtures thereof. If used, lubricants may be used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

[0136] Anhydrous pharmaceutical compositions and dosage forms are also provided, since water can facilitate the decomposition of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a means of simulating long-term storage to determine properties such as shelf life or stability of formulations over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on formulations can be very significant, since moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, shipping, and use of formulations.

[0137] Anhydrous pharmaceutical compositions should be prepared and stored so that the anhydrous nature of the anhydrous pharmaceutical composition is maintained.Therefore, anhydrous compositions are packaged in one embodiment using materials known to prevent exposure to water, so that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0138] Pharmaceutical compositions and dosage forms that contain one or more compounds that reduce the rate at which an active ingredient will decompose are also provided. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0139] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.

[0140] In some embodiments, provided herein is a tablet formulation comprising 150 mg of Compound 1. In other embodiments, provided herein is a tablet formulation comprising 300 mg of Compound 1. Exemplary 150 mg and 300 mg tablet formulations are set forth in Table 1. [Table 3]

[0141] Table 2 further describes exemplary properties of Compound 1, 150 mg tablet and Compound 1, 300 mg tablet, respectively. [Table 4]

[0142] In some embodiments of any of the methods described herein, the patient receives one or more tablets of Compound 1 substantially according to Table 1 and / or Table 2. In some embodiments, the patient receives one or more tablets of Compound 1 substantially according to Table 1 and / or Table 2, comprising about 150 mg of Compound 1. In some embodiments, the patient receives one or more tablets of Compound 1 substantially according to Table 1 and / or Table 2, comprising about 300 mg of Compound 1. In some embodiments, the patient receives a daily dose of about 150-600 mg of Compound 1 (e.g., about 150, 300, 450, or 600 mg of Compound 1).

[0143] Liquid dosage forms Liquid dosage forms for oral administration are also provided herein.Liquid dosage forms for oral administration can include pharma-ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to active ingredients, liquid dosage forms can include inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.

[0144] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0145] In addition to the active inhibitors, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0146] Amount of Compound 1 in Unit Dosage Form In certain other embodiments, provided herein are unit dosage forms of Compound 1 that comprise from about 150 mg to about 600 mg of a compound having the structure of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. Such unit dosage forms can be used to provide a daily dose of Compound 1 that is from about 150 mg to about 600 mg.

[0147] In certain other embodiments, provided herein are unit dosage forms of Compound 1 comprising about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or even about 600 mg of a compound having the structure of Compound 1. In certain embodiments, the unit dosage form comprises about 150 mg, about 185 mg, about 200 mg, about 250 mg, about 300 mg, or even about 315 mg of a compound having the structure of Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. In certain such embodiments, the unit dosage form is a capsule comprising about 185 mg, about 200 mg, about 200, about 250 mg, or even about 300 mg of the compound.

[0148] In some embodiments, the unit dosage form contains about 150 mg of Compound 1. In some embodiments, the unit dosage form is a tablet. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form containing about 150 mg of Compound 1 is substantially the same as that illustrated in Table 1.

[0149] In some embodiments, the unit dosage form comprises about 300 mg of Compound 1. In some embodiments, the unit dosage form is a tablet. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form comprises about 300 mg of Compound 1 is substantially the same as that illustrated in Table 1.

[0150] Second drug In some embodiments, a subject with renal anemia (secondary to anemia or chronic kidney disease) may be administered, in addition to Compound 1, another (e.g., a second) therapeutic agent, such as a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of certain proteins, receptors, and / or transporters (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir).

[0151] It is understood that the "other," "another," or "second" drug or therapeutic agent used in the methods described herein also encompasses metabolites formed in vivo from the administered drug. For example, the methods described herein for modulating a drug-drug interaction between Compound 1 and another (e.g., second) drug can include modulating a drug-drug interaction between Compound 1 and the administered another (e.g., second) drug and / or Compound 1 and one or more metabolites formed in vivo from the administered another (e.g., second) drug.

[0152] In some embodiments, the other (e.g., second) therapeutic agent (e.g., a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of a certain protein, receptor, and / or transporter (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir) is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, the other (e.g., second) therapeutic agent (e.g., a drug that contains a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of a certain protein, receptor, and / or transporter (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir) is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, the other (e.g., second) therapeutic agent (e.g., a drug that comprises a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of certain proteins, receptors, and / or transporters (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir) is administered prior to the initiation of therapy with Compound 1. In some embodiments, the other (e.g., second) therapeutic agent (e.g., a drug that comprises a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate), or an inhibitor and / or substrate of certain proteins, receptors, and / or transporters (e.g., probenecid, cyclosporine, rifampin, digoxin, or adefovir) is administered after the initiation of therapy with Compound 1.

[0153] In some embodiments, the subject is administered another (eg, a second) drug to treat a disease or condition in the patient that was present at the initiation of treatment with Compound 1.

[0154] In some embodiments, the subject is administered another (e.g., a second) drug to treat or prevent a disease or condition in the patient that was not present at the initiation of treatment with Compound 1 (e.g., a disease or condition that developed after the initiation of treatment with Compound 1). In some embodiments, the subject is administered another (e.g., a second) drug to treat or prevent a disease or condition in the patient that was induced by treatment with Compound 1. In some embodiments, the subject is administered another (e.g., a second) drug to treat or prevent a disease or condition in the patient that develops independent of treatment with Compound 1.

[0155] In some embodiments, the subject receives another (e.g., second) drug (e.g., a drug containing a polymeric amine (e.g., sevelamer hydrochloride or sevelamer carbonate)) to reduce phosphorus intake and lower serum phosphate levels to the normal range. In some embodiments, the subject receives another (e.g., second) drug (e.g., probenecid) to treat or prevent gout or gouty arthritis. In some embodiments, the subject receives another (e.g., second) drug (e.g., cyclosporine) to treat or prevent organ rejection prevention in kidney, liver, and heart allografts, and to treat or prevent rheumatoid arthritis and / or psoriasis. In some embodiments, the subject receives another (e.g., second) drug (e.g., rifampin) to treat or prevent tuberculosis and / or meningococcal carriage. In some embodiments, the subject is receiving another (e.g., second) drug (e.g., digoxin) to treat or prevent heart failure (e.g., increasing myocardial contractility and / or controlling resting heart rate) and / or atrial fibrillation. In some embodiments, the subject is receiving another (e.g., second) drug (e.g., adefovir) to treat or prevent chronic hepatitis B.

[0156] Drugs containing polymeric amines that bind phosphate In the methods described herein, the drug comprises a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In some embodiments, the second drug is a drug that comprises a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate).

[0157] In embodiments, the polymeric amine is poly(allylamine) crosslinked with epichlorohydrin. The cationic polymer may further include a counterion such as chloride or carbonate. In embodiments, the polymeric amine-containing composition is sevelamer carbonate (e.g., Renvela®). In embodiments, the polymeric amine-containing composition is sevelamer hydrochloride (e.g., Renagel®).

[0158] In some embodiments, the polymeric amine-containing composition is formulated for oral administration. In some embodiments, the polymeric amine-containing composition is administered as a tablet. In some embodiments, the polymeric amine-containing composition is administered as a powder. In some embodiments, the powder is a powder for oral suspension.

[0159] In some embodiments, the drug comprising a polymeric amine that binds phosphate is a composition comprising sevelamer hydrochloride. In some embodiments, the second drug comprising a polymeric amine that binds phosphate is a composition comprising sevelamer hydrochloride. In some embodiments, the drug comprising a polymeric amine that binds phosphate is a composition comprising sevelamer carbonate. In some embodiments, the second drug comprising a polymeric amine that binds phosphate is a composition comprising sevelamer carbonate.

[0160] In some embodiments, Compound 1 is administered before (e.g., at least about 1 hour or about 2 hours before) a drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate). In some embodiments, Compound 1 is administered after (e.g., at least about 1 hour or about 2 hours after) a drug that includes a polymeric amine that binds phosphate (e.g., sevelamer hydrochloride or sevelamer carbonate).

[0161] In embodiments, the subject has renal anemia (anemia associated with or secondary to chronic kidney disease).

[0162] In embodiments, subjects with renal anemia (anemia associated with or secondary to chronic kidney disease) may be administered, in addition to Compound 1, a composition comprising a polymeric amine that binds phosphate.

[0163] In some embodiments, the methods described herein provide a method for determining the AUC MAX (e.g., the AUC MAX is no more than about 25%, no more than about 20%, or no more than about 15%.

[0164] In some embodiments, a subject is administered a composition comprising a polymeric amine that binds phosphate to treat a disease or condition in the patient that was present at the initiation of treatment with Compound 1.

[0165] In some embodiments, a subject is administered a composition comprising a polymeric amine that binds phosphate to treat or prevent a disease or condition in the patient that was not present at the initiation of treatment with Compound 1 (e.g., a disease or condition that developed after the initiation of treatment with Compound 1). In some embodiments, a subject is administered a composition comprising a polymeric amine that binds phosphate to treat or prevent a disease or condition in the patient that was induced by treatment with Compound 1. In some embodiments, a subject is administered a composition comprising a polymeric amine that binds phosphate to treat or prevent a disease or condition in the patient that developed independent of treatment with Compound 1.

[0166] In some embodiments, the subject receiving a composition comprising a polymeric amine that binds phosphate receives the composition to treat or prevent high blood phosphate levels (hyperphosphatemia). In some embodiments, the subject is on dialysis due to severe kidney disease (e.g., chronic kidney disease).

[0167] In embodiments, a subject receiving a composition comprising a polymeric amine that binds phosphate receives the composition to treat or prevent a phosphorus excretion disorder.

[0168] In embodiments, a subject receiving a composition comprising a polymeric amine that binds phosphate receives the composition to reduce the risk of cardiovascular disease, renal failure, and death in a subject with CKD (chronic kidney disease).

[0169] In embodiments, subjects receiving a composition comprising a polymeric amine that binds phosphate receive the composition to reduce phosphorus intake and / or lower serum phosphate levels to the normal range.

[0170] In certain embodiments, a subject receiving a composition comprising a polymeric amine that binds phosphate receives the composition to maintain serum phosphorus at a target level (e.g., less than 5.5 mg / dL, such as about 3.5 to about 5.5 mg / dL).

[0171] In some embodiments, the polymeric amine-containing composition comprises a polymeric amine that binds phosphate. In some embodiments, the polymeric amine that binds phosphate is a sevelamer-based binder. In some embodiments, the polymeric amine that binds phosphate is sevelamer hydrochloride or sevelamer carbonate. Exemplary polymeric amine-containing compositions include sevelamer hydrochloride and sevelamer carbonate. In some embodiments, the polymeric amine-containing composition comprises sevelamer hydrochloride or sevelamer carbonate.

[0172] In embodiments, the composition comprising a polymeric amine that binds phosphate comprises sevelamer hydrochloride or sevelamer carbonate.

[0173] Compositions that include polymeric amines that bind phosphate can further include any of the excipients described herein (e.g., those described for formulations of Compound 1), as well as any combination thereof.

[0174] In embodiments, the polymeric amine-containing composition is in the form of a powder.

[0175] In some embodiments, the polymeric amine-containing composition is in the form of a tablet. Such tablets can be produced, for example, by tableting, e.g., direct compression, of the polymeric amine-containing composition as a pure powder, i.e., without any excipients. In other embodiments, suitable excipients can be added. Such excipients include anti-adherents, binders, coating agents, colorants, disintegrants, flavoring agents, glidants, lubricants, preservatives, adsorbents, sweeteners, vehicles, and mixtures thereof.

[0176] In other embodiments, tablets are obtained by compressing a granulated powder (i.e., the "internal phase") with additional excipients (the "external phase"). The internal phase of the polymeric amine-containing composition may comprise the polymeric amine and at least one excipient. The external phase of the pharmaceutical composition according to the invention may comprise at least one excipient.

[0177] Pharmaceutical compositions according to the present invention may include fillers to provide processability.

[0178] Suitable filler materials are well known in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990), Mack Publishing Co., Easton, Pa., pp. 1635-1636) and include microcrystalline cellulose, lactose and other carbohydrates, starch, pregelatinized starch, such as Starch 1500R (Colorcon Corp.), corn starch, dicalcium phosphate, potassium bicarbonate, sodium bicarbonate, cellulose, dibasic calcium phosphate anhydrous, sugars, sodium chloride, and mixtures thereof, among which lactose, microcrystalline cellulose, pregelatinized starch, and mixtures thereof are preferred. Due to their excellent disintegration and compression properties, microcrystalline cellulose (Avicel grade, FMC Corp.) and mixtures comprising microcrystalline cellulose and one or more additional fillers, such as corn starch or pregelatinized starch, are particularly useful.

[0179] In embodiments, compositions comprising polymeric amines that bind phosphate are formulated for oral administration.

[0180] In embodiments, the composition comprising the polymeric amine that binds phosphate is a tablet.

[0181] In some embodiments, the composition comprising the polymeric amine that binds phosphate is a powder (eg, a powder for oral suspension).

[0182] In some embodiments, the composition comprising the polymeric amine that binds phosphate is administered continuously and / or indefinitely, hi certain alternative embodiments, the composition comprising the polymeric amine that binds phosphate is administered as needed to maintain serum phosphorus at a level of about 3.5 to about 5.5 mg / dL.

[0183] Sevelamer Hydrochloride In embodiments, the composition comprising a polymeric amine that binds phosphate is a composition comprising sevelamer hydrochloride.

[0184] In some embodiments, a subject receives sevelamer hydrochloride to treat or prevent high blood phosphate levels (hyperphosphatemia). In some embodiments, a subject receives sevelamer hydrochloride to treat or prevent impaired phosphorus excretion. In some embodiments, a subject receives sevelamer hydrochloride to reduce the risk of cardiovascular disease, renal failure, and death in subjects with CKD (chronic kidney disease). In some embodiments, a subject receives sevelamer hydrochloride to reduce phosphorus intake and / or reduce serum phosphate levels to the normal range. In certain embodiments, a subject receives sevelamer hydrochloride to maintain serum phosphorus at a target level (e.g., about 3.5 to about 5.5 mg / dL).

[0185] In certain embodiments, sevelamer hydrochloride is administered in an amount such that serum phosphorus is maintained at a target level (eg, less than 5.5 mg / dL, such as about 3.5 to about 5.5 mg / dL).

[0186] In some embodiments, the subject receives sevelamer hydrochloride at a dose of about 400 mg to about 5000 mg. In some embodiments, the subject receives sevelamer hydrochloride at a dose of 400 mg, about 800 mg, about 1200 mg, about 1600 mg, about 2000 mg, about 2400 mg, about 2800 mg, about 3200 mg, about 3600 mg, about 4000 mg, about 4400 mg, or about 4800 mg. In some embodiments, the subject receives sevelamer hydrochloride at a dose of about 800 mg or about 1600 mg. In some embodiments, the doses described herein are initial doses at the beginning of treatment. In some embodiments, the doses described herein are adjusted doses at later times during the course of treatment. In some embodiments, the doses described herein may be administered once a day, twice a day, or three times a day.

[0187] In some embodiments, the subject is administered 1600 mg of sevelamer hydrochloride once a day. In some embodiments, the subject is initially administered 1600 mg of sevelamer hydrochloride once a day. In some embodiments, the subject is initially administered 800 mg of sevelamer hydrochloride three times a day. In some embodiments, the subject is initially administered 800 mg of sevelamer hydrochloride three times a day. In some embodiments, the subject is initially administered 1600 mg of sevelamer hydrochloride three times a day. In some embodiments, the subject is initially administered 1600 mg of sevelamer hydrochloride three times a day.

[0188] In some embodiments, the subject is administered once a week, twice a week, or three times a week. In some embodiments, the subject is administered a dose (e.g., 1600 mg) of sevelamer hydrochloride three times a week. For example, the subject may be administered sevelamer hydrochloride (e.g., 1600 mg) on ​​the third, fifth, and seventh days of a seven-day period. In some embodiments, the subject is administered a dose of compound 1 (e.g., 150, 300, 450, or 600 mg of compound 1) every day. In some embodiments, the subject is administered a dose of compound 1 (e.g., 150, 300, 450, or 600 mg of compound 1) three times a week. In some embodiments, the subject is administered a dose of compound 1 (e.g., 150, 300, 450, or 600 mg of compound 1) four times a week (e.g., on the first, third, fifth, and seventh days of a seven-day period).

[0189] In some embodiments, the maximum dose of sevelamer hydrochloride is about 13 g per day. In some embodiments, the maximum dose of sevelamer hydrochloride is about 14 g per day.

[0190] In some embodiments, the subject receives sevelamer hydrochloride orally.In some embodiments, the subject receives sevelamer hydrochloride as a tablet.

[0191] Sevelamer carbonate In embodiments, the composition comprising the polymeric amine is a composition comprising sevelamer carbonate.

[0192] In some embodiments, a subject receives sevelamer carbonate to treat or prevent high blood phosphate levels (hyperphosphatemia). In some embodiments, a subject receives sevelamer carbonate to treat or prevent impaired phosphorus excretion. In some embodiments, a subject receives sevelamer carbonate to reduce the risk of cardiovascular disease, renal failure, and death in subjects with CKD (chronic kidney disease). In some embodiments, a subject receives sevelamer carbonate to reduce phosphorus intake and / or reduce serum phosphate levels to the normal range. In certain embodiments, a subject receives sevelamer carbonate to maintain serum phosphorus at a target level (e.g., less than 5.5 mg / dL, such as about 3.5 to about 5.5 mg / dL).

[0193] In certain embodiments, sevelamer carbonate is administered in an amount such that serum phosphorus is maintained at a target level (eg, less than 5.5 mg / dL, such as about 3.5 to about 5.5 mg / dL).

[0194] In some embodiments, the subject receives sevelamer carbonate at a dose of about 400 mg to about 5000 mg per day. In some embodiments, the subject receives sevelamer carbonate at a dose of 400 mg, about 800 mg, about 1200 mg, about 1600 mg, about 2000 mg, about 2400 mg, about 2800 mg, about 3200 mg, about 3600 mg, about 4000 mg, about 4400 mg, or about 4800 mg. In some embodiments, the subject receives sevelamer carbonate at a dose of about 800 mg or about 1600 mg. In some embodiments, the doses described herein are initial doses at the beginning of treatment. In some embodiments, the doses described herein are adjusted doses at later times during the course of treatment. In some embodiments, the doses described herein may be administered once a day, twice a day, or three times a day.

[0195] In some embodiments, the subject is administered 1600 mg of sevelamer carbonate once a day. In some embodiments, the subject is initially administered 1600 mg of sevelamer carbonate once a day. In some embodiments, the subject is initially administered 800 mg of sevelamer carbonate three times a day. In some embodiments, the subject is initially administered 800 mg of sevelamer carbonate three times a day. In some embodiments, the subject is initially administered 1600 mg of sevelamer carbonate three times a day. In some embodiments, the subject is initially administered 1600 mg of sevelamer carbonate three times a day.

[0196] In some embodiments, the subject is administered once a week, twice a week, or three times a week. In some embodiments, the subject is administered a dose (e.g., 1600 mg) of sevelamer carbonate three times a week. For example, the subject may be administered sevelamer carbonate (e.g., 1600 mg) on ​​the third, fifth, and seventh days of a seven-day period. In some embodiments, the subject is administered a dose of compound 1 (e.g., 150, 300, 450, or 600 mg of compound 1) daily. In some embodiments, the subject is administered a dose of compound 1 (e.g., 150, 300, 450, or 600 mg of compound 1) three times a week. In some embodiments, the subject is administered a dose of compound 1 (e.g., 150, 300, 450, or 600 mg of compound 1) four times a week (e.g., on the first, third, fifth, and seventh days of a seven-day period).

[0197] In embodiments, the maximum dose of sevelamer carbonate is about 14 g per day.

[0198] In some embodiments, the subject receives sevelamer carbonate orally. In some embodiments, the subject receives sevelamer carbonate as a tablet. In some embodiments, the subject receives sevelamer carbonate as a powder. In some embodiments, the subject receives sevelamer carbonate as a powder for oral suspension.

[0199] Organic Anion Transporter Inhibitors In some embodiments, the drug comprises an organic anion transporter inhibitor (e.g., OAT1 / OAT3 or OATP1B1). In some embodiments, the second drug is a drug that comprises an organic anion transporter inhibitor (e.g., OAT1 / OAT3 or OATP1B1). Thus, the methods described herein may be useful for modulating drug-drug interactions between Compound 1 and organic anion transporter inhibitors (e.g., OAT1 / OAT3 or OATP1B1), including those described herein, and / or one or more metabolites thereof.

[0200] In some embodiments, the drug (e.g., the second drug) comprises an organic anion transporter inhibitor (e.g., OAT1 / OAT3 or OATP1B1). In some embodiments, the organic anion transporter inhibitor is an OAT1 / OAT3 inhibitor (e.g., an OAT1 inhibitor and / or an OAT3 inhibitor). In some embodiments, the OAT1 / OAT3 inhibitor is probenecid. In some embodiments, the organic anion transporter inhibitor is an OAT1 inhibitor. In some embodiments, the OAT1 inhibitor is probenecid or rifampicin. In some embodiments, the organic anion transporter inhibitor is an OAT3 inhibitor. In some embodiments, the OAT3 inhibitor is cimetidine, diclofenac, furosemide, gemfibrozil, ibuprofen, or probenecid. In some embodiments, the organic anion transporter inhibitor is an OATP1B1 inhibitor. In some embodiments, the OATP1B1 inhibitor is cyclosporine or rifampicin. In some embodiments, the drug (eg, the second drug) is probenecid.

[0201] In some embodiments, the dosage of a drug (e.g., a second drug) that is an organic anion transporter (e.g., an OAT1 / OAT3 inhibitor and / or an OATP1B1 inhibitor) is adjusted when co-administered with Compound 1. In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of a drug (e.g., a second drug) that is an organic anion transporter (e.g., an OAT1 / OAT3 inhibitor and / or an OATP1B1 inhibitor) is not adjusted when co-administered with Compound 1. In some embodiments, the dosage of a drug (e.g., a first drug) that is Compound 1 is adjusted when co-administered with an organic anion transporter (e.g., an OAT1 / OAT3 inhibitor and / or an OATP1B1 inhibitor). In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of the drug that is Compound 1 (e.g., the first drug) is not adjusted when co-administered with an organic anion transporter (e.g., an OAT1 / OAT3 inhibitor and / or an OATP1B1 inhibitor).

[0202] Still further embodiments of methods involving treating a disease or condition using an organic anion transporter (e.g., an OAT1 / OAT3 inhibitor and / or an OATP1B1 inhibitor) include those described herein.

[0203] OAT1 / OAT3 Inhibitors In some embodiments, the drug comprises an OAT1 / OAT3 inhibitor (e.g., an OAT1 inhibitor and / or an OAT3 inhibitor). In some embodiments, the second drug is a drug comprising an OAT1 / OAT3 inhibitor (e.g., an OAT1 inhibitor and / or an OAT3 inhibitor). Thus, the methods described herein may be useful for modulating drug-drug interactions between Compound 1 and an OAT1 / OAT3 inhibitor (e.g., an OAT1 inhibitor and / or an OAT3 inhibitor), including those described herein, and / or one or more metabolites thereof.

[0204] Exemplary OAT1 / OAT3 inhibitors include, but are not limited to, probenecid, rifampicin, cimetidine, diclofenac, furosemide, gemfibrozil, ibuprofen, and probenecid. In some embodiments, the OAT1 / OAT3 inhibitor is an OAT1 inhibitor (e.g., probenecid or rifampicin). In some embodiments, the OAT1 / OAT3 inhibitor is an OAT3 inhibitor (e.g., cimetidine, diclofenac, furosemide, gemfibrozil, ibuprofen, or probenecid). In some embodiments, the OAT1 / OAT3 inhibitor is probenecid. In some embodiments, the OAT1 / OAT3 inhibitor is rifampicin.

[0205] In some embodiments, an OAT1 / OAT3 inhibitor (e.g., probenecid or rifampicin) is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, an OAT1 / OAT3 inhibitor (e.g., probenecid or rifampicin) is not administered in combination (e.g., simultaneously) with Compound 1 (e.g., administration of the two drugs is separated by a time interval as described herein).

[0206] In some embodiments, the dosage of a drug (e.g., a second drug) that is an OAT1 / OAT3 inhibitor (e.g., probenecid or rifampicin) is adjusted when co-administered with Compound 1. In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of a drug (e.g., a second drug) that is an OAT1 / OAT3 inhibitor (e.g., probenecid or rifampicin) is not adjusted when co-administered with Compound 1. In some embodiments, the dosage of a drug (e.g., a first drug) that is Compound 1 is adjusted when co-administered with an OAT1 / OAT3 inhibitor (e.g., probenecid or rifampicin). In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of a drug (e.g., a first drug) that is Compound 1 is not adjusted when co-administered with an OAT1 / OAT3 inhibitor (e.g., probenecid or rifampicin).

[0207] Still further embodiments of methods involving treating a disease or condition with an OAT1 / OAT3 inhibitor include those described herein.

[0208] Probenecid In some embodiments, the drug (e.g., the second drug) is probenecid, which may be a pan-UGT inhibitor and / or an OAT1 / OAT3 inhibitor. Thus, the methods described herein may be useful for modulating drug-drug interactions between compound 1 and a pan-UGT inhibitor, including those described herein (e.g., probenecid) and / or one or more metabolites thereof. The methods described herein may also be useful for modulating drug-drug interactions between compound 1 and an OAT1 / OAT3 inhibitor, including those described herein (e.g., probenecid) and / or one or more metabolites thereof.

[0209] In some embodiments, the subject receives probenecid to treat or prevent gout, gouty arthritis, and / or other medical conditions. In some embodiments, the subject receives probenecid at a dose of about 250 mg, 500 mg, 750 mg, 1000 mg, or more than 1000 mg per day. In some embodiments, the subject receives probenecid at a dose of about 500 mg per day. In some embodiments, the doses described herein are initial doses at the beginning of treatment. In some embodiments, the doses described herein are adjusted doses at later times during the course of treatment.

[0210] In certain embodiments, the probenecid is administered continuously and / or indefinitely, hi certain embodiments, the probenecid is administered once a day, twice a day, or three times a day.

[0211] In some embodiments, probenecid is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, probenecid is not administered in combination (e.g., simultaneously) with Compound 1 (e.g., administration of the two drugs is separated by a time interval as described herein).

[0212] In some embodiments, the dosage of probenecid is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence of Compound 1 or in monotherapy. In some embodiments, the dosage of probenecid is not adjusted when coadministered with Compound 1. In some embodiments, the dosage of Compound 1 is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence of probenecid or in monotherapy. In some embodiments, the dosage of Compound 1 is not adjusted when coadministered with probenecid.

[0213] Rifampin In some embodiments, the drug (e.g., the second drug) is rifampin, which can be an OATP1B1 inhibitor and / or an OAT1 inhibitor. In some embodiments, the subject receives rifampicin to treat or prevent tuberculosis, meningococcal carriage, and / or other medical conditions. In some embodiments, the subject receives rifampin at a dose of about 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, or more than 20 mg / kg per day.

[0214] In some embodiments, the subject receives rifampin at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, or more than about 1200 mg per day. In some embodiments, the subject receives rifampin at a dose of about 600 mg per day. In some embodiments, the doses described herein are initial doses at the beginning of treatment. In some embodiments, the doses described herein are adjusted doses at later times during the course of treatment.

[0215] In certain embodiments, the rifampin drug is administered continuously and / or indefinitely, hi certain embodiments, the rifampin drug is administered once daily, twice daily, or three times daily.

[0216] In some embodiments, the rifampin drug is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, the rifampin drug is not administered in combination (e.g., simultaneously) with Compound 1 (e.g., administration of the two drugs is separated by a time interval as described herein).

[0217] In some embodiments, the dosage of rifampin is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence of Compound 1 or in monotherapy. In some embodiments, the dosage of rifampin is not adjusted when coadministered with Compound 1. In some embodiments, the dosage of Compound 1 is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence of rifampin or in monotherapy. In some embodiments, the dosage of Compound 1 is not adjusted when coadministered with rifampin.

[0218] OATP1B1 Inhibitors In some embodiments, the drug comprises an OATP1B1 inhibitor (e.g., cyclosporine). In some embodiments, the second drug is a drug comprising an OATP1B1 inhibitor (e.g., cyclosporine). Thus, the methods described herein may be useful for modulating drug-drug interactions between Compound 1 and OATP1B1 inhibitors (e.g., cyclosporine), including those described herein, and / or one or more metabolites thereof.

[0219] Exemplary OATP1B1 inhibitors include, but are not limited to, cyclosporine, gemfibrozil, statins, antibiotics, and antiretrovirals. In some embodiments, the OATP1B1 inhibitor is cyclosporine.

[0220] In some embodiments, an OATP1B1 inhibitor (e.g., cyclosporine) is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, an OATP1B1 inhibitor (e.g., cyclosporine) is not administered in combination (e.g., simultaneously) with Compound 1 (e.g., administration of the two drugs is separated by a time interval as described herein).

[0221] In some embodiments, the dosage of a drug (e.g., a second drug) that is an OATP1B1 inhibitor (e.g., cyclosporine) is adjusted when co-administered with Compound 1. In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of a drug (e.g., a second drug) that is an OATP1B1 inhibitor (e.g., cyclosporine) is not adjusted when co-administered with Compound 1. In some embodiments, the dosage of a drug (e.g., a first drug) that is Compound 1 is adjusted when co-administered with an OATP1B1 inhibitor (e.g., cyclosporine). In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of a drug (e.g., a first drug) that is Compound 1 is not adjusted when co-administered with an OATP1B1 inhibitor (e.g., cyclosporine).

[0222] Still further embodiments of methods involving treating a disease or condition with an OATP1B1 inhibitor (eg, cyclosporine) include those described herein.

[0223] Cyclosporine In some embodiments, the drug (e.g., the second drug) is cyclosporine, which may be a BCRP inhibitor, an OATP1B1 inhibitor, and / or a P-glycoprotein 1 (Pgp) inhibitor. Thus, the methods described herein may be useful for modulating drug-drug interactions between compound 1 and a BCRP inhibitor, including those described herein (e.g., cyclosporine) and / or one or more metabolites thereof. The methods described herein may also be useful for modulating drug-drug interactions between compound 1 and an OATP1B1 inhibitor, including those described herein (e.g., cyclosporine) and / or one or more metabolites thereof. In addition, the methods described herein may also be useful for modulating drug-drug interactions between compound 1 and a P-glycoprotein 1 inhibitor, including those described herein (e.g., cyclosporine) and / or one or more metabolites thereof.

[0224] In some embodiments, the subject receives cyclosporine to treat or prevent prevention of organ rejection in kidney, liver, and heart allografts. In some embodiments, the subject receives cyclosporine to treat or prevent rheumatoid arthritis, psoriasis, and / or other medical conditions. In some embodiments, the subject receives cyclosporine at a dose of about 0.5 mg / kg / day, 1 mg / kg / day, 1.5 mg / kg / day, 2 mg / kg / day, 2.5 mg / kg / day, 3 mg / kg / day, 3.5 mg / kg / day, 4 mg / kg / day, 4.5 mg / kg / day, 5 mg / kg / day, 6 mg / kg / day, 7 mg / kg / day, 8 mg / kg / day, 9 mg / kg / day, 10 mg / kg / day, 11 mg / kg / day, 12 mg / kg / day, or greater than 12 mg / kg / day. In some embodiments, the subject receives cyclosporine at a dose of about 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 2000 mg, or more than 2000 mg per day. In some embodiments, the subject receives cyclosporine at a dose of about 500 mg per day. In some embodiments, the doses described herein are initial doses at the beginning of treatment. In some embodiments, the doses described herein are adjusted doses at later times during the course of treatment.

[0225] In certain embodiments, the cyclosporine drug is administered continuously and / or indefinitely, hi certain embodiments, the cyclosporine drug is administered once a day, twice a day, or three times a day.

[0226] In some embodiments, the cyclosporine drug is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, the cyclosporine drug is not administered in combination (e.g., simultaneously) with Compound 1 (e.g., administration of the two drugs is separated by a time interval as described herein).

[0227] In some embodiments, the dosage of cyclosporine is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence of Compound 1 or in monotherapy. In some embodiments, the dosage of cyclosporine is not adjusted when co-administered with Compound 1. In some embodiments, the dosage of Compound 1 is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence of a cyclosporine drug or in monotherapy. In some embodiments, the dosage of Compound 1 is not adjusted when co-administered with cyclosporine.

[0228] P-glycoprotein transporter (P-gp) substrates In some embodiments, the drug comprises a p-glycoprotein transporter (P-gp) substrate (e.g., digoxin). In some embodiments, the second drug is a drug that comprises a p-glycoprotein transporter substrate (e.g., digoxin). Thus, the methods described herein may be useful for modulating drug-drug interactions between Compound 1 and a p-glycoprotein transporter substrate (e.g., digoxin) and / or one or more metabolites thereof, including those described herein.

[0229] Exemplary p-glycoprotein transporter substrates include, but are not limited to, calcium channel blockers, cyclosporine, dabigatran etexilate, digoxin, erythromycin, loperamide, protease inhibitors, and tacrolimus. In some embodiments, the p-glycoprotein transporter substrate is digoxin.

[0230] In some embodiments, a p-glycoprotein transporter substrate (e.g., digoxin) is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, a p-glycoprotein transporter substrate (e.g., digoxin) is not administered in combination (e.g., simultaneously) with Compound 1 (e.g., administration of the two drugs is separated by a time period described herein).

[0231] In some embodiments, the dosage of a drug (e.g., a second drug) that is a p-glycoprotein transporter substrate (e.g., digoxin) is adjusted when co-administered with Compound 1. In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of a drug (e.g., a second drug) that is a p-glycoprotein transporter substrate (e.g., digoxin) is not adjusted when co-administered with Compound 1. In some embodiments, the dosage of a drug (e.g., a first drug) that is Compound 1 is adjusted when co-administered with a p-glycoprotein transporter substrate (e.g., digoxin). In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of a drug (e.g., a first drug) that is Compound 1 is not adjusted when co-administered with a p-glycoprotein transporter substrate (e.g., digoxin).

[0232] Still further embodiments of methods involving treating a disease or condition using a p-glycoprotein transporter substrate (eg, digoxin) include those described herein.

[0233] Digoxin In some embodiments, the drug (e.g., the second drug) is digoxin. In some embodiments, the subject receives digoxin to treat or prevent heart failure (e.g., increasing myocardial contractility and / or controlling resting heart rate), atrial fibrillation, and / or other medical conditions. In some embodiments, the subject receives digoxin at a dose of about 5mcg / kg, 10mcg / kg, 15mcg / kg, 20mcg / kg, 25mcg / kg, 30mcg / kg, 35mcg / kg, 40mcg / kg, 45mcg / kg, or more than 45mcg / kg. In some embodiments, the subject receives digoxin at a dose of about 0.25mg, 0.5mg, 0.75mg, 1mg, 1.25mg, or more than 1.25mg per day. In some embodiments, the subject receives digoxin at a dose of about 0.5mg per day. In some embodiments, the doses described herein are initial doses at the beginning of treatment, in some embodiments, the doses described herein are adjusted doses at later times during the course of treatment.

[0234] In certain embodiments, the digoxin drug is administered continuously and / or indefinitely, hi certain embodiments, the digoxin drug is administered once a day, twice a day, or three times a day.

[0235] In some embodiments, a digoxin drug is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, a digoxin drug is not administered in combination (e.g., simultaneously) with Compound 1 (e.g., administration of the two drugs is separated by a time interval as described herein).

[0236] In some embodiments, the dosage of the digoxin drug is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence or in monotherapy of Compound 1. In some embodiments, the dosage of digoxin is not adjusted when co-administered with Compound 1. In some embodiments, the dosage of Compound 1 is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence or in monotherapy of the digoxin drug. In some embodiments, the dosage of Compound 1 is not adjusted when co-administered with digoxin.

[0237] OAT1 / OAT3 substrate In some embodiments, the drug comprises an OAT1 / OAT3 substrate (e.g., an OAT1 substrate and / or an OAT3 substrate). In some embodiments, the second drug is a drug that comprises an OAT1 / OAT3 substrate (e.g., an OAT1 substrate and / or an OAT3 substrate). Thus, the methods described herein may be useful for modulating drug-drug interactions between Compound 1 and an OAT1 / OAT3 substrate (e.g., an OAT1 substrate and / or an OAT3 substrate), including those described herein, and / or one or more metabolites thereof.

[0238] Exemplary OAT1 / OAT3 substrates (eg, OAT1 substrates and / or OAT3 substrates) include, but are not limited to, adefovir, cefaclor, ceftizoxime, cimetidine, famotidine, furosemide, oseltamivir carboxylate, penicillin G, and sitagliptin.

[0239] In some embodiments, the OAT1 / OAT3 substrate is an OAT1 substrate (e.g., adefovir). In some embodiments, the OAT1 / OAT3 substrate is an OAT3 substrate (e.g., cefaclor, ceftizoxime, cimetidine, famotidine, furosemide, oseltamivir carboxylate, penicillin G, or sitagliptin). In some embodiments, the OAT1 / OAT3 substrate is adefovir.

[0240] In some embodiments, an OAT1 / OAT3 substrate (e.g., adefovir) is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, an OAT1 / OAT3 substrate (e.g., adefovir) is not administered in combination (e.g., simultaneously) with Compound 1 (e.g., administration of the two drugs is separated by a time interval as described herein).

[0241] In some embodiments, the dosage of a drug (e.g., a second drug) that is an OAT1 / OAT3 substrate (e.g., adefovir) is adjusted when co-administered with Compound 1. In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of a drug (e.g., a second drug) that is an OAT1 / OAT3 substrate (e.g., adefovir) is not adjusted when co-administered with Compound 1. In some embodiments, the dosage of a drug (e.g., a first drug) that is Compound 1 is adjusted when co-administered with an OAT1 / OAT3 substrate (e.g., adefovir). In some embodiments, the dosage is increased. In some embodiments, the dosage is decreased. In some embodiments, the dosage of a drug (e.g., a first drug) that is Compound 1 is not adjusted when co-administered with an OAT1 / OAT3 substrate (e.g., adefovir).

[0242] Still further embodiments of methods involving treating a disease or condition using an OAT1 / OAT3 substrate (eg, adefovir) include those described herein.

[0243] In some embodiments, the OAT1 / OAT3 substrate is not furosemide.

[0244] Adefovir In some embodiments, the drug (e.g., the second drug) is adefovir. In some embodiments, the subject receives adefovir to treat or prevent chronic hepatitis B and / or other medical conditions. In some embodiments, the subject receives adefovir at a dose of about 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or more than 10 mg per day. In some embodiments, the subject receives adefovir at a dose of about 10 mg per day. In some embodiments, the doses described herein are initial doses at the beginning of treatment. In some embodiments, the doses described herein are adjusted doses at later times during the course of treatment.

[0245] In certain embodiments, the adefovir drug is administered continuously and / or indefinitely. In certain embodiments, the adefovir drug is administered once a day, twice a day, or three times a day. In certain embodiments, the adefovir drug is administered once a day, once every two days, once every three days, or once every seven days.

[0246] In some embodiments, the adefovir drug is administered in combination (e.g., simultaneously) with Compound 1. In some embodiments, the adefovir drug is not administered in combination (e.g., simultaneously) with Compound 1 (e.g., administration of the two drugs is separated by a time interval as described herein).

[0247] In some embodiments, the dosage of adefovir is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence of Compound 1 or in monotherapy. In some embodiments, the dosage of adefovir is not adjusted when coadministered with Compound 1. In some embodiments, the dosage of Compound 1 is adjusted (e.g., adjusted as described herein) compared to the amount when administered in the absence of adefovir or in monotherapy. In some embodiments, the dosage of Compound 1 is not adjusted when coadministered with adefovir.

[0248] Diseases associated with HIF prolyl hydroxylase regulation In certain embodiments, the methods of the invention include subjects having a disease associated with HIF prolyl hydroxylase regulation.

[0249] Diseases associated with HIF prolyl hydroxylase modulation include peripheral vascular disease (PVD); coronary artery disease (CAD); heart failure; ischemia; anemia; wound healing; ulcers; ischemic ulcers; inadequate blood supply; poor capillary circulation; small artery atherosclerosis; venous stasis; atherosclerotic lesions (e.g., intracoronary); angina; myocardial infarction; diabetes; hypertension; Buerger's disease; diseases associated with abnormal levels of VEGF, GAPDH, and / or EPO; Crohn's disease; ulcerative colitis; psoriasis; sarcoidosis; rheumatoid arthritis; hemangiomas; Osler-Weber vasculitis disease; hereditary hemorrhagic telangiectasia; solid or hematologic tumors and acquired immune deficiency syndromes; atrial arrhythmias; ischemic tissue damage in tissues such as: cardiac tissues, such as the myocardium and ventricles; neural tissues, such as skeletal muscle, cerebellum; internal organs, such as the stomach, intestine, pancreas, liver, spleen, and lungs; and distal appendages, such as the fingers and toes.

[0250] Specifically, the methods provided herein are directed to treating, among others, peripheral vascular disease (PVD); coronary artery disease (CAD); heart failure; ischemia; anemia; wound healing; ulcers; ischemic ulcers; inadequate blood supply; poor capillary circulation; small artery atherosclerosis; venous stasis; atherosclerotic lesions (e.g., intracoronary); angina; myocardial infarction; diabetes; hypertension; Buerger's disease; diseases associated with abnormal levels of VEGF, GAPDH, and / or EPO; Crohn's disease; ulcerative colitis; psoriasis; sarcoidosis. the administration of Compound 1 and another therapeutic agent (e.g., a drug described herein) to a subject having ischemic tissue damage in tissues such as: cardiac tissue, such as the myocardium and ventricles, neural tissue, such as skeletal muscle, cerebellum, visceral organs, such as the stomach, intestine, pancreas, liver, spleen, and lungs, and distal appendages, such as the fingers and toes.

[0251] In certain embodiments, the methods provided herein include administering Compound 1 and another therapeutic agent (e.g., a drug described herein) to a subject having anemia, such as anemia secondary to non-dialysis-dependent chronic kidney disease.

[0252] In some embodiments, the subject has renal anemia (anemia secondary to or associated with chronic kidney disease).

[0253] In certain embodiments, the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease. In certain embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. In other embodiments, the chronic kidney disease is non-dialysis dependent chronic kidney disease. In yet other embodiments, the subject has not previously been treated for anemia, such as anemia secondary to chronic kidney disease. In alternative embodiments, the subject has previously been treated for anemia, such as anemia secondary to chronic kidney disease.

[0254] Compound 1 Dosage and Administration Regimen Specific dosages for use of Compound 1 can be administered in any manner known to one of skill in the art. Exemplary dosages are provided herein, including in the Examples.

[0255] In some embodiments, the dose of Compound 1 is about 150 mg to about 600 mg, about 150 mg to 750 mg, about 150 mg to 900 mg, about 150 mg to 1200 mg, about 150 mg to 1500 mg, about 75 mg to 1200 mg, about 75 mg to 1500 mg, or about 75 mg to 1800 mg. In some embodiments, the dose of Compound 1 is about 75 mg to about 1200 mg, about 150 mg to about 600 mg, or about 150 mg to about 750 mg. In embodiments, the dose of Compound 1 is about 75 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg. In embodiments, the dose of Compound 1 is at least about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg.In embodiments, the dose of Compound 1 is about 75 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg or less.

[0256] In embodiments, such doses may be administered orally once daily, twice daily, three times daily, three times weekly, or once weekly.

[0257] In some embodiments, such doses are initial doses at the beginning of treatment, in some embodiments, such doses are adjusted doses at later times during the course of treatment.

[0258] The dose of Compound 1 may be taken orally. The dose of Compound 1 may be taken during fasting, with liquid, or with any type of food. In certain embodiments, the dose of Compound 1 may be taken 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after a meal, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours before a meal. The dose of Compound 1 may be taken at any time during the day. In certain embodiments, the repeated doses are administered at the same time during the day. In certain embodiments, the administered doses are administered in the morning, around noon, or in the evening. In certain embodiments, the doses are administered between 4:00 a.m. and 2:00 p.m. In certain embodiments, the doses are administered between 5:00 a.m. and 1:00 p.m. In certain embodiments, the doses are administered between 6:00 a.m. and 12:00 noon. In certain embodiments, the doses are administered between 7:00 a.m. and 11:00 a.m. In certain embodiments, the dose is administered between 8:00 a.m. and 10:00 a.m. In certain embodiments, the dose is administered before, during, or after breakfast. Administration and dosing regimens can be adjusted as described herein.

[0259] Dose levels of the compound include 150, 300, 450, and 600 mg. The drug is then taken once a day during the course of treatment. Subjects should take the study drug with 4 ounces of water or other oral beverage, regardless of food intake. Doses are taken at approximately the same time each day, preferably between 7 am and 2 pm.

[0260] In certain embodiments, subjects are initially treated with 300 mg of Compound 1 daily (300 mg / day).

[0261] In certain embodiments, subjects are initially treated with 450 mg of Compound 1 daily (450 mg / day).

[0262] This section provides some exemplary doses of Compound 1. In certain embodiments, such doses are initial doses at the beginning of treatment. In other embodiments, such doses are adjusted doses at later times during the course of treatment.

[0263] In certain embodiments, the daily dose of compound 1 is about 150 mg to about 600 mg. In certain embodiments, the daily dose of the compound is about 150 mg to about 300 mg or about 300 to about 600 mg. In certain embodiments, the daily dose is about 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg of compound 1, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the daily dose of compound 1, or a pharma- ceutically acceptable salt thereof, is at least about 150 mg, at least about 300 mg, at least about 450 mg, or even at least about 600 mg.

[0264] In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg of Compound 1. In certain embodiments, the daily dose of Compound 1 is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. In some embodiments, the maximum dose is about 600 mg.

[0265] In some embodiments, the starting dose is about 300 mg, and the dose is adjusted (e.g., according to the patient's condition), hi some embodiments, the maximum dose is about 600 mg.

[0266] In some embodiments, the starting dose is about 450 mg, and the dose is adjusted (e.g., according to the patient's condition), hi some embodiments, the maximum dose is about 600 mg.

[0267] In certain embodiments, the daily dose of 450 mg of compound 1 may be reduced by about 150 mg, so that the daily dose of the compound is about 300 mg. In certain embodiments, the daily dose of compound 1 may be reduced by about 300 mg, so that the daily dose of the compound is about 150 mg. In certain embodiments, the daily dose of compound 1 may be increased or decreased by about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg. In certain embodiments, the daily dose may be increased or decreased by about 75 mg to about 300 mg, about 100 mg to about 300 mg, about 125 mg to about 300 mg, about 150 mg to about 300 mg, about 175 mg to about 300 mg, about 200 mg to about 300 mg, about 225 mg to about 300 mg, about 250 mg to about 300 mg, or about 275 mg to about 300 mg. In certain embodiments, the daily dose of Compound 1, or a pharma- ceutically acceptable salt thereof, may be increased or decreased by about 75 mg to about 250 mg, about 100 mg to about 225 mg, or about 125 mg to about 200 mg. In certain such embodiments, the daily dose of Compound 1 does not exceed about 600 mg.

[0268] Dose adjustment In certain embodiments, the dose is administered to a patient having anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, administered in a formulation described herein; taking a first measurement of the patient's hemoglobin level, followed by taking a second measurement of the patient's hemoglobin level, where the patient's hemoglobin level at the second measurement is less than about 10.0 g / dL and the hemoglobin level is less than about 10.0 g / dL at the second measurement. or if the patient's hemoglobin level at the second measurement is less than about 10.0 g / dL and the hemoglobin level has changed by up to about 0.4 g / dL compared to the level at the first measurement, or if the patient's hemoglobin level at the second measurement is about 10.0 to about 10.9 g / dL and the hemoglobin level has decreased by less than about 0.5 g / dL compared to the level at the first measurement, by administering an adjusted daily dose of the compound that is greater than the initial daily dose. In certain such embodiments, the adjusted daily dose of the compound is about 150 mg greater than the initial daily dose.

[0269] In certain embodiments, the dose is administered to a patient having anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt thereof, administered in a formulation described herein; taking a first measurement of the patient's hemoglobin level, followed by taking a second measurement of the patient's hemoglobin level, where the patient's hemoglobin level at the second measurement is less than about 10.0 g / dL and the hemoglobin level has increased by more than about 1.5 g / dL compared to the level at the first measurement, or the patient's hemoglobin level at the second measurement is between about 10.0 and about 10.9 g / dL and the hemoglobin level has increased by more than about 1.5 g / dL compared to the level at the first measurement. If the patient's hemoglobin level at the second measurement is about 11.0 to about 12.2 g / dL and the hemoglobin level is increased by about 1.0 to about 1.4 g / dL compared to the level at the first measurement, or if the patient's hemoglobin level at the second measurement is about 12.3 to about 12.9 g / dL and the hemoglobin level is decreased by up to about 0.4 g / dL or increased by up to about 0.4 g / dL compared to the first measurement, or if the patient's hemoglobin level at the second measurement is about 12.3 to about 12.9 g / dL and the hemoglobin level is increased by about 0.5 to about 0.9 g / dL compared to the level at the first measurement, the hemoglobin level may be adjusted by administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, the adjusted daily dose of the compound is about 150 mg less than the initial daily dose. In certain embodiments, the minimum dose level is 150 mg per day. Patients already on the lowest dose level will continue on 150 mg per day unless Hgb increases to 13.0 g / dL or greater.

[0270] In certain embodiments, the dose may include administering to a patient having anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, administered in a formulation; taking a first measurement of the patient's hemoglobin level; and thereafter taking a second measurement of the patient's hemoglobin level, wherein the patient's hemoglobin level at the second measurement is about 11.0 to about 12.2 g / dL and the hemoglobin level is about 11.0 to about 12.2 g / dL compared to the level at the first measurement. If the patient's hemoglobin level at the second measurement is about 12.3 to about 12.9 g / dL and the hemoglobin level has increased by about 1.0 to about 1.4 g / dL compared to the level at the first measurement, or if the patient's hemoglobin level at the second measurement is about 12.3 to about 12.9 g / dL and the hemoglobin level has increased by more than about 1.5 g / dL compared to the level at the first measurement, the initial daily dose may be adjusted by administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, the adjusted daily dose of the compound is about 300 mg less than the initial daily dose. In certain embodiments, the minimum dose level is 150 mg per day. Patients already at the minimum dose level continue at 150 mg per day unless Hgb increases to 13.0 g / dL or greater.

[0271] In certain embodiments, the dose may be adjusted by administering to a patient with anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, administered in a formulation, taking a first measurement of the patient's hemoglobin level, and then taking a second measurement of the patient's hemoglobin level, where if the patient's hemoglobin level at the second measurement is 13.0 g / dL or higher, administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, administration is discontinued. In certain such embodiments, if Hgb rises to 13 g / dL or higher, administration is discontinued and not resumed until Hgb has decreased to 12.5 g / dL or lower. Factors that may temporarily alter Hgb levels should be considered before discontinuing administration. Hgb is assessed every two weeks during this period.

[0272] In certain embodiments, the dose may be adjusted by administering to a patient with anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, taking a first measurement of the patient's hemoglobin level, and then taking a second measurement of the patient's hemoglobin level, where if the patient's hemoglobin level at the second measurement is 12.5 g / dL or higher, administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, administration is discontinued. In certain such embodiments, if Hgb rises to 12.5 g / dL or higher, administration is discontinued and not resumed until Hgb has decreased to 12.0 g / dL or lower. Factors that may temporarily alter Hgb levels should be considered before discontinuing administration. Hgb is assessed every two weeks during this period.

[0273] In certain embodiments, the dose may be adjusted by administering to a patient with anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, taking a first measurement of the patient's hemoglobin level, and then taking a second measurement of the patient's hemoglobin level, where if the patient's hemoglobin level at the second measurement is 13.0 g / dL or greater if the patient is an adult male, or 12.5 g / dL or greater if the patient is an adult female, administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, administration is discontinued. In certain such embodiments, if Hgb rises above 13.0 g / dL if the patient is an adult male, or above 12.5 g / dL if the patient is an adult female, administration is interrupted and not resumed until Hgb decreases below 12.5 g / dL if the patient is an adult male, or below 12.0 g / dL if the patient is an adult female. Factors that may temporarily alter Hgb levels should be considered before discontinuing administration. Hgb is evaluated every two weeks during this period.

[0274] In certain embodiments, the dose includes administering to a patient having anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, administered in a formulation; taking a first measurement of the patient's hemoglobin level, followed by taking a second measurement of the patient's hemoglobin level, where the patient's hemoglobin level at the second measurement is less than about 9.5-10.5 g / dL or about 9.75-10.25 g / dL, the hemoglobin level has decreased by less than about 0.2-0.8, about 0.3-0.7, or about 0.4-0.6 g / dL as compared to the level at the first measurement, or the patient's hemoglobin level at the second measurement is decreased by less than about 0.2-0.8, about 0.3-0.7, or about 0.4-0.6 g / dL as compared to the level at the first measurement, or If the hemoglobin level is less than about 9.5-10.5 g / dL or about 9.75-10.25 g / dL and the hemoglobin level has changed by up to about 0.1-0.7, about 0.2-0.6, or about 0.3-0.5 g / dL compared to the level at the first measurement, or if the patient's hemoglobin level at the second measurement is about 9.5-10.5 g / dL or about 9.75 to about 10.25 g / dL and about 10.4-11.4 g / dL or about 10.65-11.15 g / dL and the hemoglobin level has decreased by less than about 0.2-0.8, about 0.3-0.7, or about 0.4-0.6 g / dL compared to the level at the first measurement, the patient may be adjusted by administering an adjusted daily dose of the compound that is greater than the initial daily dose. In certain such embodiments, the adjusted daily dose of the compound is about 150 mg more than the initial daily dose.

[0275] In certain embodiments, the dose includes administering to a patient having anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt thereof, administered in a formulation; taking a first measurement of the patient's hemoglobin level, followed by taking a second measurement of the patient's hemoglobin level, wherein the patient's hemoglobin level at the second measurement is less than about 9.5 to about 10.5 g / dL or about 9.75 to about 10.25 g / dL and the hemoglobin level is less than about 1.2 to about 1.8, about 1.3 to about 1.7, or about 1.8 g / dL compared to the level at the first measurement. or the patient's hemoglobin level at the time of the second measurement is about 9.5 to about 10.5, or about 9.75 to about 10.25 g / dL and about 10.4 to about 11.4 g / dL, or about 10.65 to about 11.15 g / dL, and the hemoglobin level has increased by more than about 1.2 to about 1.8, about 1.3 to about 1.7, or about 1.4 to about 1.6 g / dL compared to the level at the time of the first measurement, or the patient's hemoglobin level at the time of the second measurement is about 10.5 to about 11.5 g / dL, or about 10.75 to about 11.25 g / dL, and about 11.7 to about 12.7 g / dL, or about 11.95 to about 12.45 g / dL. or about 1.5 to about 1.6 g / dL compared to the level at the first measurement, or if the patient's hemoglobin level at the second measurement is about 11.8 to about 12.8 g / dL, or about 12.05 to about 12.55 g / dL, and about 12.4 to about 13.9 g / dL, or about 12.65 to about 13.15 g / dL and the hemoglobin level is increased by about 0.7 to about 1.3, about 0.8 to about 1.2, or about 0.9 to about 1.1 g / dL, and about 1.1 to about 1.7, about 1.2 to about 1.6, or about 1.3 to about 1.5 g / dL compared to the level at the first measurement, or is increased by up to about 0.1 to about 0.7, about 0.2 to about 0.6, or about 0.3 to about 0.5 g / dL compared to the level at the time of the first measurement, or is increased by up to about 0.1 to about 0.7, about 0.2 to about 0.6, or about 0.3 to about 0.5 g / dL compared to the level at the time of the second measurement, or is increased by up to about 0.1 to about 0.7, about 0.2 to about 0.6, or about 0.3 to about 0.5 g / dL compared to the level at the time of the first ...If Hgb has increased by about 2 to about 0.8 g / dL, about 0.3 to about 0.7 g / dL, about 0.4 to about 0.6 g / dL, about 0.6 to about 1.2 g / dL, about 0.7 to about 1.1 g / dL, or about 0.8 to 1.0 g / dL, the patient may be adjusted by administering an adjusted daily dose of the compound less than the initial daily dose. In certain such embodiments, the adjusted daily dose of the compound is about 150 mg less than the initial daily dose. In certain embodiments, the minimum dose level is 150 mg per day. Patients already at the minimum dose level will continue at 150 mg per day unless Hgb increases to 12.0 g / dL, 12.5 g / dL, or 13.0 g / dL or greater.

[0276] In certain embodiments, the dose includes administering to a patient having anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, administered in a formulation; taking a first measurement of the patient's hemoglobin level, and thereafter taking a second measurement of the patient's hemoglobin level, wherein the patient's hemoglobin level at the second measurement is between about 10.5 and 11.5 g / dL, or between about 10.75 and 11.25 g / dL, and between about 11.7 and 12.7 g / dL, or between about 11.95 and 12.45 g / dL. g / dL and the hemoglobin level has increased by more than about 1.2 to 1.8 g / dL, about 1.3 to about 1.7 g / dL, or about 1.4 to about 1.6 g / dL compared to the level at the first measurement, or the patient's hemoglobin level at the second measurement is about 11.8 to 12.8 g / dL, or about 12.05 to about 12.55 g / dL, and about 12.4 to about 13.9 g / dL, or about 12.65 to about 13.15 g / dL. g / dL, and the hemoglobin level has increased by about 0.7 to about 1.3 g / dL, about 0.8 to about 1.2 g / dL, or about 0.9 to about 1.1 g / dL and about 1.1 to about 1.7 g / dL, about 1.2 to about 1.6 g / dL, or about 1.3 to about 1.5 g / dL compared to the level at the first measurement, or the patient's hemoglobin level at the second measurement is about 11.8 to about 12.8 g / dL or about 12. If the hemoglobin level is between about 0.05 and about 12.55 g / dL and about 12.4 and about 13.9 g / dL or about 12.65 and about 13.15 g / dL and the hemoglobin level has increased by more than about 1.2 to about 1.8 g / dL, about 1.3 to about 1.7 g / dL, or about 1.4 to about 1.6 g / dL compared to the level at the first measurement, the hemoglobin level may be adjusted by administering an adjusted daily dose of the compound less than the initial daily dose. In certain such embodiments, the adjusted daily dose of the compound is about 300 mg less than the initial daily dose. In certain embodiments, the minimum dose level is 150 mg per day. Patients already at the minimum dose level continue at 150 mg per day unless Hgb increases to 12.0 g / dL, 12.5 g / dL, or 13.0 g / dL or more.

[0277] In certain embodiments, the dose may be adjusted by administering to a patient with anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, administered in a formulation, taking a first measurement of the patient's hemoglobin level, and then taking a second measurement of the patient's hemoglobin level, where if the patient's hemoglobin level at the second measurement is 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, 13.0 g / dL, 13.5 g / dL, or 14.0 g / dL or greater, administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, administration is discontinued. In certain such embodiments, if Hgb rises to 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, 13.0 g / dL, 13.5 g / dL, or 14.0 g / dL or greater, dosing is interrupted and not resumed until Hgb decreases to 10.5 g / dL, 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, 13.0 g / dL, or 13.5 g / dL or less. Factors that may temporarily alter Hgb levels should be considered before discontinuing dosing. Hgb is assessed every two weeks during this period.

[0278] In certain embodiments, the dose may be adjusted by administering to a patient with anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, administered in a formulation, taking a first measurement of the patient's hemoglobin level, and then taking a second measurement of the patient's hemoglobin level, where if the patient's hemoglobin level at the second measurement is 10.5 g / dL, 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, 13.0 g / dL, or 13.5 g / dL or greater, administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, administration is discontinued. In certain such embodiments, if Hgb rises above 10.5 g / dL, 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, 13.0 g / dL, or 13.5 g / dL, dosing is interrupted and not resumed until Hgb decreases below 10.0 g / dL, 10.5 g / dL, 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, or 13.0 g / dL. Factors that may temporarily alter Hgb levels should be considered before discontinuing dosing. Hgb is assessed every two weeks during this period.

[0279] In certain embodiments, the dose may be adjusted by administering to a patient having anemia an initial daily dose of a compound that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt thereof, administered in a formulation, taking a first measurement of the patient's hemoglobin level, and then taking a second measurement of the patient's hemoglobin level, where if the patient's hemoglobin level at the second measurement is greater than or equal to 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, or 14.0 g / dL if the patient is an adult male, or greater than or equal to 10.5 g / dL, 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, 13.0 g / dL, or 13.5 g / dL if the patient is an adult female, then administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, administration is discontinued. In certain such embodiments, if Hgb rises to greater than or equal to 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, 13.0 g / dL, 13.5 g / dL, or 14.0 g / dL if the patient is an adult male, or greater than or equal to 10.5 g / dL, 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, 13.0 g / dL, or 13.5 g / dL if the patient is an adult female. , dosing is interrupted and not resumed until Hgb decreases to 10.5 g / dL, 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, 13.0 g / dL, or 13.5 g / dL or less if the patient is an adult male, or 10.0 g / dL, 10.5 g / dL, 11.0 g / dL, 11.5 g / dL, 12.0 g / dL, 12.5 g / dL, or 13.0 g / dL or less if the patient is an adult female. Factors that may temporarily alter Hgb levels should be considered before discontinuing dosing. Hgb is evaluated every two weeks during this period. The dose adjustment methods described herein may be applied to treatment regimens using any of the compounds described herein, or any combination thereof.

[0280] Dose adjustment based on hemoglobin level In certain embodiments, the dose can be adjusted by administering to a patient with anemia an initial daily dose of Compound 1, administered in a formulation, taking a first measurement of the patient's hemoglobin level, then taking a second measurement of the patient's hemoglobin level, and adjusting the dose as described below. In certain embodiments, the first measurement is a baseline measurement. In certain embodiments, the dose can be adjusted by administering to a patient with anemia an initial daily dose of a compound, Compound 1, administered in a formulation as described herein, taking a first measurement of the patient's hemoglobin level, then taking a second measurement of the patient's hemoglobin level, and adjusting the dose as described below.

[0281] In certain embodiments, hemoglobin levels can be measured and monitored throughout the study, for example, via a HemoCue® point-of-care Hgb monitoring system, to determine whether to adjust the dose of the investigational drug. In certain embodiments, Hgb can be obtained every 2 weeks via HemoCue® for monitoring dose adjustments. In certain embodiments, Hgb can be obtained every 4 weeks via HemoCue® unless more frequent monitoring is clinically indicated or warranted based on dose changes. In certain embodiments, Hgb can be obtained every 4, 6, 8, 10, 12, or 16 weeks via HemoCue®. In certain embodiments, hemoglobin can also be assessed using a complete blood count (CBC) through a central laboratory for efficacy and safety evaluation, but dose adjustments are based on local HemoCue® Hgb values. In certain embodiments, the goal is to increase and maintain Hgb levels at 10-11 g / dL. In certain embodiments, the goal is to increase and maintain Hgb levels between 10-12 g / dL, hi certain embodiments, the goal is to increase and maintain Hgb levels between 10-13 g / dL.

[0282] In certain embodiments, Compound 1 is administered according to the following dose adjustment algorithm guidelines: When adjusting therapy, rate of increase, rate of decrease, and variability of Hgb are considered. A single Hgb excursion may not require a dose change.

[0283] Dose Adjustment Procedures in Patients with Chronic Kidney Disease In certain embodiments, the dose of Compound 1 is adjusted during the course of treatment of the patient as described below.In certain specific embodiments, the dose is adjusted to correct anemia in the patient.In certain specific embodiments, the patient has non-dialysis-dependent chronic kidney disease (NDD-CKD).

[0284] In certain embodiments, the baseline value is determined immediately before the first administration of Compound 1. In certain embodiments, the initial daily dose administered to the patient is 300 mg / day. In certain specific embodiments, the initial daily dose is administered in the form of two tablets of 150 mg each. In certain embodiments, the initial daily dose administered to the patient is 450 mg / day. In certain specific embodiments, the initial daily dose is administered in the form of three tablets of 150 mg each. In certain specific embodiments, the initial daily dose is administered in the morning. In certain specific embodiments, the initial daily dose is administered between 7 am and 2 pm.

[0285] In certain embodiments, the daily dose of Compound 1 is increased no more frequently than once every four weeks during the course of treatment. Reductions in the daily dose may occur more frequently, but frequent dose adjustments should be avoided.

[0286] In certain embodiments, if Hgb does not increase by more than 0.5 g / dL above baseline after 4 weeks of treatment, the daily dose of the compound is increased by 150 mg / day. The daily dose is increased by 150 mg / day every 4 weeks (maximum dose is 600 mg / day) until Hgb exceeds 10.0 g / dL. In certain specific embodiments, if Hgb does not increase by more than 0.5 g / dL above baseline after 4 weeks of treatment of NDD-CKD patients with a daily dose of compound 1, the daily dose of the compound is increased by 150 mg / day. In certain specific embodiments, the daily dose of compound 1 is increased by 150 mg / day every 4 weeks (maximum dose is 600 mg / day) until Hgb exceeds 10.0 g / dL in NDD-CKD patients.

[0287] In certain embodiments, if Hgb rises rapidly during treatment (e.g., greater than 1.0 g / dL in any two-week period), the daily dose is reduced by 150 mg / day. In certain specific embodiments, if Hgb rises rapidly during treatment with a daily dose of Compound 1 (e.g., greater than 1.0 g / dL in any two-week period), the daily dose is reduced by 150 mg / day.

[0288] In certain embodiments, if Hgb falls below 10.0 g / dL, the daily dose is increased by 150 mg / day. In certain specific embodiments, if an NDD-CKD patient's Hgb falls below 10.0 g / dL during treatment with a dose of Compound 1, the daily dose is increased by 150 mg / day.

[0289] In certain embodiments, if Hgb levels are above 11.0 g / dL, treatment is interrupted until Hgb is reduced to 10.5 g / dL or less. Then, administration is resumed with a reduced daily dose of 150 mg / day. In certain specific embodiments, if Hgb levels of NDD-CKD patients are above 11.0 g / dL, treatment with Compound 1 is interrupted until Hgb is reduced to 10.5 g / dL or less. Then, administration of Compound 1 is resumed with a reduced daily dose of 150 mg / day.

[0290] In certain embodiments, if Hgb levels are above 12.0 g / dL, the daily dose is reduced by 150 mg. In certain embodiments, if Hgb values ​​are above 13.0 g / dL, treatment is suspended until Hgb is reduced to 12.5 g / dL or less. Then, administration is resumed with a reduced daily dose of 150 mg / day. In certain specific embodiments, if Hgb values ​​of NDD-CKD patients are above 12.0 g / dL during treatment with a daily dose of Compound 1, the dose is reduced by 150 mg / day. In certain specific embodiments, if Hgb values ​​of NDD-CKD patients are above 13.0 g / dL, treatment with Compound 1 is suspended until Hgb is reduced to 12.5 g / dL or less. Then, administration of Compound 1 is resumed with a reduced daily dose of 150 mg / day.

[0291] In certain embodiments, if a dose adjustment is required to maintain Hgb at a desired level, the daily dose is adjusted by 150 mg / day. In certain specific embodiments, if a dose adjustment of Compound 1 is required to maintain Hgb at a desired level in NDD-CKD patients, the daily dose is adjusted by 150 mg / day.

[0292] In certain embodiments, the dose of Compound 1 is adjusted during the course of treatment of the patient as described below.In certain specific embodiments, the daily dose is adjusted for the maintenance treatment of anemia in the patient.In certain specific embodiments, the patient has non-dialysis-dependent chronic kidney disease (NDD-CKD).

[0293] In certain embodiments, the baseline value is determined immediately before the first administration of Compound 1. In certain embodiments, the initial daily dose administered to the patient is 300 mg / day. In certain specific embodiments, the initial daily dose is administered in the form of two tablets of 150 mg each. In certain embodiments, the initial daily dose administered to the patient is 450 mg / day. In certain specific embodiments, the initial daily dose is administered in the form of three tablets of 150 mg each. In certain specific embodiments, the initial daily dose is administered in the morning. In certain specific embodiments, the initial daily dose is administered between 7 am and 2 pm.

[0294] In certain embodiments, the daily dose of Compound 1 is increased no more frequently than once every four weeks during the course of treatment. Reductions in the daily dose may occur more frequently, but frequent dose adjustments should be avoided.

[0295] In certain embodiments, when dose adjustments are required to maintain Hgb at the desired level, the daily dose of the compound is adjusted by 150 mg / day (maximum daily dose is 600 mg / day). In certain specific embodiments, when dose adjustments are required to maintain Hgb at the desired level in NDD-CKD patients, the daily dose of Compound 1 is adjusted by 150 mg / day (maximum daily dose is 600 mg / day).

[0296] In certain embodiments, if Hgb falls below 10.0 g / dL, the daily dose is increased by 150 mg / day. In certain specific embodiments, if an NDD-CKD patient's Hgb falls below 10.0 g / dL during treatment with a dose of Compound 1, the daily dose is increased by 150 mg / day.

[0297] In certain embodiments, if Hgb levels are above 11.0 g / dL, treatment is interrupted until Hgb is reduced to 10.5 g / dL or less. Then, administration is resumed with a reduced daily dose of 150 mg / day. In certain specific embodiments, if Hgb levels of NDD-CKD patients are above 11.0 g / dL, treatment with Compound 1 is interrupted until Hgb is reduced to 10.5 g / dL or less. Then, administration of Compound 1 is resumed with a reduced daily dose of 150 mg / day.

[0298] In certain embodiments, if Hgb levels are above 12.0 g / dL, the daily dose is reduced by 150 mg / day. In certain embodiments, if Hgb levels are above 13.0 g / dL, treatment is suspended until Hgb is reduced to 12.5 g / dL or less. Then, administration is resumed with a reduced daily dose of 150 mg / day. In certain specific embodiments, if an NDD-CKD patient's Hgb levels are above 12.0 g / dL during treatment with a daily dose of Compound 1, the daily dose is reduced by 150 mg / day. In certain specific embodiments, if an NDD-CKD patient's Hgb levels are above 13.0 g / dL, treatment with Compound 1 is suspended until Hgb is reduced to 12.5 g / dL or less. Then, administration of Compound 1 is resumed with a reduced daily dose of 150 mg / day. EXAMPLES

[0299] Example 1: Clinical Information Regarding Compound 1 Mechanism of action Under normal oxygen concentrations, prolyl hydroxylase (PHD) hydroxylates and degrades hypoxia-inducible factor (HIF) α, but PHD activity is reduced under low oxygen concentrations and HIF-α protein is stabilized. As a result, gene expression including erythropoietin is increased, and erythropoiesis and iron utilization are enhanced to adapt to low oxygen environments. Without being bound by theory, by inhibiting PHD activity, compound 1 mimics the above-mentioned biological response and leads to hemoglobin production and erythropoiesis by increasing erythropoietin production following the stabilization of HIF-α protein.

[0300] PHD inhibition Compound 1 inhibits human PHD1, PHD2, and PHD3 (IC 50 Values: 15.36 nmol / L, 11.83 nmol / L, and 7.63 nmol / L, respectively) (in vitro).

[0301] Increases blood erythropoietin levels In normal rats, a single oral dose of Compound 1 was shown to increase blood erythropoietin levels.

[0302] Hemoglobin concentration In normal rats, repeated oral administration of Compound 1 for 14 days was effective in increasing hemoglobin concentration and red blood cell count.

[0303] Guidelines for initiating Compound 1 administration As a guideline for initiating treatment, hemoglobin concentrations should be less than 10 g / dL (30% hematocrit) for hemodialysis patients and less than 11 g / dL (33% hematocrit) for conservative chronic kidney disease and peritoneal dialysis patients.

[0304] When administering this drug, it should be confirmed that the patient has renal anemia and should not be administered for other anemias such as blood loss anemia, pancytopenia, etc.

[0305] Hemoglobin concentrations or hematocrit levels should be monitored periodically during treatment with this drug.

[0306] Dosing regimen Adult patients are typically administered an initial dose of 300 mg of Compound 1 orally once daily.

[0307] Once anemia correction has been achieved, adult patients are typically administered 150 mg to 600 mg of Compound 1 orally once daily.

[0308] Dose can be adjusted appropriately according to factors including progression and severity of anemia.Dose can also be adjusted appropriately based on, for example, the dose of red blood cell (RBC) promoter (e.g., erythropoiesis promoter) preparation before switching.However, the maximum daily dose of Compound 1 is 600mg.

[0309] If an appropriate increase in hemoglobin or hematocrit is not observed at the beginning of administration, and / or if it is difficult to maintain hemoglobin or hematocrit in the target range during the maintenance administration period, and if a dose adjustment is necessary, the dose should be increased or decreased within the range of 150 to 600 mg per day. Dose increases or decreases are considered by closely monitoring the change in hemoglobin or hematocrit before it deviates from the target value. However, the dose should not be increased by more than 150 mg.

[0310] If iron deficiency is observed, administration of iron supplements can be performed.

[0311] Hemoglobin levels or hematocrit are monitored periodically during administration of Compound 1 to prevent excessive hematopoietic activity. Complications including heart failure, ischemic heart disease, and death are associated with hemoglobin levels around 14 g / dL (hematocrit 42%) compared with hemoglobin levels around 10 g / dL (hematocrit 30%).

[0312] Pharmacokinetics of Compound 1 Blood levels – single dose Table 3 summarizes the changes in plasma concentrations and pharmacokinetic parameters on the first day of administration when 150 mg, 300 mg, and 600 mg of Compound 1 were repeatedly administered once daily for 10 days to healthy adult males. [Table 5]

[0313] (When a single dose of 450 mg of this drug was administered to healthy adult males while fasting or fed) C max and AUC 0-infThe geometric mean ratios (%) and their 90% confidence intervals were 73% [68%, 79%] and 94% [90%, 98%], respectively. max The median time was extended by approximately 1.5 hours when administered after a meal compared with when administered fasting. These results are summarized in Table 4. [Table 6]

[0314] distribution The human plasma protein binding rate of the drug was more than 99% (in vitro, equilibrium dialysis).

[0315] metabolism Compound 1 is metabolized via UGT to produce mainly O-glucuronide conjugates. 14 When [C]-labeled Compound 1 was orally administered once, the total radioactivity (AUC 0-∞ ) accounted for 75% of the total, while the O-glucuronide conjugates accounted for approximately 15%.

[0316] UGT1A1, UGT1A7, UGT1A8, and UGT1A9 were involved in the formation of O-glucuronide, the main metabolite of this drug in humans (in vitro). Compound 1 showed inhibitory effects on CYP2B6, CYP2C8, CYP2C9, and UGT1A1 (in vitro), but the variation ratio of AUC of each representative substrate was less than 1.25-fold (static pharmacokinetic model).

[0317] excretion 650 mg of [ 14 Following a single dose of [C]-labeled Compound 1, 58.9% of the total administered radioactivity was excreted in urine and 26.9% in feces within 72 hours after administration. The urinary excretion rates of the drug and acyl glucuronide were less than 1% of the total radioactivity. Without being bound by theory, the primary excretion route of Compound 1 is urinary excretion of the O-glucuronide conjugate via glucuronidation.

[0318] Phase III clinical trial of Compound 1 in patients with hemodialysis anemia Compound 1 was administered to patients with hemodialysis anemia without the use of erythrocyte stimulating factor for 24 weeks (the dose of Compound 1 was 300 mg once a day as the initial dose and 150 mg to 600 mg once a day as the maintenance dose). The mean hemoglobin values ​​at the 20th and 24th weeks are shown in Table 5. The incidence of side effects when this drug was administered up to the 24th week was 8.3% (2 cases out of 24 cases). [Table 7]

[0319] Example 2: Administration of Sevelamer Carbonate with Compound 1 The investigator may prescribe a composition containing a polymeric amine that binds phosphate, if desired, to a patient taking Compound 1.

[0320] A phase I, open-label, fixed-sequence study was conducted to evaluate the effect of a single oral dose of sevelamer carbonate on the pharmacokinetics of a single oral dose of vadadustat in healthy adult subjects.

[0321] The study included screening (up to 28 days), a 9-day treatment period, and a follow-up period of 14 days after the last dose.

[0322] After the screening period, subjects who met all inclusion criteria and did not violate the exclusion criteria described below were randomized into the subsequent treatment period. A total of 18 subjects were enrolled in the study.

[0323] Inclusion Criteria: 1.Male or female, aged 18-55 years (inclusive) at the time of informed consent. a. Female subjects of childbearing potential must be non-lactating, not pregnant as confirmed by a negative serum pregnancy test at Screening and Day -1, and must agree to use, and continue to use, effective contraception for at least 4 weeks prior to the first dose of study drug through 30 days after the last dose of study drug. b. Female subjects of non-childbearing potential must be surgically infertile (e.g., hysterectomy, bilateral tubal ligation, oophorectomy) or postmenopausal (follicle-stimulating hormone [FSH] >40 U / L at screening and no menses for >1 year). c. Female subjects of childbearing potential must agree not to donate eggs during the study and for at least 30 days after the last dose of investigational product. d. Male subjects who have not had a vasectomy for at least 6 months must use effective contraception during the study and for 90 days after the last dose of study drug, and must agree to not donate sperm during the study and for at least 90 days after the last dose of study drug. 2. Health assessment as determined by the investigator's judgment, documented by medical history, physical examination, vital signs assessment, 12-lead ECG, clinical laboratory assessment, and general observation. At screening, if clinical assessments (lab tests, ECG, vital signs) reveal abnormalities or deviations outside the normal range, they may be repeated once at the discretion of the investigator, and persistent deviations from the normal range must be deemed by the investigator to be not clinically significant and acceptable for study participation. b. On Day -1, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin values ​​must be within the upper limit of the normal range. All other laboratory results that are outside the normal range on Day -1 and are judged by the Investigator to be not clinically significant may be repeated. Results that continue to be outside the normal range must be judged by the Investigator to be not clinically significant and acceptable for study participation. 3. Body mass index (BMI) is 18.0 to 30 kg / m2, with a minimum weight of 45 kg for women and 50 kg for men (including borderline values). 4. Understand the procedures and requirements of the study and provide written informed consent and authorization for disclosure of protected health information. 5. Willing and able to comply with the requirements of the study protocol.

[0324] Exclusion criteria 1. Current or past history of cardiovascular, cerebrovascular, respiratory, gastrointestinal, hematological, renal, hepatic, immune, metabolic, urinary, neurological, dermatological, psychiatric, or other major disease as determined by the investigator. History of cancer (excluding treated non-melanoma skin cancer) or chemotherapy within 5 years prior to screening. 2. Any surgical or medical condition or history that the investigator determines may potentially alter the absorption, metabolism, or excretion of the investigational drug, including, but not limited to, gastric bypass surgery or gastric or duodenal ulcers. 3. Clinically significant history of dysphagia, ileus, or perforation. 4. Clinically significant history of hypercalcemia. 5. Clinically significant history of iron overload. 6. Clinically significant history of liver disease. 7. Clinically significant history of hypophosphatemia, ulcerative colitis, or gastrointestinal bleeding. 8. Contraindications and / or history of allergic or anaphylactic reactions to the investigational drug or its excipients. 9. Taking any of the following prohibited medications: a.- Any prescription drug or over-the-counter multivitamin supplement, or any non-prescription product (including herbal-containing preparations, but excluding a maximum of 2 g of acetaminophen per day) within 14 days prior to Day 1. b.- Any drug known to inhibit or induce cytochrome P450 (CYP) enzymes and / or P-glycoprotein, including St. John's Wort (Hypericum perforatum), within 14 days or 5 half-lives (whichever is longer) prior to Day 1. 10. History of substance abuse within 1 year prior to screening, or use of soft drugs (e.g., marijuana) within 3 months prior to the screening visit, or hard drugs (e.g., cocaine, phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine derivatives) within 1 year prior to screening. 11. History of regular alcohol consumption >14 drinks / week (1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months of screening, or history of alcohol abuse within 1 year prior to screening. 12. Positive drug and alcohol test at screening or day -1. 13. History of latent or active tuberculosis (TB) by documented medical history. Exposure to endemic areas within 8 weeks of screening. 14. Daily use of nicotine-containing products within 6 months of screening. 15. Consumption of any food or drink containing grapefruit or grapefruit juice, apple or orange juice, pomelo juice, pomegranate, pineapple, starfruit, Seville or Moro (blood) orange products, mustard family vegetables (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard), and charbroiled meats known to modulate CYP enzyme activity and transporters within 7 days prior to administration of the study drug. 16. Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCVab) test result within 3 months prior to Day -1 or at Screening. 17. Positive human immunodeficiency virus (HIV) antibody test result within 3 months prior to Day -1 or at the time of screening. 18.- Participation in another clinical trial or exposure to any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to Day 1. 19. Plasma donation within 7 days prior to infusion. Donation or loss of 50 mL to 499 mL of blood within 30 days prior to first infusion or more than 499 mL of blood within 56 days (excluding the amount drawn at screening). 20. Have had a tattoo or body piercing (including ear piercing) within 2 months prior to Day 1, and / or have any open wounds that may pose a risk of infection. 21.Has a condition that, in the opinion of the investigator, would interfere with the ability to provide written informed consent or comply with study instructions, or that may confound the interpretation of the results of the study or expose the subject to undue risk. 22. Previous participation in a clinical trial involving vadadustat.

[0325] Evaluation criteria Pharmacokinetics Pre-dose PK blood samples were collected on Day 1. After each dose of vadadustat (Days 1, 3, 5, and 7), blood samples for PK analysis were collected at the following time points: prior to vadadustat administration and 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, 24, and 48 hours after each dose. 48-hour post-dose samples were collected prior to vadadustat administration on Days 3, 5, and 7. The following parameters were calculated and analyzed: AUC 0-∞ , AUC 0-last , C max , T max , Kel, Cl B , V c / F, and t 1 / 2 .

[0326] Safety Safety and tolerability were assessed by adverse event reporting, evaluation of 12-lead electrocardiograms (ECGs), vital signs, physical examinations, and laboratory tests.

[0327] Treatment of subjects Subjects were dosed at approximately the same designated time on each dosing day, if applicable. Study drug was administered in a seated position with approximately 8 ounces (240 mL) of room temperature water. Subjects were instructed to drink the entire 8 ounces of water and not to chew the tablet / gelcap.

[0328] Single oral doses of vadadustat 300 mg (2 × 150 mg tablets) were administered on days 1, 3, 5, and 7. Sevelamer carbonate, a phosphate binder (1600 mg, 2 × 800 mg tablets), was administered on days 3, 5, and 7.

[0329] The 9-day treatment period was as follows: Day 1: Vadadustat was administered immediately after breakfast. Day 2: Dose-free (no study drug administered). Day 3: Vadadustat was administered immediately after breakfast, along with the required phosphate binders. Day 4: Dose not continued (no study drug was administered). Day 5: Vadadustat was administered in the fasted state, followed 1 hour later by phosphate binder (breakfast must be served within 2 minutes of phosphate binder administration and must be consumed immediately after serving). Day 6: Dose not continued (no study drug was administered). Day 7: The phosphate binder was administered immediately after breakfast and vadadustat was administered 2 hours after the phosphate binder. Day 8: Dose not continued (no study drug was administered). Day 9: Subjects were discharged from the Clinical Research Unit (CRU) after a 48-hour post-dose PK blood sample was collected.

[0330] Data analysis Vadadustat plasma PK parameter findings are summarized in Table 6. Plasma concentration-time profiles of vadadustat administered alone and co-administered with sevelamer carbonate are presented in Figure 1. [Table 8]

[0331] Coadministration of sevelamer carbonate and vadadustat reduced the AUC 0-last , AUC 0-∞、 and C max Although it reduced T max and t 1 / 2 remains similar, Cl B and V c The AUC of vadadustat was increased (Table 6 and Figure 1). ANOVA showed that the coadministration of vadadustat with a phosphate binder significantly increased 0-last and AUC 0-∞By reducing C by about 37%, max The results showed that the combination of vadadustat and sevelamer carbonate reduced the LS mean AUC 0-∞ The geometric LS mean ratio for vadadustat alone was 113.98 μg h / mL, with a geometric LS mean ratio of 62.85% (90% CI, 57.96 to 68.16). However, when vadadustat was administered 1 hour before or 2 hours after sevelamer carbonate, the change in vadadustat exposure was within the prespecified no-effect boundaries of 80% to 125%. This suggests that DDIs with phosphate binders such as sevelamer carbonate can be overcome by administering vadadustat immediately after waking, before breakfast, or 2 hours after administration of a phosphate binder (which can continue to be administered with meals).

[0332] Example 3: Administration of organic anion transporters with Compound 1 The investigator may optionally prescribe a composition containing an organic anion transporter (e.g., an OAT1 / OAT3 and / or OATP1B1 inhibitor) to patients taking Compound 1.

[0333] A phase I, open-label, two-part study was conducted in healthy male and female subjects to evaluate the potential interactions of vadadustat with cyclosporine (Part 1, Arm 1), probenecid (Part 1, Arm 2), and rifampin (Part 2).

[0334] The study included a 28-day screening period, a 6-10-day clinical period, and a follow-up period of 30 days (± 2 days) after the last dose.

[0335] After the screening period, subjects who met all inclusion criteria and did not violate the exclusion criteria described below were randomized into the subsequent clinical period.

[0336] Inclusion Criteria:

[0337] Subjects were required to meet the following inclusion criteria for participation in the clinical trial: 1.Male or female, aged 18-55 years (inclusive) at the time of informed consent. a. Female subjects of childbearing potential must be non-lactating, not pregnant as confirmed by a negative serum pregnancy test at Screening and Day -1, and must agree to use, and continue to use, effective contraception for at least 4 weeks prior to the first dose of study drug through 30 days after the last dose of study drug. b. Female subjects of non-childbearing potential must be surgically infertile (e.g., hysterectomy, bilateral tubal ligation, oophorectomy) or postmenopausal (follicle-stimulating hormone [FSH] >40 U / L at screening and no menses for >1 year). c. Female subjects of childbearing potential must not donate eggs during the study and for at least 30 days after the last dose of investigational product. d. Non-vasectomized male subjects must use effective contraception for at least 4 weeks prior to the first dose of study drug and until 90 days after the last dose of study drug, and must agree to not donate sperm during the study and for at least 90 days after the last dose of study drug. 2. Health assessment as determined by the investigator's judgment, documented by medical history, physical examination, vital signs assessment, 12-lead ECG, clinical laboratory assessment, and general observation. At screening, if clinical assessments (lab tests, ECG, vital signs) reveal abnormalities or deviations outside the normal range, they may be repeated once at the discretion of the investigator, and persistent deviations from the normal range must be deemed by the investigator to be not clinically significant and acceptable for study participation. b. On Day -1, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin values ​​must be within the upper limit of the normal range. All other laboratory results that are outside the normal range on Day -1 and are judged by the Investigator to be not clinically significant may be repeated. Results that continue to be outside the normal range must be judged by the Investigator to be not clinically significant and acceptable for study participation. 3. Body mass index is 18.0-30.0 kg / m 2 and the minimum weight is 45 kg for women and 50 kg for men (boundaries included). 4. Understand the procedures and requirements of the study and provide written informed consent and authorization for disclosure of protected health information. 5. Willing and able to comply with the requirements of the study protocol.

[0338] Exclusion criteria:

[0339] Subjects were not considered to participate in the study if they exhibited any of the following: 1. Current or past clinically significant history of cardiovascular, cerebrovascular, pulmonary, gastrointestinal, hematological, renal, hepatic, immune, metabolic, urinary, neurological, dermatological, psychiatric, or other major disease as determined by the investigator. History of cancer (excluding treated non-melanoma skin cancer) or chemotherapy within 5 years prior to screening. 2. Any surgical or medical condition or history that the investigator determines may potentially alter the absorption, metabolism, or excretion of the investigational drug, including, but not limited to, gastric bypass surgery or gastric or duodenal ulcers. 3. Contraindications and / or history of allergic or anaphylactic reactions to the investigational drug or its excipients. 4. Taking any of the following prohibited medications: a.- Any prescription drug or over-the-counter multivitamin supplement, or any non-prescription product (including herbal-containing preparations, but excluding acetaminophen) within 14 days prior to Day 1. b.- Any drug known to inhibit or induce cytochrome P450 (CYP) enzymes and / or P-glycoprotein, including St. John's Wort (Hypericum perforatum), within 14 days or 5 half-lives (whichever is longer) prior to Day 1. 5. History of substance abuse within 1 year prior to screening. 6. History of regular alcohol consumption >14 drinks / week [1 drink = 5 oz (150 mL) of wine or 12 oz (360 mL) of beer or 1.5 oz (45 mL) of hard liquor] within 6 months prior to screening. 7. Positive drug and alcohol test at screening or day -1. 8. History of latent or active tuberculosis (TB) by documented medical history. Exposure to endemic areas within 8 weeks of screening. 9. QuantiFERON®-TB positive test indicating possible TB infection at screening (if no documented test result has been performed within 2 months). 10. Currently smoking 10 or more cigarettes per day. 11. Intake of grapefruit or grapefruit juice, apple or orange juice, pomelo juice, starfruit, Seville or Moro (blood) orange products, and any food or drink containing mustard family vegetables (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard) in the 24 hours prior to Day -1, and foods containing poppy seeds (e.g., muffins, bagels, and cakes) and charcoal grilled meats known to modulate CYP enzyme activity and transporters within 6 days prior to Day -1. 12. Hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCVab) test result is positive at screening. 13. Human immunodeficiency virus antibody (HIVab) test result is positive at screening. 14.- Participation in another clinical trial or exposure to any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to Day 1. 15. Donation or loss of blood within 60 days or plasma within 7 days prior to first dose (excluding amount drawn at screening). 16. Have had a tattoo or body piercing (including ear piercing) within 2 months prior to Day 1, and / or have any open wounds that may pose a risk of infection. 17.Has a condition that, in the opinion of the investigator, would interfere with the ability to provide written informed consent or comply with study instructions, or that may confound the interpretation of the results of the study or expose the subject to undue risk.

[0340] Treatment of subjects Part 1 (cyclosporine and probenecid)

[0341] Group 1 - Cyclosporine

[0342] Subjects were randomized in a 1:1 ratio to one of two dosing sequences (A:B or B:A) in a crossover design: vadadustat 300 mg alone and vadadustat 300 mg in combination with oral cyclosporine 500 mg. Study drug was administered in the morning after an overnight fast of at least 10 hours. Subjects remained fasted for at least 4 hours after dosing. Treatment A: Vadadustat (300 mg) given orally as a single dose of 2 × 150 mg tablets. Treatment B: Vadadustat (300 mg) given orally as a single dose of 2 × 150 mg tablets, together with cyclosporine (500 mg) given orally as a single dose of 5 × 100 mg capsules.

[0343] Subjects received their first treatment (A or B) in the morning of Day 1. After a 7-day washout period, subjects crossed over to Period 2 and received their second treatment in the dosing sequence (A or B) on Day 8.

[0344] On each dosing day (Days 1 and 8), blood samples for PK analysis were collected up to 48 hours post-dose. After the 48-hour PK blood sample was collected after the last dose, subjects were discharged from the clinical trial unit (CRU) in the morning of Day 10. Telephone follow-up was performed 30 ± 2 days after the last dose.

[0345] Part 1, Group 2 (probenecid):

[0346] In the morning of day 1, subjects received a single oral dose of vadadustat (300 mg) as 2 x 150 mg tablets after an overnight fast of at least 10 hours and remained fasted for at least 4 hours after dosing. After a 2-day drug holiday (days 1-2), subjects received one oral 500 mg probenecid tablet twice daily for 4 days (days 3-6). On days when probenecid was administered alone (days 3, 4, and 6), probenecid was administered in a fasted state, 1 hour before a standard breakfast and 1 hour before an evening meal or snack. On day 5, probenecid was coadministered with a single dose of vadadustat (300 mg as 2 x 150 mg tablets) after a fast of at least 10 hours. Subjects remained fasted for at least 4 hours after dosing.

[0347] On days of vadadustat dosing (Days 1 and 5), blood samples for PK analysis were collected up to 48 hours post-dose. In addition, on days of vadadustat dosing, pooled urine samples were collected up to 24 hours post-dose. After the 48-hour PK blood sample was collected after the last dose, subjects were discharged from the CRU in the morning of Day 7. Telephone follow-up was conducted 30 days ± 2 days after the last dose.

[0348] Part 2 – Rifampin

[0349] The following study design was to be performed only if a DDI between vadadustat and cyclosporine was observed.

[0350] Subjects were randomized in a 1:1 ratio to one of two dosing sequences (A:B or B:A) in a crossover design: vadadustat 300 mg alone and vadadustat 300 mg in combination with rifampin 600 mg (intravenous). The study drug was administered in the morning after an overnight fast of at least 10 hours. Subjects remained in a fasting state for at least 4 hours after dosing. Treatment A: Vadadustat (300 mg) given orally as a single dose of 2 × 150 mg tablets. Treatment B: A single intravenous dose of rifampicin (600 mg) given over 30 minutes, immediately followed (within 5 minutes) by a single oral dose of vadadustat (300 mg as 2 × 150 mg tablets).

[0351] Rifampin 600 mg (intravenous) was administered over 30 minutes as described in the product monograph. Subjects received their first treatment (A or B) in the morning on Day 1. After a 7-day washout period, subjects crossed over to Period 2 and received their second treatment in the dosing sequence (A or B) on Day 8.

[0352] On each dosing day (Days 1 and 8), blood samples for PK analysis were collected up to 48 hours post-dose. After the 48-hour PK blood sample was collected after the last dose, subjects were discharged from the CRU in the morning of Day 10. Telephone follow-up was performed 30 days ± 2 days after the last dose.

[0353] Data analysis The plasma concentration-time profiles of vadadustat administered alone and coadministered with cyclosporine are presented in Figures 3-4.

[0354] The main parameter AUC of vadadustat after treatment with vadadustat alone or vadadustat plus cyclosporine last , AUC inf , and C max The point estimates of the mean T / R ratios for vadadustat-O-glucuronide were 116.97%, 116.89%, and 81.76%, respectively. For vadadustat-O-glucuronide, the primary parameter AUC last , AUC inf , and C max The mean T / R ratios for vadadustat and cyclosporine were 114.04%, 113.74%, and 86.63%, respectively. Overall, these data indicated little or no interaction between vadadustat and cyclosporine (Table 7). [Table 9]

[0355] Plasma concentration-time profiles of vadadustat administered alone and coadministered with probenecid are presented in Figures 5-6.

[0356] Primary parameter AUC of vadadustat after treatment with vadadustat alone or vadadustat plus probenecid last , AUC inf , and C max The point estimates of the mean T / R ratios for vadadustat were 178.95%, 182.13%, and 102.79%, respectively. These data indicate a slightly more than two-fold increase in exposure to vadadustat when administered with multiple doses of probenecid. For vadadustat-oglucuronide, the mean T / R ratios were 224.05%, 226.39%, and 110.38%, respectively (Table 8). These data also indicated an approximately two-fold increase in exposure when administered with multiple doses of probenecid. [Table 10]

[0357] When vadadustat was administered in combination with cyclosporine (an OATP1B1 and BCRP inhibitor), the C max There were no clinically relevant changes in the sigma-positive and AUC values.

[0358] Because the OATP1B1 and BCRP inhibitor cyclosporine did not alter the PK of vadadustat, further evaluation of an OATP1B1 inhibitor (single intravenous dose of rifampicin) was not warranted.

[0359] When vadadustat was administered in combination with probenecid (a UGT and OAT3 inhibitor), the AUC values ​​of both vadadustat and vadadustat O-glucuronide increased approximately 2-fold, whereas Cmax Values ​​remained relatively unchanged. Urinary excretion was decreased for both vadadustat and vadadustat O-glucuronide.

[0360] Because the AUC values ​​for both vadadustat and vadadustat-O-glucuronide increased similarly (i.e., the parent:metabolite ratio did not change), it was concluded that the increase in the AUC of vadadustat was not due to UGT inhibition.

[0361] Generally, vadadustat was well tolerated by subjects undergoing treatment with cyclosporine or probenecid.

[0362] Example 4: Administration of Digoxin or Adefovir with Compound 1 The investigator may prescribe a composition containing a p-glycoprotein transport substrate (e.g., digoxin) and / or a substrate of OAT1 (e.g., adefovir) to a patient taking Compound 1, if desired.

[0363] A phase I, open-label, fixed-sequence study was conducted to evaluate vadadustat as a DDI adjunct with digoxin and / or adefovir in healthy male and female subjects.

[0364] After the screening period, subjects who met all inclusion criteria and did not violate the exclusion criteria described below were randomized into the subsequent clinical period.

[0365] Inclusion Criteria:

[0366] Subjects were required to meet the following inclusion criteria for participation in the clinical trial: 1.Male or female, aged 18-55 years (inclusive) at the time of informed consent. a. Female subjects of childbearing potential must be non-lactating, not pregnant as confirmed by a negative serum pregnancy test at Screening and on Day -1, and must agree to use, and continue to use, effective contraception from at least 4 weeks prior to the first dose of study drug at the Screening Visit until 30 days after the last dose of study drug. b. Female subjects of non-childbearing potential must be surgically infertile (e.g., hysterectomy, bilateral tubal ligation, oophorectomy) or postmenopausal (follicle-stimulating hormone [FSH] >40 U / L at screening and no menses for >1 year). c. Female subjects of childbearing potential must not donate eggs during the study and for at least 30 days after the last dose of investigational product. d. Non-vasectomized male subjects must use effective contraception for at least 4 weeks prior to the first dose of study drug and until 90 days after the last dose of study drug, and agree not to donate sperm during the study and for at least 90 days after the last dose of study drug. See Appendix 16.1.1 for acceptable contraceptive use. 2. Health assessment as determined by the investigator's judgment, documented by medical history, physical examination, vital signs assessment, 12-lead ECG, clinical laboratory assessment, and general observation. At screening, if clinical assessments (lab tests, ECG, vital signs) reveal abnormalities or deviations outside the normal range, they may be repeated once at the discretion of the investigator, and persistent deviations from the normal range must be deemed by the investigator to be not clinically significant and acceptable for study participation. b. On Day -1, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin values ​​must be within the upper limit of the normal range. All other laboratory results that are outside the normal range on Day -1 and are judged by the Investigator to be not clinically significant may be repeated. Results that continue to be outside the normal range must be judged by the Investigator to be not clinically significant and acceptable for study participation. 3. Body mass index is 18.0-30.0 kg / m2, with a minimum weight of 45 kg for women and 50 kg for men (including borderline values). 4. Understand the procedures and requirements of the study and provide written informed consent and authorization for disclosure of protected health information. 5. Willing and able to comply with the requirements of the study protocol.

[0367] Exclusion criteria

[0368] Subjects were not considered to participate in the study if they exhibited any of the following: 1. Current or past clinically significant history of cardiovascular, cerebrovascular, pulmonary, gastrointestinal, hematological, renal, hepatic, immune, metabolic, urinary, neurological, dermatological, psychiatric, or other major disease as determined by the investigator. History of cancer (excluding treated non-melanoma skin cancer) or chemotherapy within 5 years prior to screening. 2. Any surgical or medical condition or history that the investigator determines may potentially alter the absorption, metabolism, or excretion of the investigational drug, including, but not limited to, gastric bypass surgery or gastric or duodenal ulcers. 3. Contraindications and / or history of allergic or anaphylactic reactions to the investigational drug or its excipients. 4. Taking any of the following prohibited medications: a.- Any prescription drug or over-the-counter multivitamin supplement, or any non-prescription product (including herbal-containing preparations, but excluding acetaminophen) within 14 days prior to Day 1. b.- Any drug known to inhibit or induce cytochrome P450 (CYP) enzymes and / or p-glycoprotein, including St. John's Wort (Hypericum perforatum), within 14 days or 5 half-lives (whichever is longer) prior to Day 1. 5. History of substance abuse within 1 year prior to screening. 6. History of regular alcohol consumption >14 drinks / week [1 drink = 5 oz (150 mL) of wine or 12 oz (360 mL) of beer or 1.5 oz (45 mL) of hard liquor] within 6 months prior to screening. 7. Positive drug and alcohol test at screening or day -1. 8. Currently smoking 10 or more cigarettes per day. 9. In the 24 hours prior to Day -1, consumption of grapefruit or grapefruit juice, apple or orange juice, pomelo juice, starfruit, Seville or Moro (blood) orange products, and any food or drink containing mustard family vegetables (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard), foods containing poppy seeds (e.g., muffins, bagels, and cakes), and charcoal-grilled meats known to modulate CYP enzyme activity and transporters within 6 days prior to Day -1. 10. Hepatitis B surface antigen (HBsAg) or hepatitis C virus antibody (HCVab) test result is positive at screening. 11. Positive human immunodeficiency virus antibody (HIVab) test result within 3 months prior to Day -1 or at Screening. 12.- Participation in another clinical trial or exposure to any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to Day 1. 13. Blood donation or significant blood loss within 60 days or plasma donation within 7 days prior to first dose. 14. Have had a tattoo or body piercing (including ear piercing) within 2 months prior to Day 1, and / or have any open wounds that may pose a risk of infection. 15.Has a condition that, in the opinion of the investigator, would interfere with the ability to provide written informed consent or comply with study instructions, or that may confound the interpretation of the results of the study or expose the subject to undue risk.

[0369] Treatment of subjects Group 1 - Digoxin

[0370] In the morning of Day 1, subjects received a single oral dose of digoxin 0.5 mg after an overnight fast of at least 10 hours. Subjects remained fasted for at least 4 hours after dosing. After a 12-day washout period, subjects received digoxin 600 mg once daily for 7 days starting on Day 13 (Days 13-19). When administered alone (Days 13-15 and 17-19), vadadustat was administered in the morning, at least 30 minutes before breakfast. On Day 16, subjects received a morning dose of vadadustat 600 mg along with a single oral dose of digoxin 0.5 mg after a fast of at least 10 hours.

[0371] Group 2 - Adefovir

[0372] On the morning of day 1, subjects received a single oral dose of adefovir 10 mg after an overnight fast of at least 10 hours. Subjects remained fasted for at least 4 hours after dosing. After a 3-day washout period, subjects received digoxin 600 mg once daily for days 4 through 5 (days 4–8). When administered alone, vadadustat was administered in the morning, at least 30 minutes before breakfast. On day 7, subjects received a morning dose of vadadustat 600 mg along with a single oral dose of adefovir 10 mg after an overnight fast of at least 10 hours.

[0373] Data analysis The plasma concentration-time profiles of digoxin administered alone and co-administered with vadadustat are presented in Figures 7a-7b.

[0374] AUC of the main parameters of digoxin after treatment with digoxin alone or vadadustat plus digoxin last , AUC inf , and C max The point estimates of the mean T / R ratios for the 12 patients were 91.49%, 91.37%, and 66.92%, respectively (Table 9). AUClast and AUC inf) did not change when digoxin was administered after multiple doses of vadadustat compared with when digoxin was administered alone. max was reduced by approximately 35% when digoxin and vadadustat were coadministered. [Table 11]

[0375] The plasma concentration-time profiles of adefovir administered alone and co-administered with vadadustat are presented in Figures 8a-8b.

[0376] Adefovir main parameter AUC after treatment with adefovir alone or vadadustat + adefovir last , AUC inf , and C max The point estimates of the mean T / R ratios for vadadustat and adefovir were 114.74%, 114.70%, and 95.15%, respectively. These data indicate that systemic exposure to adefovir was relatively unchanged when adefovir was administered with vadadustat compared to when adefovir was administered alone. Overall, these data demonstrated minimal interactions between vadadustat and adefovir (Table 10). [Table 12]

[0377] When vadadustat was administered in combination with digoxin, a p-glycoprotein transporter substrate, the total exposure to digoxin (AUC last and AUC inf ) did not change. Digoxin C max was decreased by approximately 35% when digoxin was coadministered with vadadustat. According to the FDA's 2017 guidance, a change in exposure of less than two-fold is considered a mild drug-drug interaction. These data suggest that vadadustat may only minimally interact with other substrates of p-glycoprotein.

[0378] When vadadustat was administered in combination with adefovir, an OAT1 substrate, no interactions between vadadustat and adefovir were observed, as systemic exposure to adefovir was relatively unchanged. These data suggest that vadadustat may only minimally interact with other substrates of OAT1.

[0379] Having described several embodiments of the present invention, it is apparent that the basic examples may be modified to provide other embodiments that utilize the compounds, methods, and processes of the present invention. It will therefore be understood that the scope of the present invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example herein.

[0380] From the present description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and can make various changes and modifications to the present invention to adapt it to various usages and conditions without departing from the spirit and scope thereof.

[0381] All U.S. or foreign references, patents, or applications cited in this application are hereby incorporated by reference in their entirety as if set forth herein. In the event of any conflict, the material literally disclosed herein will control.

Claims

1. 1. A pharmaceutical combination for use in a method of reducing or minimizing a drug-drug interaction between a first drug and a second drug, the method comprising administering to a subject: (a) an effective amount of the first drug, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) an effective amount of said second drug comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 2 hours before and / or at least 2 hours after (b).

2. 1. A pharmaceutical combination for use in a method of reducing or minimizing a drug-drug interaction between a first drug and a second drug, the method comprising administering to a subject: (a) an effective amount of the first drug, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) an effective amount of said second drug comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 1 hour before and / or at least 1 hour after (b).

3. 1. A pharmaceutical combination for use in a method for preventing a drug-drug interaction between a first drug and a second drug, the method comprising administering to a subject: (a) an effective amount of the first drug, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) an effective amount of said second drug comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 2 hours before and / or at least 2 hours after (b).

4. 1. A pharmaceutical combination for use in a method for preventing a drug-drug interaction between a first drug and a second drug, the method comprising administering to a subject: (a) an effective amount of the first drug, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) an effective amount of said second drug comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 1 hour before and / or at least 1 hour after (b).

5. 1. A pharmaceutical combination for use in a method for controlling a drug-drug interaction between a first drug and a second drug, the method comprising administering to a subject: (a) an effective amount of the first drug, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) an effective amount of said second drug comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 2 hours before and / or at least 2 hours after (b).

6. 1. A pharmaceutical combination for use in a method for controlling a drug-drug interaction between a first drug and a second drug, the method comprising administering to a subject: (a) an effective amount of the first drug, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) an effective amount of said second drug comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 1 hour before and / or at least 1 hour after (b).

7. 1. A pharmaceutical combination for use in a method for increasing the bioavailability of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 2 hours before and / or at least 2 hours after (b).

8. 1. A pharmaceutical combination for use in a method for increasing the bioavailability of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 1 hour before and / or at least 1 hour after (b).

9. 1. A pharmaceutical combination for use in a method for maintaining bioavailability of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 2 hours before and / or at least 2 hours after (b).

10. 1. A pharmaceutical combination for use in a method for maintaining bioavailability of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 1 hour before and / or at least 1 hour after (b).

11. 1. A combination pharmaceutical for use in a method for minimizing decreased absorption of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 2 hours before and / or at least 2 hours after (b).

12. 1. A combination pharmaceutical for use in a method for minimizing decreased absorption of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 1 hour before and / or at least 1 hour after (b).

13. 1. A combination pharmaceutical for use in a method for preventing decreased absorption of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 2 hours before and / or at least 2 hours after (b).

14. 1. A combination pharmaceutical for use in a method for preventing decreased absorption of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 1 hour before and / or at least 1 hour after (b).

15. A combination pharmaceutical for use in a method for controlling decreased absorption of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 2 hours before and / or at least 2 hours after (b).

16. A combination pharmaceutical for use in a method for controlling decreased absorption of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a drug, the drug being a composition comprising a polymeric amine that binds phosphate; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein (a) is administered at least 1 hour before and / or at least 1 hour after (b).

17. The pharmaceutical combination according to any one of claims 1 to 16, wherein (b) is sevelamer hydrochloride or sevelamer carbonate.

18. The pharmaceutical combination according to any one of claims 1 to 17, wherein (b) is sevelamer hydrochloride.

19. The pharmaceutical combination according to any one of claims 1 to 17, wherein (b) is sevelamer carbonate.

20. The pharmaceutical combination according to any one of claims 1 to 19, wherein (b) is administered as a tablet.

21. The pharmaceutical combination according to any one of claims 1 to 19, wherein (b) is administered as a powder.

22. The pharmaceutical combination according to any one of claims 1 to 6, wherein the first drug is administered at least 1 hour before taking the second drug.

23. The pharmaceutical combination according to any one of claims 1 to 6, wherein the first drug is administered at least 2 hours after taking the second drug.

24. The pharmaceutical combination according to any one of claims 7 to 16, wherein (a) is administered at least 1 hour before (b), and (b) is sevelamer hydrochloride or sevelamer carbonate.

25. The pharmaceutical combination according to any one of claims 7 to 16, wherein (a) is administered at least 2 hours after taking (b), and (b) is sevelamer hydrochloride or sevelamer carbonate.

26. 1. A pharmaceutical combination for use in a method of reducing or minimizing a drug-drug interaction between a first drug and a second drug, the method comprising administering to a subject: (a) an effective amount of the first drug, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of the second drug, the second drug being an OAT1 / OAT3 inhibitor; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

27. 1. A pharmaceutical combination for use in a method for preventing a drug-drug interaction between a first drug and a second drug, the method comprising administering to a subject: (a) an effective amount of the first drug, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of the second drug, the second drug being an OAT1 / OAT3 inhibitor; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

28. 1. A pharmaceutical combination for use in a method for controlling a drug-drug interaction between a first drug and a second drug, the method comprising administering to a subject: (a) an effective amount of the first drug, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of the second drug, the second drug being an OAT1 / OAT3 inhibitor; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

29. 1. A pharmaceutical combination for use in a method for maintaining bioavailability of a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a second drug, the second drug being an OAT1 / OAT3 inhibitor; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

30. 1. A pharmaceutical combination for use in a method of minimizing increased exposure to a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a second drug, the second drug being an OAT1 / OAT3 inhibitor; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

31. 1. A combination pharmaceutical for use in a method for preventing increased exposure to a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a second drug, the second drug being an OAT1 / OAT3 inhibitor; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

32. 1. A combination pharmaceutical for use in a method for controlling increased exposure to a drug, the method comprising administering to a subject: (a) an effective amount of a drug that is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; (b) administering an effective amount of a second drug, the second drug being an OAT1 / OAT3 inhibitor; the subject has renal anemia (anemia secondary to or associated with chronic kidney disease); The pharmaceutical combination, wherein the amount of (a) is adjusted compared to the amount when (b) is administered in the absence or as a monotherapy.

33. The pharmaceutical combination according to any one of claims 26 to 32, wherein the subject is at risk of or has gout or gouty arthritis.

34. The pharmaceutical combination according to any one of claims 26 to 33, wherein (b) is probenecid.

35. 35. The pharmaceutical combination of claim 34, wherein (b) is administered as a tablet.

36. The pharmaceutical combination according to any one of claims 26 to 35, wherein the amount of (a) is reduced compared to the amount administered in the absence of (b) or as a monotherapy.

37. The pharmaceutical combination of claim 36, wherein the amount of (a) is reduced by about 20% to about 80% compared to the amount administered in the absence of (b) or in monotherapy.

38. The pharmaceutical combination of claim 37, wherein the amount of (a) is reduced by about 40% to about 60% compared to the amount administered in the absence of (b) or in monotherapy.

39. 1. A combination pharmaceutical for use in a method for treating renal anemia (anemia secondary to or associated with chronic kidney disease), the method comprising administering to a subject having renal anemia an effective amount of a compound which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutical acceptable salt, solvate, or hydrate thereof; The pharmaceutical combination, wherein the compound is for administration together with a composition comprising a polymeric amine selected from sevelamer hydrochloride and sevelamer carbonate.

40. 40. The pharmaceutical combination of claim 39, wherein the compound is administered at least 1 hour prior to administration of the composition comprising a polymeric amine selected from sevelamer hydrochloride or sevelamer carbonate.

41. 41. The pharmaceutical combination of claim 40, wherein the compound is administered at least 2 hours after administration of the composition comprising a polymeric amine selected from sevelamer hydrochloride or sevelamer carbonate.

42. 1. A combination pharmaceutical for use in a method for treating renal anemia (anemia secondary to or associated with chronic kidney disease), the method comprising administering to a subject having renal anemia an effective amount of a compound which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutical acceptable salt, solvate, or hydrate thereof; The above combination pharmaceutical, wherein the compound is for administration together with an OAT1 / OAT3 inhibitor which is probenecid.

43. 43. The pharmaceutical combination of claim 42, wherein the amount of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, is reduced compared to the amount administered in the absence or as monotherapy of the OAT1 / OAT3 inhibitor that is probenecid.

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