Methods of treatment with tradipitant

Abstract

Disclosed are methods for administering tradipitant and methods for determining an effective amount of tradipitant for use in treating an individual in need thereof, the effective amount of tradipitant being determined based on one or more of whether tradipitant is administered without food and the individual's CYP3A4 metabolism.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority from U.S. Provisional Patent Application No. 63 / 476,502 and U.S. Provisional Patent Application No. 63 / 475,561, both filed December 21, 2022.

[0002] The present invention relates generally to the treatment of NK-1 mediated conditions. More particularly, the present invention relates to methods of treating NK-1 mediated conditions through the administration of the NK-1 antagonist tradipitant. [Background technology]

[0003] Mammalian tachykinins (neurokinins [NK]) are a family of peptide neurotransmitters that share a common C-terminal sequence. This group includes substance P (SP), neurokinin-A (NKA), and neurokinin-B (NKB). SP is the most abundant NK, preferentially binding to neurokinin type-1 (NK-1) receptors and involved in the regulation of many physiological processes. NK-1 receptors have been mapped to the central nervous system and found to have a wide distribution in the brain, including the midbrain, basal ganglia, hypothalamus, and limbic system. Neurokinin receptors are also widely distributed in the gastrointestinal tract, bronchial tree, and vasculature.

[0004] Tradipitant is a potent, selective neurokinin-1 receptor antagonist having the chemical names 2-[1-[[3,5-bis(trifluoromethyl)phenyl]methyl]-5-(4-pyridinyl)-1H-1,2,3-triazol-4-yl]-3-pyridinyl](2-chlorophenyl)-methanone and {2-[1-(3,5-bistrifluoromethylbenzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone, and the following chemical structure as disclosed in U.S. Pat. No. 7,320,994:

[0005] [ka]

[0006] Tradipitant is also known by the names VLY-686 and LY686017, and may be referred to herein as "VLY," for example, in figures and / or tables.

[0007] Tradipitant contains six main structural elements: a 3,5-bis-trifluoromethylphenyl moiety, two pyridine rings, a triazole ring, a chlorophenyl ring, and a methanone. Crystalline forms IV and V of tradipitant are disclosed in U.S. Patent No. 7,381,826; processes for synthesizing tradipitant are disclosed in U.S. Patent Nos. 8,772,496; 9,708,291; and 10,035,787.

[0008] In preclinical and clinical studies, tradipitant has been shown to induce long-lasting blockade of brain NK-1 receptors. Tradipitant is under assessment for efficacy in treating treatment-resistant pruritus associated with atopic dermatitis (see, e.g., WO 2016 / 141341, WO 2019 / 055225, and WO 2021 / 173641), alleviating symptoms of gastroparesis (see, e.g., WO 2019 / 099883 and WO 2020 / 117811), preventing nausea and vomiting associated with motion sickness during travel (see, e.g., WO 2020 / 069092), and treating inflammatory lung injury and improving clinical outcomes associated with severe COVID-19 pneumonia and other lower respiratory tract infections (see, e.g., WO 2021 / 195205 and WO 2023 / 034718). Each of the foregoing patents and published patent applications is incorporated by reference as if fully set forth herein.

[0009] Human metabolism of tradipitant is accomplished in vitro and in vivo through ketone reduction (metabolites M2 and M4), N-glucuronidation (metabolite M8), pyridine N-oxidation (metabolites M3 and M4), and glucuronidation (metabolite M8). Factors affecting the metabolic clearance of tradipitant and its metabolites influence an individual's exposure to the parent compound and any active metabolites.

[0010] Cytochrome P450 3A (CYP3A4) is a key isoenzyme present in the liver and is responsible for the metabolism of many clinically prescribed drugs. Known exonic CYP3A4 variants include: * 2 (rs55785340, 15722T>C; exon 7; resulting in a Ser222Pro modification); CYP3A4 * 7 (6003G>A, rs56324128; exon 3; resulting in a Gly56Asp alteration); CYP3A4 * 8 (13917G>A, rs72552799; exon 5; resulting in an Arg130Gln alteration); CYP3A4 * 9 (14301G>A, rs72552798; exon 6; resulting in a Val170Ile alteration); CYP3A4 * 10 (14313G>C, rs4986908; exon 6; resulting in an Asp174His modification); CYP3A4 * 11 (21876C>T, rs67784355; exon 11; resulting in Thr363Met alteration); CYP3A4 * 12 (21905C>T, rs12721629; exon 11; resulting in the Leu373Phe modification); CYP3A4 * 13 (22035C>T, rs4986909; exon 11; resulting in a Pro416Leu alteration); CYP3A4 * 14 (44T>C, rs12721634; exon 1; resulting in Leu15Pro modification); CYP3A4 *15 (14278G>A, rs4986907; exon 6; resulting in an Arg162Gln alteration); CYP3A4 * 16 (15612C>G, rs12721627; exon 7; resulting in a Thr185Ser alteration); CYP3A4 * 17 (15624T>C, rs4987161; exon 7; resulting in a Phe189Ser modification); CYP3A4 * 18 (20079T>C, rs28371759; exon 10; resulting in the Leu293Pro modification); CYP3A4 * 21 (20148A>G in exon 10, resulting in the substitution of Tyr319 with Cys). * 3 (23181T>C, rs4986910 and M445T); CYP3A4 * 4 (13880A>G, 352A>G, I118V and rs55951658); CYP3A4 * 5 (rs55901263, 15711C>G and P218R); CYP3A4 * 6 (17670_17671insA, 277Frameshift and rs4646438); CYP3A4 * 19 (23246C>T, rs4986913); and CYP3A4 * Other mutations have also been identified, including 20 (a single base 25898_25899insA, a 488 frameshift, insertion of rs67666821 resulting in a premature stop codon leading to a truncated, non-functional protein). * 22 is the wild type (CYP3A4 * 1 / * 1) This is a SNP mutation in intron 6 (rs35599367C>T) that reduces CYP3A4 activity compared to CYP3A4. * The 22 mutation has a low allele frequency (MAF) of 8% in Caucasians and 4% in Asian and African populations. *22 has been linked to reduced tacrolimus and cyclosporine A clearance in renal transplant patients, reduced clearance of immunosuppressants such as everolimus in renal transplant patients, and a reduced rate of sirolimus metabolism in human liver microsomes in vitro. Endoxifen blood concentrations have also been linked to reduced tacrolimus and cyclosporine A clearance in renal transplant patients, reduced clearance of immunosuppressants such as everolimus in renal transplant patients, and a reduced rate of sirolimus metabolism in human liver microsomes in vitro. * 1 / * CYP3A4 compared with 1 carrier (wt) * 22 carriers in breast cancer patients ( * 22 carrier n=16, wt n=116). Summary of the Invention [Problem to be solved by the invention]

[0011] Therefore, a method of treatment with tradipitant that eliminates interindividual, genetic, and other variability in tradipitant clearance is desirable. [Means for solving the problem]

[0012] A first aspect of the present invention provides a method of administering tradipitant to an individual in need thereof, comprising determining the individual's CYP3A4 genotype, administering a first amount of tradipitant to the individual if the individual has a CYP3A4 genotype associated with normal metabolism of tradipitant, and administering a second amount of tradipitant that is less than the first amount if the individual has a CYP3A4 genotype associated with decreased metabolism of tradipitant relative to wildtype.

[0013] In certain embodiments, the CYP3A4 genotype associated with decreased metabolism of tradipitant relative to the wild-type is at least one * 22 alleles, or more specifically, two * Contains 22 alleles.

[0014] In certain embodiments, the second, smaller amount is about 60-90%, 60-85%, 60-80%, 60-75%, or 60-70% of the first amount; about 25-70%, 30-70%, 35-70%, 40-70%, 45-70%, 50-70%, 55-70%, or 60-70% of the first amount; about 35-95%, 40-90%, 50-80%, or 60-70% of the first amount; or about 66-68% of the first amount.

[0015] In certain embodiments, the second amount is about 10-35%, 15-35%, 20-35%, 25-35%, or 30-35% of the first amount; about 30-70%, 30-65%, 30-60%, 30-55%, 30-50%, 30-45%, 30-40%, or 30-35% of the first amount; about 10-55%, 15-50%, 20-45%, 25-40%, or 30-35% of the first amount; or about 32% of the first amount.

[0016] In certain embodiments, the first amount is about 100-400 mg / day, 100-300 mg / day, 100-200 mg / day, 150-400 mg / day, 150-300 mg / day, 150-200 mg / day, about 170 mg / day, or about 85 mg / day.

[0017] A second aspect of the present invention provides a method for determining an effective amount of tradipitant to administer to an individual in need thereof, the method comprising determining the individual's CYP3A4 genotype from a biological sample collected from the individual. If the individual has a CYP3A4 genotype associated with normal tradipitant metabolism, the method comprises determining that the effective amount of tradipitant is a first amount. If the individual has a CYP3A4 genotype associated with reduced tradipitant metabolism relative to wild-type, the method comprises determining that the effective amount of tradipitant is a second amount less than the first amount.

[0018] In certain embodiments, the CYP3A4 genotype associated with decreased metabolism of tradipitant relative to the wild-type is at least one * 22 alleles, or more specifically, two * Contains 22 alleles.

[0019] In certain embodiments, the second, smaller amount is about 60-90%, 60-85%, 60-80%, 60-75%, or 60-70% of the first amount; about 25-70%, 30-70%, 35-70%, 40-70%, 45-70%, 50-70%, 55-70%, or 60-70% of the first amount; about 35-95%, 40-90%, 50-80%, or 60-70% of the first amount; or about 66-68% of the first amount.

[0020] In certain embodiments, the second, smaller amount is about 10-35%, 15-35%, 20-35%, 25-35%, or 30-35% of the first amount; about 30-70%, 30-65%, 30-60%, 30-55%, 30-50%, 30-45%, 30-40%, or 30-35% of the first amount; about 10-55%, 15-50%, 20-45%, 25-40%, or 30-35% of the first amount; or about 32% of the first amount.

[0021] In certain embodiments, the first amount is about 100-400 mg / day, 100-300 mg / day, 100-200 mg / day, 150-400 mg / day, 150-300 mg / day, 150-200 mg / day, about 170 mg / day, or about 85 mg / day.

[0022] A third aspect of the present invention provides a method of administering tradipitant to an individual in need thereof, comprising orally administering to the individual, without food, i.e., in the absence of food, a solid dosage form comprising tradipitant and one or more pharmaceutically acceptable excipients.

[0023] In certain embodiments, the method further comprises instructing the individual to fast for at least thirty (30) minutes, at least one (1) hour, at least two (2) hours, at least four (4) hours, at least eight (8) hours, or at least ten (10) hours prior to said administering. Similarly, the method further comprises having the individual fast for such a period prior to said administering.

[0024] In certain embodiments, the method further comprises instructing the individual to fast for a period of one-half (0.5) hours to about 1.5 hours prior to the administration. Similarly, the method further comprises having the individual fast for such period prior to the administration.

[0025] In certain embodiments, the method further comprises instructing the individual to fast for at least thirty (30) minutes, at least one (1) hour, at least two (2) hours, at least four (4) hours, at least eight (8) hours, or at least ten (10) hours after the administration. Similarly, the method further comprises having the individual fast for such a period after the administration.

[0026] In certain embodiments, the method further comprises instructing the individual to fast for a period of about two (2) hours to about 2.5 hours after the administration. Similarly, the method further comprises having the individual fast for such period after the administration.

[0027] In certain embodiments, tradipitant is given at a dosage of about 100-400 mg / day, 100-300 mg / day, 100-200 mg / day, 150-400 mg / day, 150-300 mg / day, 150-200 mg / day, about 170 mg / day, or about 85 mg / day.

[0028] In certain embodiments, the solid dosage form comprises a capsule or a tablet.

[0029] A fourth aspect of the present invention provides a method for administering tradipitant to an individual in need thereof, comprising determining the individual's CYP3A4 genotype. If the individual has a CYP3A4 genotype associated with normal tradipitant metabolism, the method then comprises orally administering to the individual, without food, a solid dosage form comprising a first amount of tradipitant and one or more pharmaceutically acceptable formulation excipients. On the other hand, if the individual has a CYP3A4 genotype associated with reduced tradipitant metabolism relative to the wild-type, the method then comprises orally administering to the individual, without food, a solid dosage form comprising a second amount of tradipitant, less than the first amount, and one or more pharmaceutically acceptable formulation excipients.

[0030] In certain embodiments, the CYP3A4 genotype associated with decreased metabolism of tradipitant relative to the wild-type is at least one * 22 alleles, or more specifically, two * Contains 22 alleles.

[0031] In certain embodiments, the second, smaller amount is about 60-90%, 60-85%, 60-80%, 60-75%, or 60-70% of the first amount; about 25-70%, 30-70%, 35-70%, 40-70%, 45-70%, 50-70%, 55-70%, or 60-70% of the first amount; about 35-95%, 40-90%, 50-80%, or 60-70% of the first amount; or about 66-68% of the first amount.

[0032] In certain embodiments, the second, smaller amount is about 10-35%, 15-35%, 20-35%, 25-35%, or 30-35% of the first amount; about 30-70%, 30-65%, 30-60%, 30-55%, 30-50%, 30-45%, 30-40%, or 30-35% of the first amount; about 10-55%, 15-50%, 20-45%, 25-40%, or 30-35% of the first amount; or about 32% of the first amount.

[0033] In certain embodiments, the first amount is about 100-400 mg / day, 100-300 mg / day, 100-200 mg / day, 150-400 mg / day, 150-300 mg / day, 150-200 mg / day, about 170 mg / day, or about 85 mg / day.

[0034] In certain embodiments, the solid dosage form comprises a capsule or a tablet.

[0035] In certain embodiments, the method further comprises instructing the individual to fast for at least thirty (30) minutes, at least one (1) hour, at least two (2) hours, at least four (4) hours, at least eight (8) hours, or at least ten (10) hours prior to said administering. Similarly, the method further comprises having the individual fast for such a period prior to said administering.

[0036] In certain embodiments, the method further comprises instructing the individual to fast for a period of one-half (0.5) hours to about 1.5 hours prior to the administration. Similarly, the method further comprises having the individual fast for such period prior to the administration.

[0037] In certain embodiments, the method further comprises instructing the individual to fast for at least thirty (30) minutes, at least one (1) hour, at least two (2) hours, at least four (4) hours, at least eight (8) hours, or at least ten (10) hours after the administration. Similarly, the method further comprises having the individual fast for such a period after the administration.

[0038] In certain embodiments, the method further comprises instructing the individual to fast for a period of about two (2) hours to about 2.5 hours after the administration. Similarly, the method further comprises having the individual fast for such period after the administration.

[0039] A fifth aspect of the present invention provides a method of administering tradipitant to an individual in need thereof, the method comprising: determining an effective amount of tradipitant for administration to the individual, wherein the effective amount is determined based on whether the individual has fasted prior to administration; and administering tradipitant in an immediate-release solid dosage form comprising the effective amount of tradipitant and one or more pharmaceutically acceptable formulation excipients.

[0040] In certain embodiments, the effective amount of tradipitant is a first effective amount when the individual is in a fasted state at the time of administration, and the effective amount is a second effective amount when the individual is in a fed state at the time of administration.

[0041] In certain embodiments, the first effective amount is greater than the second effective amount.

[0042] In certain embodiments, the individual has an acute onset of a tradipitant-responsive disease or disorder.

[0043] In certain embodiments, the individual has a chronic manifestation of a tradipitant-responsive disease or disorder.

[0044] A sixth aspect of the present invention provides a method for determining an effective amount of tradipitant to administer to an individual in need thereof, comprising determining the effective amount based on whether the individual is in a fasted or fed state at the time of administration.

[0045] A seventh aspect provides the use of tradipitant in any of the above methods.

[0046] An eighth aspect provides the use of tradipitant in any of the above methods.

[0047] These and other aspects, advantages and salient features of the present invention will become apparent from the following detailed description, which, when taken in conjunction with the accompany- ing drawings, discloses embodiments of the invention. [Brief explanation of the drawings]

[0048] [Figure 1] Figure 1A shows a graph plotting the ratio of tradipitant metabolite concentrations ((M2 + M3 + M4) / M8) versus CYP3A4 genotype. Figure 1B shows a graph plotting the ratio of (tradipitant concentration / metabolite M3 concentration) versus CYP3A4 genotype. [Figure 2]Figure 2A shows the plasma concentration of tradipitant (in ng / mL) in individuals with a CYP3A4*22 heterozygous genotype (*22 heterozygous) compared to that in individuals with a wild-type genotype (*1 / *1). Figure 2B shows the plasma concentration of tradipitant metabolite M2 (in ng / mL) in individuals with a CYP3A4*22 heterozygous genotype (*22 heterozygous) compared to that in individuals with a wild-type genotype (*1 / *1). Figure 2C shows the plasma concentration of tradipitant metabolite M3 (in ng / mL) in individuals with a CYP3A4*22 heterozygous genotype (*22 heterozygous) compared to that in individuals with a wild-type genotype (*1 / *1). Figure 2D shows the plasma concentration (ng / mL) of tradipitant metabolite M4 in individuals with a CYP3A4*22 heterozygous genotype (*22 heterozygous) compared to that in individuals with a wild-type genotype (*1 / *1). Figure 2E shows the plasma concentration (ng / mL) of tradipitant metabolite M8 in individuals with a CYP3A4*22 heterozygous genotype (*22 heterozygous) compared to that in individuals with a wild-type genotype (*1 / *1). Figure 2F shows the ratio of tradipitant concentration to M8 in plasma in individuals with a CYP3A4*22 heterozygous genotype (*22 heterozygous) compared to that in individuals with a wild-type genotype (*1 / *1). Figure 2G shows the ratio of plasma concentrations of all metabolites relative to M8 in individuals with a CYP3A4*22 heterozygous genotype (*22 heterozygous) to those in individuals with the wild-type genotype (*1 / *1). Figure 2H shows the ratio of plasma concentrations of tradipitant relative to M3 in individuals with a CYP3A4*22 heterozygous genotype (*22 heterozygous) to those in individuals with the wild-type genotype (*1 / *1). [Figure 3] Figure 3 shows a graph relating the apparent clearance of tradipitant to CYP3A4*22 status (missing, wild-type, heterozygous, or homozygous). [Figure 4] FIG. 4 provides a schematic diagram of the design of the study described in Example 2. [Figure 5] FIG. 5 shows a schematic diagram of the study design described in Example 2, comparing Periods 1 and 2. [Figure 6] FIG. 6 shows a schematic diagram of the study design described in Example 2 compared to Periods 3 and 4. [Figure 7] Figures 7A and 7B show the geometric mean plasma concentrations of tradipitant following oral administration of 170 mg of tradipitant to healthy volunteers in fed and fasted states using linear (Figure 7A) and semi-logarithmic (Figure 7B) axes. [Figure 8] Figures 8A and 8B show the geometric mean plasma concentrations of tradipitant following oral administration of 85 mg of tradipitant to healthy volunteers in fed and fasted states using linear (Figure 8A) and semi-logarithmic (Figure 8B) axes. [Figure 9] Figures 9A and 9B show the geometric mean plasma concentrations of metabolite M2 following oral administration of 170 mg of tradipitant to healthy volunteers in fed and fasted states using linear (Figure 9A) and semi-logarithmic (Figure 9B) axes. [Figure 10] Figures 10A and 10B show the geometric mean plasma concentrations of metabolite M2 following oral administration of 85 mg of tradipitant to healthy volunteers in the fed and fasted states using linear (Figure 10A) and semi-logarithmic (Figure 10B) axes. [Figure 11] Figures 11A and 11B show the geometric mean plasma concentrations of metabolite M3 following oral administration of 170 mg of tradipitant to healthy volunteers in the fed and fasted states using linear (Figure 11A) and semi-logarithmic (Figure 11B) axes. [Figure 12] Figures 12A and 12B show the geometric mean plasma concentrations of metabolite M3 following oral administration of 85 mg of tradipitant to healthy volunteers in the fed and fasted states using linear (Figure 12A) and semi-logarithmic (Figure 12B) axes. [Figure 13] Figures 13A and 13B show the geometric mean plasma concentrations of metabolite M4 following oral administration of 170 mg of tradipitant to healthy volunteers in fed and fasted states using linear (Figure 13A) and semi-logarithmic (Figure 13B) axes. [Figure 14] Figures 14A and 14B show the geometric mean plasma concentrations of metabolite M4 following oral administration of 85 mg of tradipitant to healthy volunteers in the fed and fasted states using linear (Figure 14A) and semi-logarithmic (Figure 14B) axes. [Figure 15] Figures 15A and 15B show the geometric mean plasma concentrations of metabolite M8 following oral administration of 170 mg of tradipitant to healthy volunteers in fed and fasted states using linear (Figure 15A) and semi-logarithmic (Figure 15B) axes. [Figure 16] Figures 16A and 16B show the geometric mean plasma concentrations of metabolite M8 following oral administration of 85 mg of tradipitant to healthy volunteers in the fed and fasted states, using linear (Figure 16A) and semi-logarithmic (Figure 16B) axes. DETAILED DESCRIPTION OF THE INVENTION

[0049] The figures are intended to depict only typical aspects of the disclosure, and therefore should not be considered as limiting the scope of the disclosure.

[0050] Various embodiments of the present invention are described herein in relation to the use of tradipitant for the treatment of one or more tradipitant-responsive diseases or disorders. As used herein, the term "tradipitant-responsive diseases or disorders" is understood to refer to diseases and disorders understood in the art to be treatable by tradipitant, such as pruritus, atopic dermatitis, gastroparesis, motion sickness, cravings, lower respiratory tract infections, and the like, including those described in U.S. Patent Nos. 7,320,994; 8,772,496; 7,381,826; 10,463,655; and 10,463,656. ,772,880; 11,324,735; and 10,821,099; and other diseases and disorders described in U.S. Patent Application Publication Nos. 2020 / 0030307; 2021 / 0228555; 2022 / 0096449; WO 2021 / 195025, WO 2021 / 173641, and WO 2023 / 034718. Each of the foregoing patent publications is incorporated herein by reference as if fully set forth herein. The term "tradipitant-responsive disease or disorder" is also understood to refer to any of the conditions described above, where the underlying disease is either diagnosed, undiagnosed, suspected, or simply corresponds to symptoms reported or exhibited by the individual, e.g., an individual for whom a "tradipitant-responsive disease or disorder" cannot or has not been ruled out. An individual experiencing a tradipitant-responsive disease or disorder can be considered to be an individual "in need of treatment" with tradipitant.

[0051] As used herein, the terms "patient," "subject," and "individual" refer to humans, as well as companion animals (e.g., dogs and cats) and other domestic animals (e.g., horses, cows, and sheep). It will be understood that the most preferred patient is a human.

[0052] The present invention further relates to the treatment of tradipitant-responsive diseases or disorders, either prophylactically or therapeutically. The terms "treatment" and "treating" are intended to refer to any process that may slow, interrupt, prevent, control, or halt the progression of the disorders described herein, and are intended to include prophylactic treatment of such disorders. The terms may refer to, but do not necessarily indicate, the complete elimination of all symptoms of the disorder.

[0053] Individuals suffering from tradipitant-responsive diseases or disorders can be treated by oral administration of tradipitant in an effective amount or effective dosage. As used herein, the terms "effective amount" and "effective dose" of tradipitant refer to an amount or dosage, respectively, that is effective to treat a disorder described herein. These terms may refer to an amount combined with a dosing frequency necessary to achieve a plasma concentration of tradipitant of at least about 100 ng / mL, e.g., 125 ng / mL or more, 150 ng / mL or more, 175 ng / mL or more, 200 ng / mL or more, or 225 ng / mL or more. Such plasma concentration levels can be achieved, for example, by administering to the individual, for example, 100-400 mg, 100-300 mg, or 100-200 mg of tradipitant per day in a single dose of 50-200 mg, 50-150 mg, or 50-100 mg twice daily (bid); 150-400 mg, 150-300 mg, or 150-200 mg of tradipitant per day in a single dose of 75-200 mg This can be achieved by oral administration of an immediate-release solid dosage form containing tradipitant at a dose of 75-150 mg, or 75-100 mg twice daily (bid); or 85-170 mg per day, e.g., 85 mg once daily (qd), 85 mg twice daily (bid), or 170 mg once daily (qd), along with one or more pharmaceutically acceptable formulation excipients. With respect to dosing, "qd" refers to once-daily dosing, and "bid" dosing typically refers to dosing once in the morning and once in the evening, generally at least about 8 hours or less than about 16 hours apart, e.g., every 10-14 hours or every 12 hours (Q12H), e.g., at 9:00 and 21:00. The immediate-release solid dosage form may be, for example, a capsule or tablet, and may contain crystalline Form IV or V of tradipitant and one or more pharmaceutically acceptable formulation excipients.

[0054] According to one aspect of the present invention, there is provided a method for treating an individual by administering tradipitant to the individual, as described herein. According to the method, the individual can be selected for treatment with tradipitant based on an initial determination that the individual is suffering from or experiencing symptoms of a tradipitant-responsive disease or disorder. Following this identification of the individual in need of tradipitant treatment, the method comprises orally administering to the individual a solid dosage form comprising tradipitant and one or more pharmaceutically acceptable formulation excipients, as described herein, wherein the tradipitant is administered without food, i.e., when the individual is in a fasting state or condition, and the tradipitant is administered in the absence of food.

[0055] In particular, the method may include instructing the individual to take tradipitant without food. In various embodiments, instructing the individual to take tradipitant without food may include instructing the individual to fast for a specific period of time prior to oral administration of tradipitant. The period of time may be, for example, at least thirty (30) minutes, at least one (1) hour, at least two (2) hours, at least four (4) hours, at least eight (8) hours, at least ten (10) hours, or about one-half (0.5) hours to about 1.5 hours prior to administering tradipitant. Instructing the individual to take tradipitant without food may further include instructing the individual to fast for a specific period of time following administration of tradipitant. The period of time can be, for example, at least one (1) hour, at least two (2) hours, at least four (4) hours, at least eight (8) hours, at least ten (10) hours, or about two (2) to about 2.5 hours after administration of tradipitant. In still further embodiments, the individual can be instructed to take tradipitant without food, e.g., fasting for a first period of time prior to administration of tradipitant and fasting for a second period of time after administration of tradipitant. The first and second periods of time can be the same or different durations, can be independently selected from the above durations, or other durations will be understood by those skilled in the art. Such methods also include actual fasting by the individual as described herein, i.e., compliance with the above instructions.

[0056] Another aspect of the present invention provides a method for administering tradipitant to an individual in need thereof. According to the method, the individual can be selected for treatment with tradipitant based on an initial determination that the individual is suffering from or experiencing symptoms of a tradipitant-responsive disease or disorder. After identifying the individual in need of tradipitant treatment, the method includes determining the individual's CYP3A4 genotype. The determining step can be performed, inter alia, before administering tradipitant. In certain embodiments, the determination can be made by obtaining or having obtained a biological sample from the patient; and determining whether the individual has a CYP3A4 gene variant genotype by performing or having performed a genotyping assay on the biological sample. In this context, "obtaining" can refer to collecting or obtaining a biological sample from a patient, while "having obtained" can refer to entrusting, directing, or otherwise having another individual, e.g., a medical or health care professional, perform the obtaining. "Having obtained" can also refer to having the obtaining previously performed, e.g., an assay to identify the individual's CYP3A4 genotype has previously been performed, the results of which can be reviewed in the individual's medical record. Similarly, in this context, "performing the genotyping assay" can refer to physically performing the step of testing the individual's DNA using a genotyping assay, while "having performed" can refer to having entrusted, directing, or otherwise having another individual, e.g., a medical or health care professional, perform the performing. The expression "performed" can also refer to having the performance of the assay previously performed.Performing the assay may include extracting or having extracted genomic DNA or mRNA from the biological sample, and sequencing the CYP3A4 DNA derived from the extracted genomic DNA or mRNA. The sequencing step may further include amplifying or having amplified the CYP3A4 region in the extracted genomic DNA or mRNA to prepare a DNA sample enriched for DNA from the CYP3A4 gene region; and sequencing the DNA sample by hybridizing the DNA sample to a nucleic acid probe to determine whether the patient has a CYP3A4 variant genotype.

[0057] In certain embodiments, the CYP3A4 mutation detected in the selected individual is an intron 6 single nucleotide polymorphism (SNP) (rs35599367C>T, CYP3A4 * 22) CYP3A4 * Individuals who are carriers of the 22 allele are heterozygous ( * One copy of the 22 allele, as used herein * 22) or homozygous ( * 22 allele) other mutations will also be known and understood by those skilled in the art, as discussed above.

[0058] The method may further include administering tradipitant to the individual at a dosage determined based on the individual's CYP3A4 genotype. If the individual has a CYP3A4 genotype associated with normal tradipitant metabolism, the method includes administering tradipitant to the individual in a first amount. However, if the individual has a CYP3A4 genotype associated with reduced tradipitant metabolism relative to the wild-type, then the method instead includes administering tradipitant in a second amount, wherein the second amount is less than the first amount. Examples of CYP3A4 genotypes associated with reduced tradipitant metabolism relative to the wild-type include at least one * 22 alleles (i.e., * CYP3A4 genotypes including 22 heterozygotes, or two * CYP3A4 genotype containing 22 alleles (i.e., * 22 allele homozygous type).

[0059] In certain embodiments, the second, smaller amount of tradipitant may be about 60-90%, 60-85%, 60-80%, 60-75%, or 60-70% of the first amount; about 25-70%, 30-70%, 35-70%, 40-70%, 45-70%, 50-70%, 55-70%, or 60-70% of the first amount; about 35-95%, 40-90%, 50-80%, or 60-70% of the first amount; or about 66-68% of the first amount. The first amount is considered to be 100% of the amount that would be administered to an individual who has a CYP3A4 genotype associated with normal tradipitant metabolism or who does not have a CYP3A4 genotype associated with reduced tradipitant metabolism relative to the wild-type. Such individuals may have a CYP3A4 genotype associated with normal tradipitant metabolism or a CYP3A4 genotype associated with reduced tradipitant metabolism relative to the wild-type. * 1 / *1) may actually have a CYP3A4 genotype, or may simply have one or more mutations that do not significantly affect the metabolism of tradipitant. If the second, lower amount of tradipitant is about 66-68% of the first amount, this represents a reduction of about 32-34% relative to the normally effective amount. Such a dosage reduction may occur if the CYP3A4 genotype is * It may be suitable for individuals to have at least one or exactly one of the 22 alleles.

[0060] In other embodiments, the first amount may be similarly defined, and the second, smaller amount of tradipitant may be about 10-35%, 15-35%, 20-35%, 25-35%, or 30-35% of the first amount; about 30-70%, 30-65%, 30-60%, 30-55%, 30-50%, 30-45%, 30-40%, or 30-35% of the first amount; about 10-55%, 15-50%, 20-45%, 25-40%, or 30-35% of the first amount; or about 32% of the first amount. Such dosage reductions may be appropriate for individuals whose CYP3A4 genotype includes at least one or exactly two *22 alleles.

[0061] CYP3A4 *Because CYP3A4 status has been shown to significantly affect the metabolic clearance of tradipitant, as described herein in Example 1, identifying the CYP3A4 genotype of an individual requiring treatment with tradipitant can allow for the development of an appropriate dosing regimen to ensure the patient receives the desired level of exposure to the parent compound and its active metabolites of tradipitant. In particular, an individual receiving tradipitant in the first amount, also referred to as a "normal amount" or a "normal effective amount," may receive an effective dosage of, for example, 150-400 mg / day, 100-400 mg / day, 150-300 mg / day, 100-300 mg / day, 150-200 mg / day, 100-200 mg / day, about 170 mg / day, or about 85 mg / day, e.g., 75-200 mg, 50-200 mg, 75-150 mg, 50-150 mg, 75-100 mg, 50-100 mg, or about 85 mg twice daily (bid), or about 85 mg once daily (qd), while an individual receiving tradipitant in the second, smaller amount may receive a proportionally reduced dosage as discussed above. Regardless of whether a given individual has a CYP3A4 genotype associated with normal tradipitant metabolism and is receiving the first amount, or has a CYP3A4 genotype associated with reduced wild-type metabolism of tradipitant and is receiving the second, lower amount, in both cases, the administered dosage may be sufficient to achieve and maintain a plasma tradipitant concentration level in the individual of at least about 100 ng / mL, e.g., 125 ng / mL or more, 150 ng / mL or more, 175 ng / mL or more, 200 ng / mL or more, or 225 ng / mL or more, over the treatment period.

[0062] In another embodiment, an individual in need of tradipitant treatment can be selected for tradipitant treatment based on an initial determination that the individual is suffering from or experiencing symptoms of a tradipitant-responsive disease or disorder. After such identification of the individual in need of tradipitant treatment, the method includes determining whether the individual is being treated with or has consumed a compound that is a CYP3A4 inhibitor. The determining step can, inter alia, be performed prior to administering the tradipitant.

[0063] The method may further include administering tradipitant to the individual at a dosage determined based on whether a CYP3A4 inhibitor is co-administered with the tradipitant. If a CYP3A4 inhibitor is not being co-administered with the individual, the method may include administering tradipitant to the individual in a first amount, as if the individual had a CYP3A4 genotype associated with normal tradipitant metabolism. However, if a CYP3A4 inhibitor is co-administered with tradipitant to the individual, the method may include administering tradipitant to the individual in a second amount, as if the individual had a CYP3A4 genotype associated with reduced wild-type metabolism of tradipitant, where the second amount is less than the first amount. In certain embodiments, the CYP3A4 inhibitor may be selected from amiodarone, aprepitant, cimetidine, ciprofloxacin, clarithromycin, diltiazem, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, posaconazole, voriconazole, and verapamil. In certain embodiments, the CYP3A4 inhibitor may be considered a strong CYP3A4 inhibitor and may be selected from clarithromycin, itraconazole, ketoconazole, and posaconazole, or from ketoconazole and grapefruit juice.

[0064] As described above, in certain embodiments, the second, smaller amount of tradipitant can be about 60-90%, 60-85%, 60-80%, 60-75%, or 60-70% of the first amount; about 25-70%, 30-70%, 35-70%, 40-70%, 45-70%, 50-70%, 55-70%, or 60-70% of the first amount; about 35-95%, 40-90%, 50-80%, or 60-70% of the first amount; or about 66-68% of the first amount. The first amount is considered to be 100% of the amount that would have been administered to an individual receiving co-administration of a CYP3A4 inhibitor and tradipitant. In certain embodiments, co-administration of tradipitant with a CYP3A4 inhibitor is associated with an approximately 26.3% decrease in apparent clearance, an approximately 26% increase in Cmax, and an approximately 36% increase in AUC.

[0065] When the second, smaller amount of tradipitant is about 66-68% of the first amount, this represents a reduction of about 32-34% relative to the typically effective amount. Such a dosage reduction may be suitable for individuals who are co-administered with tradipitant and a CYP3A4 inhibitor. Administering the second, smaller amount to such patients facilitates the use of tradipitant while avoiding exposure to higher levels of tradipitant due to variability in CYP3A4 metabolism.

[0066] In other embodiments, the first amount may be similarly defined, and the second, smaller amount of tradipitant may be about 10-35%, 15-35%, 20-35%, 25-35%, or 30-35% of the first amount; about 30-70%, 30-65%, 30-60%, 30-55%, 30-50%, 30-45%, 30-40%, or 30-35% of the first amount; about 10-55%, 15-50%, 20-45%, 25-40%, or 30-35% of the first amount; or about 32% of the first amount. Such dosage reductions may be appropriate for individuals receiving co-administration of tradipitant and a CYP3A4 inhibitor.

[0067] Coadministration of tradipitant with a CYP3A4 inhibitor, especially a strong CYP3A4 inhibitor, can increase tradipitant exposure. Therefore, identifying individuals who require tradipitant treatment and who are or will be receiving tradipitant concomitantly with a CYP3A4 inhibitor can help tailor an appropriate tradipitant dosing regimen to provide the desired patient exposure to the parent compound and its active metabolites. In particular, an individual receiving tradipitant in the first amount, also referred to as a "conventional amount" or a "conventional effective amount," may receive an effective dosage of, for example, 150-400 mg / day, 100-400 mg / day, 150-300 mg / day, 100-300 mg / day, 150-200 mg / day, 100-200 mg / day, about 170 mg / day, or about 85 mg / day, e.g., 75-200 mg, 50-200 mg, 75-150 mg, 50-150 mg, 75-100 mg, 50-100 mg, or about 85 mg twice daily (bid), or about 85 mg once daily (qd), while an individual receiving tradipitant in the second, smaller amount may receive a proportionally reduced dosage as discussed above. Regardless of whether a given individual is administered tradipitant in the absence of a CYP3A4 inhibitor and receives the first amount, or whether tradipitant and a CYP3A4 inhibitor are co-administered and receives the second, smaller amount, in both cases, the administered dosage may be sufficient to achieve and maintain a plasma tradipitant concentration level of at least about 100 ng / mL in the individual, e.g., 125 ng / mL or more, 150 ng / mL or more, 175 ng / mL or more, 200 ng / mL or more, or 225 ng / mL or more, over the treatment period.

[0068] According to another aspect of the present invention, there is provided a method for determining an effective amount of tradipitant to be administered to an individual in need thereof. In one embodiment, the method includes determining the CYP3A4 genotype of the individual from a biological sample, as described above. If the individual is found to have a CYP3A4 genotype associated with normal tradipitant metabolism, e.g., a wild-type, the method includes administering the effective amount of tradipitant to a first amount. If the individual is found to have a CYP3A4 genotype associated with reduced tradipitant metabolism compared to the wild-type, the method then includes determining the effective amount of tradipitant to a second amount less than the first amount. A CYP3A4 genotype associated with reduced tradipitant metabolism is characterized by at least one, and in some cases, two, CYP3A4 genotypes. * It may contain 22 alleles.

[0069] In another embodiment, the method includes determining whether the individual is being treated with or has consumed a compound known as a CYP3A4 inhibitor, whereby the CYP3A4 inhibitor may be co-administered with tradipitant. If a CYP3A4 inhibitor is co-administered, the method includes determining that an effective amount of tradipitant is a first amount, while if co-administration of tradipitant with a CYP3A4 inhibitor occurs, the method then includes determining that an effective amount of tradipitant is a second amount less than the first amount. In certain embodiments, the CYP3A4 inhibitor may be selected from amiodarone, aprepitant, cimetidine, ciprofloxacin, clarithromycin, diltiazem, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, posaconazole, voriconazole, and verapamil. In certain embodiments, the CYP3A4 inhibitor is considered to be a strong CYP3A4 inhibitor and may be selected from clarithromycin, itraconazole, ketoconazole, and posaconazole, or from ketoconazole and grapefruit juice. In certain embodiments, the first amount of tradipitant may be, for example, 75 to 200 mg, 50 to 200 mg, 75 to 150 mg, 50 to 150 mg, 75 to 100 mg, 50 to 100 mg, or or about 85 mg twice daily (bid), or about 85 mg once daily (qd), e.g., 150-400 mg / day, 100-400 mg / day, 150-300 mg / day, 100-300 mg / day, 150-200 mg / day, 100-200 mg / day, about 170 mg / day, or about 85 mg / day, wherein the second, smaller amount of tradipitant can be a proportional reduction in the dosages discussed herein.For example, in certain embodiments, the second, smaller amount of tradipitant can be about 60-90%, 60-85%, 60-80%, 60-75%, or 60-70% of the first amount; about 25-70%, 30-70%, 35-70%, 40-70%, 45-70%, 50-70%, 55-70%, or 60-70% of the first amount; about 35-95%, 40-90%, 50-80%, or 60-70% of the first amount; or about 66-68% of the first amount. Such dosage reductions are applicable to patients with at least one or exactly one CYP3A4 genotype. * It may be suitable for individuals who contain the 22 allele or who are currently or will be co-administered with tradipitant and a CYP3A4 inhibitor.

[0070] In other embodiments, the second, smaller amount of tradipitant may be about 10-35%, 15-35%, 20-35%, 25-35%, or 30-35% of the first amount; about 30-70%, 30-65%, 30-60%, 30-55%, 30-50%, 30-45%, 30-40%, or 30-35% of the first amount; about 10-55%, 15-50%, 20-45%, 25-40%, or 30-35% of the first amount; or about 32% of the first amount. Such dosage reductions may be observed in patients with at least one or exactly two CYP3A4 genotypes. * It may be suitable for individuals who contain the 22 allele or who are currently or will be co-administered with tradipitant and a CYP3A4 inhibitor.

[0071] Regardless of which dosage is determined to be effective for a particular individual in the methods described herein for determining an effective amount of tradipitant, the dosage administered may be sufficient to achieve and maintain a plasma tradipitant concentration level in the individual to whom the dosage is administered, which may be at least about 100 ng / mL, e.g., 125 ng / mL or greater, 150 ng / mL or greater, 175 ng / mL or greater, 200 ng / mL or greater, or 225 ng / mL or greater, over the treatment period.

[0072] According to another aspect of the present invention, there is provided a method for administering tradipitant to an individual in need thereof. The method includes determining the individual's CYP3A4 genotype as described herein or determining whether the individual is receiving a CYP3A4 inhibitor. If the individual has a CYP3A4 genotype associated with normal tradipitant metabolism and / or is not receiving a CYP3A4 inhibitor, the method includes orally administering to the individual, without food, e.g., in the absence of food, a solid dosage form comprising a first amount of tradipitant and one or more pharmaceutically acceptable formulation excipients. If the individual has a CYP3A4 genotype associated with reduced wild-type metabolism of tradipitant or if the individual is receiving a CYP3A4 inhibitor, the method includes orally administering to the individual, without food, e.g., in the absence of food, a solid dosage form comprising a second amount of tradipitant, less than the first amount, and one or more pharmaceutically acceptable formulation excipients. In certain embodiments, the immediate release solid dosage form may be a capsule or a tablet.

[0073] Examples of CYP3A4 genotypes associated with reduced metabolism of tradipitant compared to the wild-type include those with at least one * CYP3A4 genotype containing 22 alleles (i.e., * 22-allele heterozygote), or * CYP3A4 genotype containing 22 alleles (i.e.,* 22 allele homozygotes). In certain embodiments, the CYP3A4 inhibitor may be selected from amiodarone, aprepitant, cimetidine, ciprofloxacin, clarithromycin, diltiazem, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, posaconazole, voriconazole, and verapamil. In certain embodiments, the CYP3A4 inhibitor is considered a strong CYP3A4 inhibitor and may be selected from clarithromycin, itraconazole, ketoconazole, and posaconazole, or from ketoconazole and grapefruit juice.

[0074] As described in Example 1 herein, CYP3A4 *Because 22 conditions have been shown to significantly affect the metabolic clearance of tradipitant, identifying the CYP3A4 genotype of individuals requiring treatment with tradipitant may allow for appropriate dosing of tradipitant to achieve desired exposure levels to the parent compound and its active metabolites. In particular, an individual receiving tradipitant in the first amount may receive an effective dosage of, for example, 150-400 mg / day, 100-400 mg / day, 150-300 mg / day, 100-300 mg / day, 150-200 mg / day, 100-200 mg / day, about 170 mg / day, or about 85 mg / day, e.g., 75-200 mg, 50-200 mg, 75-150 mg, 50-150 mg, 75-100 mg, 50-100 mg, or about 85 mg twice daily (bid), or about 85 mg once daily (qd), while an individual receiving tradipitant in the second, smaller amount may receive a proportionally reduced dosage as discussed above. In certain embodiments, the second, smaller amount of tradipitant can be about 60-90%, 60-85%, 60-80%, 60-75%, or 60-70% of the first amount; about 25-70%, 30-70%, 35-70%, 40-70%, 45-70%, 50-70%, 55-70%, or 60-70% of the first amount; about 35-95%, 40-90%, 50-80%, or 60-70% of the first amount; or about 66-68% of the first amount. Such dosage reductions are applicable to patients with at least one or exactly one CYP3A4 genotype. *This may be particularly suitable for individuals comprising the 22 allele, as well as for individuals receiving co-administration of tradipitant and a CYP3A4 inhibitor as described herein. In other embodiments, the second, smaller amount of tradipitant may be about 10-35%, 15-35%, 20-35%, 25-35%, or 30-35% of the first amount; about 30-70%, 30-65%, 30-60%, 30-55%, 30-50%, 30-45%, 30-40%, or 30-35% of the first amount; about 10-55%, 15-50%, 20-45%, 25-40%, or 30-35% of the first amount; or about 32% of the first amount. Such dosage reduction may be particularly suitable for individuals whose CYP3A4 genotype includes at least one or exactly two *22 alleles, as well as for individuals who are receiving co-administration of tradipitant and a CYP3A4 inhibitor as described herein.

[0075] According to the methods described herein, whether the individual is found to have a CYP3A4 genotype associated with normal tradipitant metabolism and is administered the first amount of tradipitant, whether the individual is not administered a CYP3A4 inhibitor concurrently with tradipitant and is therefore administered the first amount of tradipitant, or whether the individual is found to have a CYP3A4 genotype associated with reduced (relative to wild-type) tradipitant metabolism or is co-administered with a CYP3A4 inhibitor and is administered the second, smaller amount of tradipitant, the administered dosage may be sufficient to achieve and maintain a plasma tradipitant concentration level in the individual of at least about 100 ng / mL, e.g., 125 ng / mL or more, 150 ng / mL or more, 175 ng / mL or more, 200 ng / mL or more, or 225 ng / mL or more.

[0076] In particular, the method may include instructing the individual to take tradipitant without food, e.g., by fasting, and / or to take tradipitant without food, e.g., by fasting for a specified period of time prior to oral administration of tradipitant. The period of time may be, for example, at least thirty (30) minutes, at least one (1) hour, at least two (2) hours, at least four (4) hours, at least eight (8) hours, at least ten (10) hours, or about one-half (0.5) to one-and-a-half hours prior to administering tradipitant. The method may also or alternatively include instructing the individual to take tradipitant without food, e.g., by fasting, and / or instructing the individual who has taken tradipitant to abstain from food, e.g., by fasting, for a specified period of time following administration of tradipitant. The period of time can be, for example, at least one (1) hour, at least two (2) hours, at least four (4) hours, at least eight (8) hours, at least ten (10) hours, or about two (2) hours to about 2.5 hours after administration of the tradipitant. In still further embodiments, the individual may be instructed to take tradipitant without food, e.g., by fasting, and / or the individual may be instructed to take tradipitant without food, e.g., by fasting for a first period before administration of tradipitant and a second period after administration. The first and second periods of time may be the same or different durations and may be independently selected from the above durations.

[0077] According to another aspect of the present invention, there is provided a method for administering tradipitant to an individual in need thereof. The individual may be experiencing, for example, an acute episode of a tradipitant-responsive disease or disorder or a chronic episode of a tradipitant-responsive disease or disorder. The method includes determining an effective amount of tradipitant for administration to the individual based on whether the individual has fasted prior to administration. Tradipitant may then be administered in an immediate-release solid dosage form comprising the effective amount of tradipitant and one or more pharmaceutically acceptable formulation excipients.

[0078] If the individual is fasting at the time of administration and takes the tradipitant without food, a first effective amount of tradipitant can be administered. If the individual is fed at the time of administration, e.g., the tradipitant is taken with food or immediately after consuming food, a second effective amount of tradipitant less than the first effective amount can be administered as described elsewhere herein. In particular, an individual receiving tradipitant in the first amount may receive an effective dosage of, for example, 150-400 mg / day, 100-400 mg / day, 150-300 mg / day, 100-300 mg / day, 150-200 mg / day, 100-200 mg / day, about 170 mg / day, or about 85 mg / day, e.g., 75-200 mg, 50-200 mg, 75-150 mg, 50-150 mg, 75-100 mg, 50-100 mg, or about 85 mg twice daily (bid), or about 85 mg once daily (qd), while an individual receiving tradipitant in the second, smaller amount may receive a proportionally reduced dosage as discussed above. In certain embodiments, the second, smaller amount of tradipitant can be about 60-90%, 60-85%, 60-80%, 60-75%, or 60-70% of the first amount; about 25-70%, 30-70%, 35-70%, 40-70%, 45-70%, 50-70%, 55-70%, or 60-70% of the first amount; about 35-95%, 40-90%, 50-80%, or 60-70% of the first amount; or about 66-68% of the first amount. Such dosage reductions may be suitable for individuals who take tradipitant with or without food. In other embodiments, the second, smaller amount of tradipitant may be about 10-35%, 15-35%, 20-35%, 25-35%, or 30-35% of the first amount; about 30-70%, 30-65%, 30-60%, 30-55%, 30-50%, 30-45%, 30-40%, or 30-35% of the first amount; about 10-55%, 15-50%, 20-45%, 25-40%, or 30-35% of the first amount; or about 32% of the first amount.Such dosage reductions may be suitable for individuals who take tradipitant with food, as described herein. Also provided are related methods for determining an effective amount of tradipitant to administer to an individual in need thereof, comprising determining the effective amount based on whether the individual takes the tradipitant with or without food (e.g., whether the individual is fasting or fed at the time of administration). Respective amounts for each condition may be determined as described above.

[0079] Those skilled in the art will recognize that further preferred embodiments may be selected by combining the above preferred embodiments or by reference to the examples provided herein. [Example]

[0080] Example 1: Role of CYP3A4 in the metabolism of tradipitant To investigate the role of CYP3A4 genotype in the metabolism of tradipitant, pharmacokinetics are analyzed in terms of CYP3A4 genotype in a human Phase 3 study in which tradipitant is administered. In this study, all CYP3A4 alleles (recognized by the Human Cytochrome P450 Allele Nomenclature Database) are reviewed. The analysis involves the analysis of various ratios of the parent compound (tradipitant) or its metabolites: Ratio A = sum of (M2 + M3 + M4) / M8, and Ratio B = (tradipitant) / (M3) This includes linear models that are tested with

[0081] After adjusting for covariates such as principal components (PCs), age, sex, and body mass index (BMI), CYP3A4 * 22 was selected as the target mutation, and its p-value was 1 × 10 -5 The mutations and their respective ratio distributions are shown in Figure 1A (Ratio A) and Figure 1B (Ratio B). * twenty two / *22+ * 3 / * 1 genotype of CYP3A4 (i.e., * 22 mutation) compared with individuals homozygous for the mutation. * twenty two / * 1 CYP3A4 genotype (i.e., * Heterozygous for the 22 mutation ( * The effects of multiple alleles of interest are cumulative, as indicated by the median ratio present in homozygous (22 heterozygous) individuals. * twenty two / * Tissue samples from 22 mice show a 1.7- to 2.5-fold reduction in mRNA or protein expression compared to wild-type mice, ultimately resulting in a reduction in M3 and a shift in metabolism through other pathways.

[0082] The graphs shown in Figures 2A-2H show the plasma concentrations of tradipitant (Figure 2A), metabolite M2 (Figure 2B), metabolite M3 (Figure 2C), metabolite M4 (Figure 2D), metabolite M8 (Figure 2E), the ratio of tradipitant to M8 (Figure 2F), the ratio of all metabolites to M8 (i.e., (M2 + M3 + M4) / M8) (Figure 2G), and the ratio of tradipitant to M3 (Figure 2H) in individuals in the study population. Figures 2A-2D show that the concentrations of tradipitant, M2, M3, and M4 are * 22 heterozygous group ( * 22 heterozygote) is clearly higher than the wild type. * This reflects the reduced clearance capacity of tradipitant in individuals with the 22 allele. Figure 2F shows that the median ratio of tradipitant to M8 was * 22 heterozygous group ( * 22 heterozygote), the wild type ( * 22 allele).

[0083] Figure 3 shows the apparent clearance of tradipitant as a function of CYP3A4 *22 shows a graph correlating the tradipitant apparent clearance with the status (missing, wild-type, heterozygous, or homozygous), where each circle represents a value from one subject and the line represents the median value. * twenty two( * The plot is for individuals with the wild-type (WT) genotype compared to individuals with the heterozygous 22 genotype. * The ratio of clearance (CL) for the 22 heterozygotes is calculated as exp(median(HET)-median(WT)). Under these calculations, P values ​​are reported for t-tests comparing ETA values. This graph shows the relationship between the clearance (CL) of the 22 heterozygotes and the ETA of the single CYP3A4. * This indicates that the presence of the 22 allele significantly alters the clearance of tradipitant, i.e., approximately 66% of the clearance observed in wild-type individuals. The ETA is then: log(individual value for clearance / standard value for clearance), where "standard value" is essentially the median value. Because the ratio is centered around 1.0 (half are above the median and half are below the median), the log of these values ​​is centered at zero.

[0084] * In this study population, 22 MAF mutations were responsible for * twenty two / * 22 No individuals with homozygous genotypes were identified. * twenty two / * Tradipitant clearance in 22 individuals was * It can be expected that the clearance observed in the 22 heterozygous individuals would be even lower than that observed in the 22 heterozygous individuals. In the above analysis, eleven (11) individuals out of 2,060 samples * 3 Hetero / * Twenty-two individuals have been identified as heterozygous for the genotype. Ten (10) of these individuals have both mutations on the same chromosome, while one (1) has the mutations on different chromosomes. Two (2) also * 3 Hetero / *22 homozygous individuals have been identified.

[0085] These findings are due to mutations in the CYP3A4 gene, particularly CYP3A4 * This supports the conclusion that the 22 allele has functional significance for the metabolism of tradipitant. * The presence of a variant of interest, including 22, can lead to a loss of metabolic activity, which can accumulate with the number of variants of interest present in an individual's genetic sequence. The associated reduction in mRNA or protein expression can result in clinically significant reductions in tradipitant metabolism. For example, heterozygous individuals may experience only 66% of the clearance of tradipitant, a 34% decrease, compared to individuals with the wild-type CYP3A4 genotype given a comparable dose.

[0086] Example 2: A Phase 4, 2-Way, Crossover, Open-Label Study Evaluating the Pharmacokinetics of a Single Dose of Tradipitant in Healthy Participants An open-label, phase 4, two-way crossover study will be conducted to evaluate the effect of food on the pharmacokinetics and bioavailability of single-dose capsules containing 170 mg tradipitant and 85 mg tradipitant. An overview of the study design is provided in Figure 4. The study will include two cohorts, each of which will undergo a screening phase and an evaluation phase. Cohort 1 will only undergo Periods 1 and 2 (Figure 5), and Cohort 2 will only undergo Periods 3 and 4 (Figure 6). Participants in Cohort 1 will be eligible to participate in Cohort 2.

[0087] The screening phase (days -21 to -2, Figures 5-6) consists of a screening visit, where informed consent is obtained from potential participants and their eligibility is initially assessed based on vital signs, body measurements, physical examination, ECG, laboratory tests, drug and alcohol screening, and medical history. Clinical testing includes a pharmacogenetic sample for whole genome sequencing analysis. Participants may include men or women aged 18 to 55 years, including at the time of screening; body mass index (BMI) ≥ 18.0 and ≥ 39.0 kg / m. 2 Below (BMI=weight (kg) / [height (m)] 2); female participants of childbearing potential must be non-pregnant and non-lactating. Participants must be healthy as determined by medical and psychiatric history, physical examination, electrocardiogram, and blood chemistry and hematology; willing to comply with study procedures and restrictions; willing to provide a pharmacogenetic sample; and must test negative for selected substances of tampering in screening. Individuals must have the following: a history of psychiatric disorder (within 12 months prior to screening); current clinically significant cardiovascular, respiratory, nervous system, hepatic, hematopoietic, renal, gastrointestinal, or metabolic dysfunction that is not currently controlled and stable; a history of intolerance and / or hypersensitivity to other NK-1 receptor antagonists; clinically significant deviations from normal in laboratory test results, vital sign measurements, or physical examination findings at screening as determined by the clinical investigator; major surgery, trauma (including pelvic / leg fractures), illness (e.g., sepsis), or immobilization for 3 days or more within the past month; active cancer or cancer treatment within the past 6 months prior to screening; current or previously had a central venous catheter within the past month; liver dysfunction as indicated by AST, ALT, or bilirubin levels greater than twice the upper limit of normal. Participants may be excluded from participation based on the following: isolated elevated bilirubin levels (>2x the upper limit of normal) due to Gilbert syndrome; pregnancy or recent pregnancy (within 6 weeks prior to screening) or breastfeeding; a history of drug or alcohol abuse as defined in DSM-V, Diagnostic Criteria for Drug and Alcohol Abuse, and / or regular consumption of alcoholic beverages (>2 drinks / day or >14 drinks / week) within 12 months prior to screening; randomization in a previous clinical trial of tradipitant; and being a suicide risk in the opinion of the investigator.Further exclusion criteria included participants who were unwilling or unable to comply with medication restrictions or who were unwilling or unable to adequately wash out from restricted medications; any condition requiring regular use of medication; regular consumption of caffeine, including coffee, tea, and / or other caffeine-containing beverages or foods, averaging more than 3 cups (24 oz) per day; inability to tolerate venipuncture and / or venous access; participants who used tobacco products in the 3 months prior to dosing (smokers were defined as any participant who reported using cigarettes, cigars, tobacco, nicotine gum, nicotine patches, or e-cigarettes); participation in the evaluation of any therapeutic drug within 30 days or 5 half-lives (if known), whichever is longer, on Day -1; use of prescription or over-the-counter medications, including herbal products (e.g., St. John's wort), other than for hormone production regulation, within 1 week of the first dose; Consumption of any food or beverage containing alcohol, grapefruit or grapefruit juice, apple or orange juice, vegetables of the mustard family (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard), or charbroiled meats within one week of administration of the first dose until the end-of-study evaluation; abnormal diet (<1600 or >3500 kcal / day), substantial change in diet within one week of administration of the first dose until the end-of-study evaluation, or vegetarianism; history (including family history) or current evidence of congenital long QT syndrome or known acquired prolonged QT interval; and history of liver disease and / or positive one or more of the following serologic results: a) positive hepatitis C antibody test (anti-HCV), b) positive HIV (ELISA and Western) test result, and / or c) positive hepatitis B surface antigen (HBsAg).

[0088] After the screening period, two evaluation phases each consisted of two periods, for a total of four periods. Each period consisted of a baseline visit and a single-dose treatment period with 48 hours of on-site observation and 72 hours of PK sampling. The four periods were separated by at least 11 days of washout. The evaluation phase concluded with an end-of-study visit on Day 4 of Period 2 for Cohort 1 (Figure 5) and Day 4 of Period 4 for Cohort 2 (Figure 6). Baseline assessments were repeated at the beginning of Periods 2 and 4. During the baseline visit, assessments of vital signs, weight, clinical laboratory safety tests, drug, alcohol, and cotinine screening, physical examination, and, in the case of WOCBP, urine and serum pregnancy tests were performed, and any adverse events were recorded.

[0089] Predose blood sampling for tradipitant and its metabolites (M2, M3, M4, and M8) will be collected within 2 hours prior to dosing on Day 1. Participants will receive study medication under open-label conditions. Each participant in Cohort 1 (Figure 5) will receive a 170 mg dose of tradipitant orally (PO) in the form of two 85 mg tradipitant capsules administered in either the fasted or fed condition at Visit 3 and the other condition at Visit 6. Each participant in Cohort 2 will receive one 85 mg tradipitant capsule PO in either the fasted or fed condition at Visit 10 and the other condition at Visit 13. Tradipitant capsules are white, opaque, hard gelatin capsules available in 85 mg strengths. The 85 mg capsule formulation also contains spray-dried lactose monohydrate, microcrystalline cellulose (Avicel PH102 and PH200), povidone, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate as formulation excipients.

[0090] Participants will receive the study medication between 07:00 and 09:00. Participants receiving the medication under fasting conditions (10-hour fast) will receive the study medication with 240 mL of room-temperature tap water and swallow the capsule whole without chewing. Additional water will be withheld from 1 hour before dosing until 1 hour after drug administration. Otherwise, fluid intake will be ad libitum. Participants receiving the study medication under fed conditions will begin consuming a high-calorie, high-fat meal within 30 minutes before and finish the meal before dosing. The meal will be consistent with the US FDA's suggested high-fat breakfast, consisting of two buttered eggs, two strips of bacon, two slices of buttered toast, four ounces of hash browns, and eight ounces of whole milk. (US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER), Assessing the Effects of Food on Drugs in INDs and NDAs - Clinical Pharmacology Considerations Guidance for Industry, available at https: / / www.fda.gov / media / 121313 / download, p. 12, Appendix 1 (June 2022) (accessed November 11, 2022).)

[0091] In both fed and fasted conditions, food will be provided 4 hours after dosing. Subsequent meals and their contents will be at the discretion of the study site and will be consistent across subjects. The following foods and beverages will be prohibited at any meal for the duration of the study: alcohol, grapefruit (juice), apple (juice), orange (juice), mustard family vegetables (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard), and charbroiled meats.

[0092] Pharmacokinetic (PK) blood samples will be collected for periods 1 through 4 at pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, 24, 30, 36, 48, and 72 hours post-dose, plus or minus 5 minutes post-dose. Samples will be analyzed for the test substance, tradipitant, and metabolites M2, M3, M4, and M8. Participants will be released from the facility after 48 hours and return on Day 4 for the 72-hour blood collection.

[0093] End-of-Study (EOS) / Early Discontinuation (ED) evaluations will be conducted after the final PK sample collection on Day 4 of Period 2 for Cohort 1 and Day 4 of Period 4 for Cohort 2, or upon discontinuation if the participant withdraws early from the study. During the EOS / ED evaluations, physical examinations will be performed, vital signs and weight will be assessed, and 12-lead ECGs and laboratory tests will be performed. AEs and associated medications will be recorded for the entire duration of the study.

[0094] result A total of fifteen (15) and sixteen (16) subjects will be enrolled in Cohorts 1 and 2, respectively, and will complete both periods. These 31 individuals comprise the PK analysis population. Five (5) subjects from Cohort 1 also participated in Cohort 2. The following abbreviations are used herein: AUC area under the plasma concentration-time curve; AUC(0-t) Area under the plasma concentration-time curve to the end at concentrations ≥ LOQ AUC(inf) Area under the plasma concentration-time curve (to infinity) CI confidence interval Cmax maximum plasma concentration gMean Geometric mean hr time LSGMR Least Squares Geometric Mean Ratio mg milligram mL milliliter ng nanogram PK Pharmacokinetics t time t 1 / 2 Elimination half-life Tmax Time to maximum plasma concentration WSCV intrasubject coefficient of variation λz Disappearance rate constant

[0095] Trajipitant After a 170 mg dose in the fed state, the geometric mean (gMean) plasma concentrations of tradipitant (Figures 7A-7B) and values ​​of Cmax, AUC(0-t), and AUC(inf) (Table 1) were substantially higher than those after oral administration under fasted conditions. The least squares geometric mean ratios (LSGMR) were 703.87% for Cmax, 328.21% and 381.70% for AUC(0-t) and AUC(inf), respectively (Table 2).

[0096] [Table 1]

[0097] [Table 2]

[0098] The median Tmax increased from 1.50 hours under fasted conditions to 4.00 hours under fed conditions (Table 1).

[0099] Similar significant increases were observed after 85 mg administration in the fed state, as shown in Figures 8A-8B (gMean concentration) and Table 3 (Cmax and AUC), with LSGMRs of 437.59%, 234.21%, and 263.08% (Table 4). Dosing in the fed state increased Tmax by 2-fold (Table 3).

[0100] [Table 3]

[0101] [Table 4]

[0102] At both doses, administration under fed conditions resulted in significant increases in the geometric mean (gMean) Cmax and AUC and a prolongation of the median Tmax, indicating an increased extent and decreased rate of absorption.

[0103] Metabolite M2 Consistent with the effect of fed state on the absorption of parent compound tradipitant, the plasma geometric mean concentrations (gMean) of metabolite M2 after a 170 mg oral dose (Figures 9A-9B) and the Cmax, AUC(0-t), and AUC(inf) values ​​(Table 5) were significantly higher after oral administration under fed compared with fasted conditions. The LSGMRs were 654.35% for Cmax and 352.60% and 350.82% for AUC(0-t) and AUC(inf), respectively (Table 6). The median Tmax remained unchanged for 4 hours when the 170 mg capsules were administered under fed conditions (Table 5).

[0104] Similar significant increases were observed after administration of 85 mg in the fed state, as shown in Figures 10A-10B (gMean concentrations) and Table 7 (Cmax and AUC), with LSGMRs of 407.70%, 240.71%, and 238.83% (Table 8). The median Tmax remained unchanged (4 hours) when the 170 mg capsules were administered in the fed state (Table 7). For both doses, gMean values ​​of Cmax and AUC increased significantly when administered in the fed state, with no change in median Tmax, indicating an increased extent of absorption.

[0105] [Table 5]

[0106] [Table 6]

[0107] [Table 7]

[0108] [Table 8]

[0109] Metabolite M3 Consistent with the effect of the fed state on the absorption of parent tradipitant, the plasma geometric mean concentrations (gMean) of metabolite M3 (Figures 11A-11B) and Cmax, AUC(0-t), and AUC(inf) values ​​(Table 9) after oral administration of 170 mg of tradipitant were significantly higher after oral administration under fed compared to fasted conditions. The LSGMRs were 526.84% for Cmax and 356.01% for AUC(0-t) (Table 10). When the 170 mg capsule was administered under fed conditions, the median Tmax was prolonged to 4 hours compared to 3 hours under fasted conditions (Table 9).

[0110] Similar significant increases were observed after administration of 85 mg of tradipitant in the fed state, as shown in Figures 12A-12B (gMean concentrations) and Table 11 (Cmax and AUC), with LSGMRs of 370.57%, 255.71%, and 263.76% (Table 12). For both doses, gMean values ​​of Cmax and AUC were significantly increased and median Tmax was prolonged when administered in the fed state, indicating an increased extent and decreased rate of absorption.

[0111] [Table 9]

[0112] [Table 10]

[0113] [Table 11]

[0114] [Table 12]

[0115] Metabolite M4 Consistent with the effect of the fed state on the absorption of parent tradipitant, the plasma geometric mean concentrations (gMean) of metabolite M4 (Figures 13A-13B) and Cmax, AUC(0-t), and AUC(inf) values ​​(Table 13) after oral administration of 170 mg of tradipitant were significantly higher after oral administration under fed compared to fasted conditions. The LSGMRs were 547.40% for Cmax, 357.77% for AUC(0-t), and 320.49% for AUC(inf) (Table 14). When the 170 mg capsule was administered under fed conditions, the median Tmax was prolonged to 6 hours compared to 4 hours under fasted conditions (Table 13).

[0116] Similar significant increases were observed after administration of 85 mg of tradipitant in the fed state, as shown in Figures 14A-14B (gMean concentrations) and Table 15 (Cmax and AUC), with LSGMRs of 339.57%, 243.58%, and 239.45% (Table 16). When the 85 mg capsule was administered in the fed state, the median Tmax was prolonged to 6 hours compared to the fasted state (4.09 hours) (Table 15). For both doses, administration in the fed state significantly increased the gMean values ​​of Cmax and AUC, and prolonged the median Tmax, indicating an increased extent and decreased rate of absorption.

[0117] [Table 13]

[0118] [Table 14]

[0119] [Table 15]

[0120] [Table 16]

[0121] Metabolite M8 Consistent with the effect of the fed state on the absorption of parent tradipitant, the plasma geometric mean concentrations (gMean) of metabolite M8 (Figures 15A-15B) and Cmax, AUC(0-t), and AUC(inf) values ​​(Table 17) after oral administration of 170 mg of tradipitant were significantly higher after oral administration under fed compared to fasted conditions. The LSGMRs were 559.09% for Cmax, 365.76% for AUC(0-t), and 352.97% for AUC(inf) (Table 18). When the 170 mg capsule was administered under fed conditions, the median Tmax was shortened to 8 hours compared to the fasted state (30 hours) (Table 17).

[0122] Similar significant increases were observed after administration of 85 mg in the fed state, as shown in Figures 16A-16B (gMean concentrations) and Table 19 (Cmax and AUC), with LSGMRs of 428.64%, 293.76%, and 273.24% (Table 20). When the 85 mg capsule was administered in the fed state, the median Tmax was shortened to 8 hours compared to the fasted state (15 hours) (Table 19).

[0123] At both doses, administration in the fed state significantly increased the gMean values ​​of Cmax and AUC, and shortened the median Tmax, indicating an increased extent and rate of absorption.

[0124] [Table 17]

[0125] [Table 18]

[0126] [Table 19]

[0127] [Table 20]

[0128] conclusion The geometric mean values ​​of Cmax and AUC(inf) following administration of both 85 mg and 170 mg tradipitant under fed conditions are compared in Table 21. Although the two doses were administered to different subject groups, the ratios of the geometric means were approximately 2.0 for all comparisons, demonstrating dose proportionality for the two capsules under fed conditions.

[0129] [Table 21]

[0130] The geometric mean values ​​of Cmax and AUC(inf) after administration of 85 mg and 170 mg of tradipitant under fed conditions are compared in Table 22. Although the two doses were administered to different subject groups, the ratios of the geometric mean Cmax values ​​for tradipitant and the four metabolites were less than proportional, ranging from 1.23 to 1.64. Regarding AUC(inf), only tradipitant exhibited a nearly proportional relationship (ratio of 1.92), while those for metabolites M2, M3, M4, and M8 ranged from 1.08 to 1.78. This suggests that, under fasted conditions, the parent compound tradipitant may exhibit dose-proportionality in exposure (AUC), while the four metabolites exhibited less than proportional relationships.

[0131] [Table 22]

[0132] At both the 170 mg and 85 mg doses, administration under fed conditions was associated with significantly increased gMean values ​​of Cmax, AUC(0-t), and AUC(inf) of tradipitant and prolonged median Tmax, indicating an increased extent and decreased rate of absorption. Results for metabolites M2, M3, M4, and M8 were consistent with those of the parent compound with respect to Cmax, AUC, and Tmax, except for M8, which exhibited a shortened median Tmax under fed conditions.

[0133] Based on comparisons of the two dose groups under fed conditions, the geometric mean ratios of Cmax and AUC(inf) were approximately 2.0 for all comparisons, indicating dose proportionality for the two capsules. On the other hand, based on comparisons of the two dose groups under fasted conditions, the geometric mean ratios of Cmax for tradipitant and the four metabolites suggested less than dose proportionality. For AUC(inf), tradipitant was close to dose proportional, but no proportionality was observed for the four metabolites.

[0134] As used herein, the terms "first," "second," etc. do not denote any order, quantity, or importance, but rather are used to distinguish one element from another, and the terms "a" and "an" as used herein do not denote a limitation of quantity, but rather the presence of at least one of the referenced term. The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measuring the specific quantity). The suffix "(s)" as used herein is intended to include both the singular and plural forms of the term it modifies, thereby including one or more of the term (e.g., metal(s) includes one or more metals). Ranges disclosed herein are inclusive and independently combinable (e.g., "a range of up to about 25 mm, or, more specifically, about 5 mm to about 20 mm" includes the endpoints and all intermediate values ​​of the range "about 5 mm to about 25 mm," etc.).

[0135] While various embodiments have been described herein, it will be recognized from the specification that various combinations of the elements, variations, or modifications herein may be made by one skilled in the art and are within the scope of the invention. Many modifications may also be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the specific embodiments disclosed, but that the invention may include all embodiments falling within the scope of the appended claims.

Claims

1. 1. A method of administering tradipitant to an individual in need thereof, comprising: determining the individual's CYP3A4 genotype; and administering tradipitant to the individual in a first amount if the individual has a CYP3A4 genotype associated with normal tradipitant metabolism; administering tradipitant in a second amount less than the first amount if the individual has a CYP3A4 genotype associated with reduced metabolism of tradipitant relative to a wild-type genotype; The method comprising:

2. The CYP3A4 genotype associated with reduced metabolism of tradipitant compared to the wild type is at least one ＊ The method of claim 1, comprising 22 alleles.

3. The CYP3A4 genotype associated with reduced metabolism of tradipitant compared to the wild type is ＊ The method of claim 1, comprising 22 alleles.

4. 3. The method of claim 1 or claim 2, wherein the second, smaller amount is about 35% to 95% of the first amount.

5. 4. The method of claim 1 or claim 3, wherein the second, smaller amount is about 10% to 55% of the first amount.

6. 10. The method of claim 1, wherein the first amount is between about 100 mg and 400 mg.

7. 10. The method of claim 1, wherein the first amount is about 85 mg.

8. 1. A method for determining an effective amount of tradipitant to administer to an individual in need thereof, comprising: determining the individual's CYP3A4 genotype from the biological sample; and determining that the effective amount of tradipitant is a first amount if the individual has a CYP3A4 genotype associated with normal tradipitant metabolism; determining that the effective amount of tradipitant is a second amount that is less than the first amount if the individual has a CYP3A4 genotype associated with reduced metabolism of tradipitant relative to a wild-type genotype; The method comprising:

9. The CYP3A4 genotype associated with reduced metabolism of tradipitant compared to the wild type is at least one ＊ The method of claim 8, comprising 22 alleles.

10. The CYP3A4 genotype associated with reduced metabolism of tradipitant compared to the wild type is ＊ The method of claim 8, comprising 22 alleles.

11. 10. The method of claim 8 or claim 9, wherein the second, smaller amount is about 35% to 95% of the first amount.

12. 11. The method of claim 8 or claim 10, wherein the second, smaller amount is about 10% to 55% of the first amount.

13. 9. The method of claim 8, wherein the first amount is between about 100 mg and 400 mg.

14. 9. The method of claim 8, wherein the first amount is about 85 mg.

15. 1. A method of administering tradipitant to an individual in need thereof, comprising: orally administering to the individual, without food, a solid dosage form comprising tradipitant and one or more pharmaceutically acceptable excipients. The method comprising:

16. 16. The method of claim 15, further comprising instructing the individual to fast for at least 30 minutes prior to said administering.

17. 16. The method of claim 15, further comprising instructing the individual to fast for at least one hour prior to said administering.

18. 16. The method of claim 15, further comprising instructing the individual to fast for at least two hours prior to said administering.

19. 16. The method of claim 15, further comprising instructing the individual to fast for at least four hours prior to said administering.

20. 16. The method of claim 15, further comprising instructing the individual to fast for at least 8 hours prior to said administering.

21. 16. The method of claim 15, further comprising instructing the individual to fast for at least 10 hours prior to said administering.

22. 16. The method of claim 15, further comprising instructing the individual to fast for a period of 0.5 to 1.5 hours prior to said administration.

23. 16. The method of claim 15, further comprising instructing the individual to fast for at least 30 minutes after the administration.

24. 16. The method of claim 15, further comprising instructing the individual to fast for at least one hour after the administration.

25. 16. The method of claim 15, further comprising instructing the individual to fast for at least two hours after the administration.

26. 16. The method of claim 15, further comprising instructing the individual to fast for at least four hours after the administration.

27. 16. The method of claim 15, further comprising instructing the individual to fast for a period of 2 to 2.5 hours after the administration.

28. 16. The method of claim 15, wherein the solid dosage form comprises tradipitant in an amount of 100 mg to 400 mg.

29. 16. The method of claim 15, wherein the solid dosage form comprises tradipitant in an amount of 150 mg to 400 mg.

30. 16. The method of claim 15, wherein the solid dosage form comprises tradipitant in an amount of 170 mg.

31. 16. The method of claim 15, wherein the solid dosage form comprises tradipitant in an amount of 85 mg.

32. 16. The method of claim 15, wherein the solid dosage form comprises a capsule or a tablet.

33. 1. A method of administering tradipitant to an individual in need thereof, comprising: determining the individual's CYP3A4 genotype; and if the individual has a CYP3A4 genotype associated with normal tradipitant metabolism, orally administering to the individual, without food, a solid dosage form comprising a first amount of tradipitant and one or more pharmaceutically acceptable formulation excipients; and if the individual has a CYP3A4 genotype associated with reduced metabolism of tradipitant relative to a wild-type, orally administering to the individual, without food, a solid dosage form comprising a second amount of tradipitant that is less than the first amount and one or more pharmaceutically acceptable formulation excipients. The method comprising:

34. The CYP3A4 genotype associated with reduced metabolism of tradipitant compared to the wild type is at least one ＊ 34. The method of claim 33, comprising 22 alleles.

35. The CYP3A4 genotype associated with reduced metabolism of tradipitant compared to the wild type is ＊ 34. The method of claim 33, comprising 22 alleles.

36. 35. The method of claim 33 or claim 34, wherein the second, smaller amount is about 35% to 95% of the first amount.

37. 36. The method of claim 33 or claim 35, wherein the second, smaller amount is about 10% to 55% of the first amount.

38. 34. The method of claim 33, wherein the first amount is between about 100 mg and 400 mg.

39. 34. The method of claim 33, wherein the first amount is about 85 mg.

40. 34. The method of claim 33, further comprising instructing the individual to fast for at least 30 minutes prior to said administering.

41. 34. The method of claim 33, further comprising instructing the individual to fast for at least one hour prior to said administering.

42. 34. The method of claim 33, further comprising instructing the individual to fast for at least two hours prior to said administering.

43. 34. The method of claim 33, further comprising instructing the individual to fast for at least four hours prior to said administering.

44. 34. The method of claim 33, further comprising instructing the individual to fast for at least 8 hours prior to said administering.

45. 34. The method of claim 33, further comprising instructing the individual to fast for at least 10 hours prior to said administering.

46. 34. The method of claim 33, further comprising instructing the individual to fast for a period of 0.5 to 1.5 hours prior to said administration.

47. 34. The method of claim 33, further comprising instructing the individual to fast for at least 30 minutes after the administration.

48. 34. The method of claim 33, further comprising instructing the individual to fast for at least one hour after the administration.

49. 34. The method of claim 33, further comprising instructing the individual to fast for at least two hours after the administration.

50. 34. The method of claim 33, further comprising instructing the individual to fast for at least four hours after the administration.

51. 34. The method of claim 33, further comprising instructing the individual to fast for a period of 2 to 2.5 hours after said administration.

52. 34. The method of claim 33, wherein the solid dosage form comprises a capsule or a tablet.

53. 1. A method of administering tradipitant to an individual in need thereof, comprising: determining an effective amount of tradipitant for administration to the individual, wherein the effective amount is determined based on whether the individual is fasting prior to administration; and administering tradipitant in an immediate-release solid dosage form comprising the effective amount of tradipitant and one or more pharmaceutically acceptable excipients. The method comprising:

54. 54. The method of claim 53, wherein the effective amount of tradipitant is a first effective amount when the individual is in a fasted state at the time of administration, and wherein the effective amount is a second effective amount when the individual is in a fed state at the time of administration.

55. 55. The method of claim 54, wherein the first effective amount is greater than the second effective amount.

56. 54. The method of claim 53, wherein the individual is experiencing an acute episode of a tradipitant-responsive disease or disorder.

57. 54. The method of claim 53, wherein the individual has a chronic manifestation of a tradipitant-responsive disease or disorder.

58. 1. A method for determining an effective amount of tradipitant for administration to an individual in need thereof, comprising: determining said effective amount based on whether said individual is in a fasted or fed state at the time of said administration.

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