Methods of treatment using tradipitant

Abstract

Disclosed herein are methods of administering tradipitant, and methods of determining an effective amount of tradipitant for treating a subject in need thereof. And determining the effective dose of the tradipitant of the individual according to one or more factors of whether the tradipitant is administered in an empty stomach state and the CYP3A4 metabolic condition of the individual.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims priority to U.S. Provisional Patent Application Nos. 63 / 476,502 and 63 / 476,561, both filed on December 21, 2022. Background Art

[0003] The present invention relates generally to the treatment of NK-1 mediated diseases. More specifically, the present invention relates to methods of treating NK-1 mediated diseases by administering the NK-1 antagonist tradipitant.

[0004] Mammalian tachykinins (neurokinins [NK]) are a family of peptide neurotransmitters with a common C-terminal sequence. This class includes substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). SP is the most abundant substance in NK and preferentially binds to the neurokinin type 1 (NK-1) receptor, participating in the regulation of many physiological processes. NK-1 receptors have been mapped to the central nervous system and are found widely distributed in the brain, including the midbrain, basal ganglia, hypothalamus, and limbic system. Neurokinin receptors are also widely distributed in the intestine, bronchial tree, and vascular system.

[0005] Tridipitant is a potent and selective neurokinin-1 receptor antagonist. Its chemical names are 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-bis(trifluoromethyl)benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chlorophenyl)-methanone. Its chemical structure is disclosed in U.S. Patent 7,320,994 as follows:

[0006]

[0007] Tradipitant is also known as VLY-686 and LY686017 and is sometimes referred to herein as simply "VLY," for example, in the figures and / or tables.

[0008] Tridipitant contains six main structural components: a 3,5-bis-trifluoromethylphenyl moiety, two pyridine rings, a triazole ring, a chlorophenyl ring, and a ketone. U.S. Patent 7,381,826 discloses Forms IV and V of Tridipitant; U.S. Patents 8,772,496, 9,708,291, and 10,035,787 disclose methods for synthesizing Tridipitant.

[0009] In preclinical and clinical studies, trodipitant has a persistent blocking effect on brain NK-1 receptors. Trodipitant is currently being evaluated for its efficacy in treating refractory pruritus associated with atopic dermatitis (see, for example, WO 2016 / 141341, WO 2019 / 055225, and WO 2021 / 173641), relieving gastroparesis symptoms (see, for example, WO 2019 / 099883 and WO 2020 / 117811), preventing nausea and vomiting associated with motion sickness during travel (see, for example, WO 2020 / 069092), and treating inflammatory lung damage and improving clinical outcomes associated with severe novel coronavirus (SARS-CoV-2) infection and other lower respiratory tract infections (see, for example, WO 2021 / 195205 and WO 2023 / 034718). Each of the above patents and published patent applications is incorporated herein by reference as if fully set forth herein.

[0010] Tradipitant is metabolized in humans and in vitro via ketone body reduction (metabolites M2 and M4), N-glucuronidation (metabolite M8), pyridine N-oxidation (metabolites M3 and M4), and glucuronidation (metabolite M8). Factors that affect the metabolic clearance of tradipitant and its metabolites will affect an individual's exposure to the parent compound and any active metabolites.

[0011] Cytochrome P450 3A (CYP3A4) is the major isoenzyme in the liver and is responsible for the metabolism of many clinically prescribed drugs. Known exonic CYP3A4 variants include but are not limited to CYP3A4*2 (rs55785340, 15722T>C; exon 7; resulting in a Ser222Pro change); CYP3A4*7 (6003G>A, rs56324128; exon 3; resulting in a Gly56Asp change); CYP3A4*8 (13917G>A, rs72552799; exon 5; resulting in an Arg130Gln change); CYP3A4*9 (1 4301G>A,rs72552798; exon 6; resulting in a change in Val170Ile); CYP3A4*10 (14313G>C,rs4986908; exon 6; resulting in a change in Asp174His); CYP3A4*11 (21876C>T,rs67784355; exon 11; resulting in a change in Thr363Met); CYP3A4*12 (21905C>T,rs12721629; exon 11; resulting in a change in Thr363Met); CYP3A4*13 (22035C>T,rs4986909; exon 11; resulting in Pro416Leu); CYP3A4*14 (44T>C,rs12721634; exon 1; resulting in Leu15Pro); CYP3A4*15 (14278G>A,rs4986907; exon 6; resulting in Arg162Gln); CYP3A4*16 (15612C >G, rs12721627; exon 7; resulting in a Thr185Ser change); CYP3A4*17 (15624T>C, rs4987161; exon 7; resulting in a Phe189Ser change); CYP3A4*18 (20079T>C, rs28371759; exon 10; resulting in a Leu293Pro change); CYP3A4*21 (20148A>G, in exon 10, resulting in a Tyr319 to Cys substitution).Other variants were also found, including the missense variants CYP3A4*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, 277 frameshift and rs4646438); CYP3A4*19 (23246C>T, rs4986913); and CYP3A4*20 (insertion of a single base 25898_25899insA, 488 frameshift, rs67666821 resulting in a premature stop codon, thereby forming a nonfunctional truncated protein). Furthermore, CYP3A4*22, a SNP variant in intron 6 (rs35599367C>T), is associated with reduced CYP3A4 activity compared to the wild-type variant (CYP3A4*1 / *1). The minor allele frequency (MAF) of the *22 variant is 8% in Caucasians and 4% in Asian and African populations. Numerous clinical studies have shown that CYP3A4*22 is associated with reduced clearance of tacrolimus and cyclosporine A in renal transplant recipients, reduced clearance of immunosuppressants such as everolimus in renal transplant recipients, and reduced rapamycin metabolism in human liver microsomes in vitro. Breast cancer patients with CYP3A4*22 also have elevated plasma concentrations of endoxifen compared to *1 / *1 carriers (n = 16 *22 carriers, n = 116 wild-type).

[0012] Therefore, an ideal therapeutic approach would take into account inter-individual variability in trodipitant clearance, including genetic and other factors. Summary of the Invention

[0013] A first aspect of the present invention provides a method of administering tridipitant to an individual in need thereof, comprising: determining the individual's CYP3A4 genotype; and if the individual has a CYP3A4 genotype associated with normal tridipitant metabolism, administering tridipitant to the individual in a first amount. However, if the individual has a CYP3A4 genotype associated with decreased tridipitant metabolism compared to wild-type, the method comprises administering a second amount of tridipitant, wherein the second amount is less than the first amount.

[0014] In certain embodiments, the CYP3A4 genotype associated with reduced metabolism of tridipitant compared to wild type includes at least one *22 allele, or more specifically, two *22 alleles.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] A second aspect of the present invention provides a method for determining an effective dose of tridipitant for administration to an individual in need thereof, 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 tridipitant metabolism, the method comprises determining the effective dose of tridipitant to be a first amount. If the individual has a CYP3A4 genotype associated with decreased tridipitant metabolism compared to wild-type individuals, the method comprises determining the effective amount of tridipitant to be a second amount less than the first amount.

[0019] In certain embodiments, the CYP3A4 genotype associated with reduced metabolism of tridipitant compared to wild type includes at least one *22 allele, or more specifically, two *22 alleles.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] A third aspect of the present invention provides a method of administering tridipitant to an individual in need thereof, comprising orally administering to the individual a solid dosage form comprising tridipitant and one or more pharmaceutically acceptable excipients in a fasting state (ie, without food).

[0024] 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 administration. Likewise, the method further comprises instructing the individual to fast for this period of time prior to administration.

[0025] In certain embodiments, the method further comprises instructing the individual to fast for at least half an hour (0.5) to about 1.5 hours prior to administration. Likewise, the method further comprises instructing the individual to fast for this period of time prior to administration.

[0026] 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 administration. Likewise, the method further comprises instructing the individual to fast for this period of time after administration.

[0027] In certain embodiments, the method further comprises instructing the individual to fast for about two (2) hours to about 2.5 hours after administration. Likewise, the method further comprises instructing the individual to fast for this period of time after administration.

[0028] In certain embodiments, tradipitant is administered at a dose 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.

[0029] In certain embodiments, the solid dosage form comprises a capsule or a tablet.

[0030] A fourth aspect of the present invention provides a method for administering tridipitant to an individual in need thereof, comprising: determining the individual's CYP3A4 genotype. If the individual has a CYP3A4 genotype associated with normal tridipitant metabolism, the method further comprises orally administering to the individual, in a fasted state (i.e., without food), a solid dosage form comprising a first amount of tridipitant and one or more pharmaceutically acceptable excipients. However, if the individual has a CYP3A4 genotype associated with reduced tridipitant metabolism compared to wild-type, the method further comprises orally administering to the individual, in a fasted state (i.e., without food), a solid dosage form comprising a second amount of tridipitant and one or more pharmaceutically acceptable excipients, wherein the second amount is less than the first amount.

[0031] In certain embodiments, the CYP3A4 genotype associated with reduced metabolism of tridipitant compared to wild type includes at least one *22 allele, or more specifically, two *22 alleles.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] In certain embodiments, the solid dosage form comprises a capsule or a tablet.

[0036] 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 administration. Likewise, the method further comprises instructing the individual to fast for this period of time prior to administration.

[0037] In certain embodiments, the method further comprises instructing the individual to fast for at least half an hour (0.5) to about 1.5 hours prior to administration. Likewise, the method further comprises instructing the individual to fast for this period of time prior to administration.

[0038] 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 administration. Likewise, the method further comprises instructing the individual to fast for this period of time after administration.

[0039] In certain embodiments, the method further comprises instructing the individual to fast for about two (2) hours to about 2.5 hours after administration. Likewise, the method further comprises instructing the individual to fast for this period of time after administration.

[0040] A fifth aspect of the present invention provides a method for administering tridipitant to an individual in need thereof, comprising: determining an effective amount of tridipitant for administration to the individual, wherein the effective amount depends on whether the individual is fasting before administration; and administering the drug in a solid immediate-release dosage form comprising the effective amount of tridipitant and one or more pharmaceutically acceptable excipients.

[0041] In certain embodiments, if the individual is in a fasting state at the time of administration, the effective amount of tripitant is a first effective amount, and if the individual is in a fed state at the time of administration, the effective amount of tripitant is a second effective amount.

[0042] In certain embodiments, the first effective amount is greater than the second effective amount.

[0043] In certain embodiments, the individual is experiencing an acute manifestation of a drug-responsive disease or disorder.

[0044] In certain embodiments, the individual is experiencing a chronic manifestation of a disease or condition responsive to tripitant.

[0045] A sixth aspect of the present invention provides a method for determining an effective dose of tripitant for administration to an individual in need thereof, comprising: determining the effective amount based on whether the individual is in a fasting state or a fed state at the time of administration.

[0046] A seventh aspect provides trodipitant for use in any of the above methods.

[0047] An eighth aspect provides a use of trodipitant according to any of the above methods.

[0048] These and other aspects, advantages, and salient features of the invention will become apparent from the following detailed description, which, when taken in conjunction with the annexed drawings, discloses embodiments of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1A A graph showing the ratio of the concentrations of the tredipitant metabolites ((M2+M3+M4) / M8) versus the CYP3A4 genotype is shown.

[0050] Figure 1B A graph showing the ratio of (tradipitant concentration / metabolite M3 concentration) versus CYP3A4 genotype is shown.

[0051] Figure 2A Shown are the concentrations of tridipitant (in ng / mL) in plasma of individuals with the CYP3A4*22 heterozygous genotype (*22het) and the wild-type genotype (*1 / *1).

[0052] Figure 2B Shown are the concentrations (in ng / mL) of the tridipitant metabolite M2 in plasma of individuals with the CYP3A4*22 heterozygous genotype (*22het) and the wild-type genotype (*1 / *1).

[0053] Figure 2C Shown are the concentrations (in ng / mL) of the tridipitant metabolite M3 in plasma of individuals with the CYP3A4*22 heterozygous genotype (*22het) and the wild-type genotype (*1 / *1).

[0054] Figure 2D Shown are the concentrations (in ng / mL) of the tridipitant metabolite M4 in plasma of individuals with the CYP3A4*22 heterozygous genotype (*22het) and the wild-type genotype (*1 / *1).

[0055] Figure 2E Shown are the concentrations (in ng / mL) of the tridipitant metabolite M8 in plasma of individuals with the CYP3A4*22 heterozygous genotype (*22het) and the wild-type genotype (*1 / *1).

[0056] Figure 2F Shown are the concentration ratios of tridipitant and M8 in plasma of individuals with the CYP3A4*22 heterozygous genotype (*22het) and the wild-type genotype (*1 / *1).

[0057] Figure 2GShown are the concentration ratios of all metabolites to M8 in the plasma of individuals with the CYP3A4*22 heterozygous genotype (*22het) and the wild-type genotype (*1 / *1).

[0058] Figure 2H Shown are the concentration ratios of tridipitant and M3 in plasma for individuals with the CYP3A4*22 heterozygous genotype (*22het) and the wild-type genotype (*1 / *1).

[0059] Figure 3 A graph showing the relationship between apparent clearance of trodipitant and CYP3A4*22 status (deleted, wild type, heterozygous, or homozygous) is shown.

[0060] Figure 4 A schematic diagram of the study design described in Example 2 is provided.

[0061] Figure 5 A schematic diagram of the study design described in Example 2, relating to Phases 1 and 2, is shown.

[0062] Figure 6 A schematic diagram of the study design described in Example 2, covering Phases 3 and 4, is shown.

[0063] Figure 7A and 7B Shown are the geometric mean plasma concentrations of tridipitant following oral administration of 170 mg tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 7A ) and semi-logarithmic axes ( Figure 7B ).

[0064] Figure 8A and 8B Shown are the geometric mean plasma concentrations of tridipitant following oral administration of 85 mg tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 8A ) and semi-logarithmic axes ( Figure 8B ).

[0065] Figure 9A and 9B Shown are the geometric mean plasma concentrations of metabolite M2 following oral administration of 170 mg of tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 9A ) and semi-logarithmic axes ( Figure 9B ).

[0066] Figure 10A and 10B Shown are the geometric mean plasma concentrations of metabolite M2 following oral administration of 85 mg of tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 10A ) and semi-logarithmic axes ( Figure 10B).

[0067] Figure 11A and 11B Shown are the geometric mean plasma concentrations of metabolite M3 following oral administration of 170 mg of tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 11A ) and semi-logarithmic axes ( Figure 11B ).

[0068] Figure 12A and 12B Shown are the geometric mean plasma concentrations of metabolite M3 following oral administration of 85 mg of tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 12A ) and semi-logarithmic axes ( Figure 12B ).

[0069] Figure 13A and 13B Shown are the geometric mean plasma concentrations of metabolite M4 following oral administration of 170 mg of tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 13A ) and semi-logarithmic axes ( Figure 13B ).

[0070] Figure 14A and 14B Shown are the geometric mean plasma concentrations of metabolite M4 following oral administration of 85 mg of tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 14A ) and semi-logarithmic axes ( Figure 14B ).

[0071] Figure 15A and 15B Shown are the geometric mean plasma concentrations of metabolite M8 following oral administration of 170 mg of tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 15A ) and semi-logarithmic axes ( Figure 15B ).

[0072] Figure 16A and 16B Shown are the geometric mean plasma concentrations of metabolite M8 following oral administration of 85 mg of tridipitant to healthy volunteers under fed and fasting conditions, with linear axes ( Figure 16A ) and semi-logarithmic axes ( Figure 16B ).

[0073] The drawings are intended to depict only typical aspects of the disclosure, and therefore should not be considered as limiting the scope of the disclosure. DETAILED DESCRIPTION

[0074] Various embodiments of the present invention are described herein that relate to the use of trodipitant to treat one or more trodipitant-responsive diseases or conditions. As used herein, the term "deldipitant-responsive disease or condition" should be understood to refer to diseases and conditions known in the art to be treatable with deldipitant, which may include, for example, pruritus, atopic dermatitis, gastroparesis, motion sickness, cravings, lower respiratory tract infections, and other diseases and conditions described in U.S. Patent Nos. 7,320,994, 8,772,496, 7,381,826, 10,463,655, 10,772,880, 11,324,735, and 10,821,099, and U.S. and WO Patent Application Publication Nos. US2020 / 0030307, ​​US2021 / 0228555, US2022 / 0096449, WO 2021 / 195025, WO 2021 / 173641, and WO 2023 / 034718. Each of the above patent publications is incorporated herein by reference as if fully set forth herein. The term "deldipitant-responsive disease or disorder" may also be understood to refer to any of the symptoms described above, regardless of whether the underlying disease is diagnosed, undiagnosed, suspected, or merely consistent with the symptoms reported or exhibited by the individual, e.g., an individual in whom "deldipitant-responsive disease or disorder" cannot or has not been ruled out. An individual with a disease or condition that is responsive to deldipitant may be considered an individual "in need of treatment with deldipitant."

[0075] As used herein, the terms "patient," "subject," and "individual" refer to humans, as well as companion animals (eg, dogs and cats) and other domesticated animals (eg, horses, cattle, and sheep). It will be understood that the most preferred patient is a human.

[0076] The present invention also relates to prophylactic or therapeutic treatment of drug-responsive diseases or conditions. The term "treatment" refers to all processes that may slow, interrupt, prevent, control, or stop the progression of the conditions described herein, and includes prophylactic treatment of such conditions. The term may, but does not necessarily, refer to the complete elimination of all symptoms of the disease.

[0077] Individuals with a disease or condition responsive to tredipitant can be treated by orally administering an effective amount or effective dose of tredipitant. As used herein, the term "effective amount" or "effective dose" refers to an amount or dose effective for treating a disease described herein. These terms can refer to the dose and frequency of administration required to achieve a tredipitant plasma concentration 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 orally administering to a subject a solid immediate-release dosage form comprising one or more pharmaceutically acceptable excipients and tridipitant at a dose of, for example, 100-400 mg / day, 100-300 mg / day, or 100-200 mg / day, which can be administered as 50-200 mg twice daily, 50-150 mg twice daily, or 50-100 mg twice daily; or 150-400 mg / day, 150-300 mg / day, or 150-200 mg / day, which can be administered as 75-200 mg twice daily, 75-150 mg twice daily, or 75-100 mg twice daily; or 85-170 mg / day, which can be administered as, for example, 85 mg once daily, 85 mg twice daily, or 170 mg once daily. With respect to administration, "qd" refers to administration once daily; "bid" generally refers to administration once in the morning and evening, generally with an interval of not less than about 8 hours or more than about 16 hours, for example, once every 10 to 14 hours or 12 hours (Q12H), for example, at 9:00 and 21:00. A solid immediate-release dosage form can be, for example, a capsule or tablet and can include tredipitant in crystalline form IV or V and one or more pharmaceutically acceptable excipients.

[0078] According to one aspect of the present invention, a method for treating an individual described herein by administering tredipitant to the individual is provided. According to the method, an individual in need of treatment with tredipitant can be selected based on a preliminary determination that the individual suffers from or experiences symptoms of a disease or condition responsive to tredipitant. After determining that the individual is in need of treatment with tredipitant, the method comprises orally administering to the individual a solid dosage form comprising tredipitant and one or more pharmaceutically acceptable excipients described herein, wherein tredipitant is administered in a fasted state, i.e., when the individual is in a fasting state or condition.

[0079] In particular, the method can include instructing the individual to take tredipitant in a fasting state. In various embodiments, instructing the individual to take tredipitant in a fasting state can include instructing the individual to fast for a specified period of time before orally taking tredipitant. The time period can 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 a period of about half (0.5) hours to about 1.5 hours before administering tredipitant. Instructing the individual to take tredipitant in a fasting state can also include instructing the individual to fast for a period of time after administering tredipitant. The time period 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 a period of about two (2) to about 2.5 hours after administering tredipitant. In other embodiments, the individual can be instructed to take tridipitant while fasting, for example, by fasting for a first period of time prior to administration of tridipitant and a second period of time after administration of tridipitant. The first and second periods of time can be the same duration or different durations and can be independently selected from the durations described above or from other durations as would be understood by a skilled clinician. The method further includes the individual actually fasting as described herein, i.e., adhering to the above instructions.

[0080] According to another aspect of the present invention, a method for administering tridipitant to an individual in need thereof is provided. According to the method, an individual in need of treatment with tridipitant can be selected based on a preliminary determination that the individual suffers from or experiences symptoms of a disease or condition responsive to tridipitant. After determining the individual in need of treatment with tridipitant, the method includes determining the individual's CYP3A4 genotype. This determination step can, in particular, be performed prior to administering tridipitant. In certain embodiments, such a determination can be made by obtaining or having obtained a biological sample from a patient; and performing or having performed a genotyping assay on the biological sample to determine whether the individual has a CYP3A4 variant genotype. In this context, "obtaining" may refer to collecting or obtaining a biological sample from a patient, while "obtained" may refer to, instruct, or otherwise cause another person (e.g., a medical or healthcare professional) to obtain the sample. "Obtained" may also mean that the acquisition has been previously facilitated, e.g., a test to identify the individual's CYP3A4 genotype was performed in the past, and the results are available for review in the individual's medical records. Similarly, as used herein, "performing a genotyping test" may refer to actually performing the steps of examining an individual's DNA using a genotyping test, while "performed" may refer to delegating, directing, or otherwise causing another person (e.g., a medical or healthcare professional) to perform the test. "Performed" may also refer to having previously caused the test to be performed. Performing (or having performed) the assay may include the steps of extracting or having extracted genomic DNA or mRNA from a biological sample, and sequencing or having sequenced CYP3A4 DNA derived from the extracted genomic DNA or extracted mRNA. The sequencing (or having sequenced) step may also include amplifying or having amplified the CYP3A4 region of the extracted genomic DNA or mRNA to prepare a DNA sample enriched for DNA from the CYP3A4 gene region; and sequencing (or having sequenced) the DNA sample by hybridizing the DNA sample with a nucleic acid probe to determine whether the patient has a CYP3A4 variant genotype.

[0081] In certain embodiments, the CYP3A4 variant detected in a selected individual may be an intron 6 single nucleotide polymorphism (SNP) (rs35599367C>T, CYP3A4*22). Carriers of the CYP3A4*22 allele may be heterozygous (one copy of the *22 allele, referred to herein as *22het) or homozygous (two copies of the *22 allele). As described above, other variants may also be known and understood by those skilled in the art.

[0082] The method may also include administering tridipitant to the individual at a dose determined based on the individual's CYP3A4 genotype. If the individual has a CYP3A4 genotype associated with normal tridipitant metabolism, the method includes administering tridipitant to the individual in a first amount. However, if the individual has a CYP3A4 genotype associated with decreased tridipitant metabolism compared to wild-type, the method instead includes administering a second amount of tridipitant, wherein the second amount is less than the first amount. Examples of CYP3A4 genotypes associated with decreased tridipitant metabolism compared to wild-type include a CYP3A4 genotype comprising at least one *22 allele (i.e., *22het), or a CYP3A4 genotype comprising two *22 alleles (i.e., *22 allele homozygotes).

[0083] In certain embodiments, the second, smaller amount of tridipitant 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 administered to an individual with a CYP3A4 genotype associated with normal tridipitant metabolism or an individual without a CYP3A4 genotype associated with reduced tridipitant metabolism relative to wild type. Such individuals may actually carry the wild type (*1 / *1) genotype or may carry one or more variations that do not significantly affect tridipitant metabolism. When the second smaller amount of tridipitant is about 66-68% of the first amount, this represents a reduction of about 32-34% relative to the normal effective dose.Such a dose reduction may be applicable to individuals whose CYP3A4 genotype comprises at least one or exactly one *22 allele.

[0084] In other embodiments, the first amount can be defined in the same manner, and the second, smaller amount of tredipitant can 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 a dose reduction may be applicable to individuals whose CYP3A4 genotype comprises at least one or exactly two *22 alleles.

[0085] Because CYP3A4*22 status has been shown to significantly influence the metabolic clearance of tredipitant, as described in Example 1 herein, determining the CYP3A4 genotype of an individual requiring treatment with tredipitant enables tredipitant to be administered in a manner that facilitates the patient's desired exposure levels to the parent compound and any active metabolites. In particular, an individual receiving a first amount (also referred to as a "normal amount" or "normal effective amount") of tridipitant can be administered an effective dose, i.e., 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, at a dose of, for example, 75-200 mg twice daily, 50-200 mg twice daily, 75-150 mg twice daily, 50-150 mg twice daily, 75-100 mg twice daily, 50-100 mg twice daily, about 85 mg twice daily, or about 85 mg once daily, while an individual receiving a second, smaller amount of tridipitant can receive a proportionally reduced dose, as discussed above. Regardless of whether the particular individual has a CYP3A4 genotype associated with normal metabolism of tridipitant and receives a first amount, or has a CYP3A4 genotype associated with reduced metabolism of tridipitant relative to wild-type and receives a second, smaller amount, the dose administered in either case can be sufficient to achieve and maintain a tridipitant plasma concentration level in the individual of at least about 100 ng / mL, e.g., greater than 125 ng / mL, greater than 150 ng / mL, greater than 175 ng / mL, greater than 200 ng / mL, or greater than 225 ng / mL, during the treatment period.

[0086] In another embodiment, a subject in need of treatment with tradipitant can be selected for tradipitant treatment based on a preliminary determination that the subject suffers from or experiences symptoms of a disease or condition responsive to tradipitant. After determining that the subject is in need of treatment with tradipitant, the method includes determining whether the subject is currently receiving treatment with a CYP3A4 inhibitor or has previously taken such a compound. This determination step can particularly be performed prior to administering tradipitant.

[0087] The method may further comprise administering tredipitant to the individual, the dosage of which depends on whether a CYP3A4 inhibitor is co-administered with tredipitant. Where a CYP3A4 inhibitor is not co-administered with tredipitant, the method comprises administering tredipitant to the individual in a first amount, similar to the case where the individual has a CYP3A4 genotype associated with normal tredipitant metabolism. However, where a CYP3A4 inhibitor is co-administered with tredipitant to the individual, the method may comprise administering tredipitant to the individual in a second amount, wherein the second amount is less than the first amount, similar to the case where the individual has a CYP3A4 genotype associated with reduced tredipitant metabolism relative to wild-type. 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 a specific embodiment, the CYP3A4 inhibitor may be considered a strong CYP3A4 inhibitor and may be selected from the group consisting of: clarithromycin, itraconazole, ketoconazole, and posaconazole, or ketoconazole and grapefruit juice.

[0088] As described above, in certain embodiments, the second, smaller amount of trodipitant 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 should be 100% of the amount required for a subject to be co-administered with a CYP3A4 inhibitor and trodipitant. In certain embodiments, co-administration of trodipitant with a CYP3A4 inhibitor results in a decrease in apparent clearance of about 26.3%, an increase in Cmax of about 26%, and an increase in AUC of about 36%.

[0089] When the second, smaller amount of tridipitant is approximately 66-68% of the first amount, this represents a reduction of approximately 32-34% relative to the normal effective dose. Such a dose reduction may be appropriate for patients receiving tridipitant concurrently with a CYP3A4 inhibitor. Giving such a smaller second dose to such patients facilitates the use of tridipitant while avoiding excessive tridipitant concentrations due to differential metabolism by CYP3A4.

[0090] In other embodiments, the first amount can be defined in the same manner, and the second, smaller amount of tridipitant can 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 dose reductions may be applicable to patients co-administering tridipitant and a CYP3A4 inhibitor.

[0091] Co-administration of trodipitant with CYP3A4 inhibitors, particularly strong CYP3A4 inhibitors, results in increased trodipitant exposure. Therefore, individuals identified as requiring trodipitant treatment who are currently or will be co-administering trodipitant and a CYP3A4 inhibitor should be administered trodipitant in a manner that achieves the desired exposure of the parent compound and any active metabolites. In particular, an individual receiving a first amount (also referred to as a "normal amount" or "normal effective amount") of tridipitant can be administered an effective dose, i.e., 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, at a dose of, for example, 75-200 mg twice daily, 50-200 mg twice daily, 75-150 mg twice daily, 50-150 mg twice daily, 75-100 mg twice daily, 50-100 mg twice daily, about 85 mg twice daily, or about 85 mg once daily, while an individual receiving a second, smaller amount of tridipitant can receive a proportionally reduced dose, as discussed herein. Regardless of whether a particular individual is administered tridipitant in the absence of a CYP3A4 inhibitor and receives a first amount, or is co-administered tridipitant and a CYP3A4 inhibitor and receives a second, smaller amount, the dose administered in either case can be sufficient to achieve and maintain tridipitant plasma concentration levels in the individual of at least about 100 ng / mL, e.g., greater than 125 ng / mL, greater than 150 ng / mL, greater than 175 ng / mL, greater than 200 ng / mL, or greater than 225 ng / mL, during the treatment period.

[0092] According to another aspect of the present invention, a method for determining an effective amount of tridipitant to be administered to an individual in need thereof is provided. In one embodiment, as described above, the method includes determining the individual's CYP3A4 genotype from a biological sample. If the individual is found to have a CYP3A4 genotype associated with normal tridipitant metabolism, such as wild-type, the method includes determining the effective amount of tridipitant to be a first amount, and if the individual is found to have a CYP3A4 genotype associated with reduced tridipitant metabolism relative to wild-type, the method includes determining the effective amount of tridipitant to be a second amount less than the first amount. A CYP3A4 genotype associated with reduced tridipitant metabolism may include at least one CYP3A4*22 allele, and in some cases, two CYP3A4*22 alleles.

[0093] In another embodiment, the method includes determining whether the individual is currently being treated with or has already taken a compound known to be a CYP3A4 inhibitor, such that the CYP3A4 inhibitor can be administered concurrently with trodipitant. If the CYP3A4 inhibitor will not be administered concurrently, the method includes determining the effective amount of trodipitant to be a first amount, and if trodipitant and the CYP3A4 inhibitor are being administered concurrently, the method includes determining the effective amount of trodipitant to be a second amount less than the first amount. In certain embodiments, the CYP3A4 inhibitor can be selected from amiodarone, aprepitant, cimetidine, ciprofloxacin, clarithromycin, diltiazem, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, posaconazole, voriconazole, and verapamil. In specific embodiments, the CYP3A4 inhibitor can be considered a strong CYP3A4 inhibitor and can be selected from clarithromycin, itraconazole, ketoconazole, and posaconazole, or ketoconazole and grapefruit juice. In certain embodiments, the dosage of the first amount of tridipitant can be, 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, administered at a dosage of, for example, 75-200 mg twice daily, 50-200 mg twice daily, 75-150 mg twice daily, 50-150 mg twice daily, 75-100 mg twice daily, 50-100 mg twice daily, about 85 mg twice daily, or about 85 mg once daily, and the dosage of the second, smaller amount of tridipitant can be reduced as discussed herein. For example, in certain embodiments, the second, smaller amount of tridipitant 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 a dose reduction may be applicable to individuals whose CYP3A4 genotype comprises at least one or exactly one *22 allele, or individuals who are being or will be co-administered with tridipitant and a CYP3A4 inhibitor.

[0094] In other embodiments, the second, smaller amount of tridipitant can 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 a dose reduction may be applicable to individuals whose CYP3A4 genotype comprises at least one or exactly two *22 alleles, or individuals who are currently or will be receiving tridipitant and a CYP3A4 inhibitor concurrently.

[0095] In the methods described herein for determining an effective amount of tridipitant, regardless of which dose is determined to be effective for a particular individual, the dose administered is sufficient to achieve and maintain a plasma concentration level of tridipitant in the individual to whom the dose is administered. During treatment, the plasma concentration level can be at least about 100 ng / mL, e.g., greater than 125 ng / mL, greater than 150 ng / mL, greater than 175 ng / mL, greater than 200 ng / mL, or greater than 225 ng / mL.

[0096] According to another aspect of the present invention, a method for administering tridipitant to an individual in need thereof is provided. The method comprises determining the individual's CYP3A4 genotype (as described herein), or determining whether the individual is currently administering a CYP3A4 inhibitor. If the individual's CYP3A4 genotype is associated with normal metabolism of tridipitant, and / or the individual is not administering a CYP3A4 inhibitor, the method comprises orally administering to the individual a solid dosage form in a fasting state (e.g., without food), the solid dosage form comprising a first amount of tridipitant and one or more pharmaceutically acceptable excipients. If the individual carries a CYP3A4 genotype associated with reduced tridipitant metabolism compared to wild-type, or the individual is currently administering a CYP3A4 inhibitor, the method comprises orally administering to the individual a solid dosage form in a fasting state (e.g., without food), the solid dosage form comprising a second amount of tridipitant less than the first amount and one or more pharmaceutically acceptable excipients. In certain embodiments, the solid immediate-release dosage form can be a capsule or a tablet.

[0097] Examples of CYP3A4 genotypes associated with decreased metabolism of tredipitant compared to wild-type include CYP3A4 genotypes comprising at least one *22 allele (i.e., heterozygous for the *22 allele), or CYP3A4 genotypes comprising the *22 allele (i.e., homozygous for the *22 allele). 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 specific embodiments, the CYP3A4 inhibitor may be considered a strong CYP3A4 inhibitor and may be selected from: clarithromycin, itraconazole, ketoconazole, and posaconazole, or ketoconazole and grapefruit juice.

[0098] Because CYP3A4*22 status has been shown to significantly influence the metabolic clearance of trodipitant as described in Example 1 herein, determining the CYP3A4 genotype of an individual requiring trodipitant treatment facilitates administration of trodipitant to achieve the desired exposure levels of the parent compound and any active metabolites. In particular, a subject receiving a first amount of tridipitant can be administered an effective dose, i.e., 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, at a dose of, for example, 75-200 mg twice daily, 50-200 mg twice daily, 75-150 mg twice daily, 50-150 mg twice daily, 75-100 mg twice daily, 50-100 mg twice daily, about 85 mg twice daily, or about 85 mg once daily, while a subject receiving a second, smaller amount of tridipitant may need to receive a correspondingly reduced dose. In certain embodiments, the second, smaller amount of tridipitant 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 a dose reduction may be applicable to individuals whose CYP3A4 genotype comprises at least one or exactly one *22 allele, and similarly, to individuals who are co-administered tridipitant and a CYP3A4 inhibitor as described herein. In other embodiments, the second, smaller amount of tridipitant can 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 a dose reduction may be applicable to individuals whose CYP3A4 genotype comprises at least one or exactly two *22 alleles, and similarly, to individuals who are co-administered tridipitant and a CYP3A4 inhibitor as described herein.

[0099] According to the methods described herein, regardless of which condition is met, i.e., whether the individual is found to have a CYP3A4 genotype associated with normal metabolism of tredipitant and a first amount of tredipitant is administered, whether a CYP3A4 inhibitor and tredipitant are not co-administered to the individual and therefore tredipitant is administered in a first amount, or whether the individual is found to have a CYP3A4 genotype associated with reduced metabolism of tredipitant (relative to wild type), or tredipitant and a CYP3A4 inhibitor are co-administered and a second, smaller dose of tredipitant is administered, the dose administered in either case can be sufficient to achieve and maintain a plasma concentration level of tredipitant in the individual of at least about 100 ng / mL, e.g., greater than 125 ng / mL, greater than 150 ng / mL, greater than 175 ng / mL, greater than 200 ng / mL, or greater than 225 ng / mL.

[0100] Specifically, the method may include instructing the individual to take tredipitant in an empty stomach, such as by fasting, and / or instructing the individual to take tredipitant in an empty stomach, such as by fasting for a specific period of time prior to oral administration of tredipitant. The time period 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 a period of about half (0.5) hours to 1.5 hours before administration of tredipitant. The method may also or alternatively include instructing the individual to take tredipitant without eating, such as by fasting, and / or instructing the individual to take tredipitant without eating, such as by fasting for a period of time after administration of tredipitant. The time period may 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 a period of about two (2) hours to about 2.5 hours after administration of tredipitant. In other embodiments, the individual can be instructed to take tridipitant in a fasting state, e.g., without food, and / or the individual can take tridipitant in a fasting state, e.g., without food for a first period of time before taking tridipitant and without food for a second period of time after taking tridipitant. The first and second periods of time can be the same duration or different durations and can be independently selected from the durations described above.

[0101] According to another aspect of the present invention, a method of administering trodipitant to an individual in need thereof is provided. For example, the individual may be experiencing acute manifestations of a disease or disorder responsive to trodipitant, or chronic manifestations of a disease or disorder responsive to trodipitant. The method includes determining an effective dose for administration based on whether the individual is fasting prior to administration. The trodipitant may then be administered in a solid immediate-release dosage form comprising the effective dose and one or more pharmaceutically acceptable excipients.

[0102] If the subject is fasting at the time of administration, and trodipitant is taken on an empty stomach, a first effective amount of trodipitant may be administered. If the subject is fed at the time of administration, e.g., taking trodipitant with or immediately after a meal, a second effective amount of trodipitant may be administered, the second effective amount being less than the first effective amount, as described elsewhere herein. In particular, a subject receiving a first amount of tridipitant can be administered an effective dose, i.e., 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, at a dose of, for example, 75-200 mg twice daily, 50-200 mg twice daily, 75-150 mg twice daily, 50-150 mg twice daily, 75-100 mg twice daily, 50-100 mg twice daily, about 85 mg twice daily, or about 85 mg once daily, while a subject receiving a second, smaller amount of tridipitant may need to receive a correspondingly reduced dose. In certain embodiments, the second, smaller amount of tredipitant 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. This dose reduction may be appropriate for individuals who take tredipitant with food or who do not need to take tredipitant on an empty stomach. In other embodiments, the second, smaller amount of tridipitant can 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. This dose reduction may be appropriate for individuals who take tridipitant with food as described herein. Also provided are related methods for determining an effective dose of tridipitant to be administered to an individual in need thereof, comprising: determining the effective amount based on whether the individual takes tridipitant with food (e.g., whether the individual is fasting or fed at the time of administration). The corresponding dose in each case can be determined as described above.

[0103] Those skilled in the art will understand that other preferred embodiments may be selected by combining the above preferred embodiments or referring to the embodiments given herein.

[0104] Example 1: Role of CYP3A4 in the metabolism of tredipitant

[0105] To investigate the role of CYP3A4 genotype in the metabolism of trodipitant, we analyzed the pharmacokinetics of trodipitant according to CYP3A4 genotype in human patients treated in a Phase III clinical trial. All CYP3A4 alleles (identified by the Human Cytochrome P450 Allele Nomenclature Database) were examined. The analysis included a linear model that tested different ratios of the parent compound (trodipitant) or its metabolites, including:

[0106] Ratio A = sum of (M2+M3+M4) / M8, and

[0107] Ratio B = (tradipitant) / (M3).

[0108] After adjusting for covariates including principal component (PC), age, sex, and body mass index (BMI), CYP3A4*22 was identified as a variant of interest with a p-value of 1x10 -5 . Figure 1A (Ratio A) and Figure 1B (Ratio B) shows the distribution of variants and their respective ratios. The effects of multiple alleles of interest are cumulative, as shown by the median ratio of individuals with the CYP3A4 genotype *22 / *1 (i.e., heterozygotes for the *22 variant of interest (*22het)) to individuals with the CYP3A4 genotype *22 / *22 + *3 / *1 (i.e., homozygotes for the *22 variant of interest). Tissue samples from homozygotes (*22 / *22) showed a 1.7- to 2.5-fold decrease in mRNA or protein expression compared to wild-type individuals. This ultimately leads to a reduction in M3 and a shift toward metabolism via alternative pathways.

[0109] Figures 2A-2H The graphs shown illustrate the plasma concentrations of trodipitant for individuals in the study population ( 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 ). Figures 2A-2D The results showed that the median concentrations of trodipitant, M2, M3, and M4 in the *22 heterozygote group (*22het) were significantly higher than those in the wild type group, reflecting that individuals carrying the *22 allele have a reduced ability to eliminate trodipitant. Figure 2F This indicates that compared with the wild type (no *22 allele), the median ratio of trodipitant to M8 in the *22 heterozygous group (*22het) was significantly larger.

[0110] Figure 3 A graph showing the relationship between apparent clearance of tredipitant and CYP3A4*22 status (deletion, wild-type, heterozygous, or homozygous) is shown, with each circle representing the value from a single subject and the line representing the median. The apparent clearance of tredipitant is plotted for individuals with the wild-type (WT) genotype and those with the heterozygous *22 (*22het) genotype. The ratio of clearance (CL) for *22het to WT was calculated as exp(median (HET) - median (WT)). Below these calculations, the P value for the comparison of ETA values ​​using a t-test is reported. The graph shows that the presence of a single CYP3A4*22 allele results in a significant difference in clearance of tredipitant, with clearance approximately 66% of that observed in wild-type individuals. The post hoc ETA is as follows: log(individual clearance value / typical clearance value), where the "typical value" is essentially the median. Because the ratio is centered around 1.0 (half the values ​​are > median and half are < median), the logarithms of these values ​​are centered around zero.

[0111] Due to the MAF of the *22 variant, no individuals with the homozygous *22 / *22 genotype were found in the study population. However, it is expected that the clearance of trodipitant in homozygous *22 / *22 individuals will still be significantly lower than the clearance observed in *22het individuals. Analysis showed that among the 2,060 samples, 11 individuals were identified as having the *3het / *22het genotype. Among these, 10 individuals had both variants located on the same chromosome, while 1 individual had both variants located on different chromosomes. Another two (2) individuals were identified as having the *3het / *22hom genotype.

[0112] These findings support the conclusion that CYP3A4 genetic variation, particularly the CYP3A4*22 allele, has functional significance for the metabolism of tridipitant. The presence of target variants, including the *22 allele, may result in a loss of metabolic activity, and this loss may accumulate as the number of target alleles in an individual's genetic sequence increases. The associated reduction in mRNA or protein expression may result in a clinically significant reduction in tridipitant metabolism; for example, a heterozygote may experience only 66% of the tridipitant clearance experienced by an individual with a wild-type CYP3A4 genotype at the equivalent dose, a 34% reduction.

[0113] Example 2: A Phase 4, Two-Way, Crossover, Open-Label Study to Evaluate the Pharmacokinetics of a Single Dose of Tradipitant in Healthy Subjects

[0114] An open-label, four-period, two-way crossover study was conducted to evaluate the effects of food on the pharmacokinetics and bioavailability of single-dose capsules containing 170 mg and 85 mg of tradipitant. Figure 4 The study design is outlined. The study consisted of two cohorts, each undergoing a screening phase and an assessment phase. Cohort 1 underwent only phases 1 and 2 ( Figure 5 ), while cohort 2 only undergoes phases 3 and 4 ( Figure 6 ). Participants in queue 1 may become participants in queue 2.

[0115] Screening phase (Day -21 to Day -2, Figure 5-6 ) included a screening visit where informed consent was obtained from potential participants and their eligibility was initially assessed based on vital signs, body measurements, physical examination, electrocardiogram, clinical laboratory tests, drug and alcohol screening, and medical history. Clinical laboratory testing included pharmacogenetic samples for whole-genome sequencing. Participants were required to be male or female aged 18-55 years (inclusive) at screening; body mass index (BMI) ≥18.0 and ≤39.0 kg / m 2 (BMI = weight (kg) / [height (m)] 2); Female participants of childbearing age must be non-pregnant and non-lactating. Participants must be in good health, as determined by medical history, psychiatric history, physical examination, electrocardiogram, serum chemistry and hematology; willing to comply with study procedures and restrictions; willing to provide pharmacogenetic samples; and test negative for selected substances of abuse at screening. Individuals may be excluded for the following reasons: history of psychiatric illness (within 12 months prior to screening); current clinically significant cardiovascular, respiratory, neurological, hepatic, hematopoietic, renal, gastrointestinal or metabolic dysfunction, unless the condition is currently controlled and stable; history of intolerance and / or allergy to other NK-1 receptor antagonists; clinical laboratory results, vital sign measurements or physical examination results at screening that are significantly different from normal values ​​as determined by the clinical investigator; major surgery, trauma (including pelvic / leg fractures), illness (such as sepsis) or immobility for 3 or more days in the past month; active cancer within 6 months prior to screening or received cancer treatment; had a central venous catheter placed or received a central venous catheter within the past month; had AST, ALT, or bilirubin >2 times the upper limit of normal indicating impaired liver function, unless bilirubin alone >2 times the upper limit of normal due to Gilbert's syndrome; was pregnant or recently pregnant (within 6 weeks before screening) or was breastfeeding; had a history of drug or alcohol abuse as defined by the DSM-V Diagnostic Criteria for Drug and Alcohol Abuse and / or regularly consumed alcoholic beverages (>2 drinks per day or >14 drinks per week) within 12 months before screening; had been randomized in a previous traditional trial; and participants considered by the researchers to be at risk for suicide.Further exclusion criteria included participants who were unwilling or unable to adhere to medication restrictions or unwilling or unable to adequately wean themselves from restricted medication use; any condition requiring regular medication use; regular caffeine consumption, including coffee, tea, and / or other caffeinated beverages or foods, exceeding an average of 3 cups (24 ounces) per day; inability to perform venipuncture and / or intolerance to intravenous access; use of tobacco products in the 3 months prior to administration (a tobacco user was defined as any participant who reported using cigarettes, cigars, tobacco, nicotine gum, nicotine patches, or e-cigarettes); participation in the evaluation of any study product within 30 days or 5 half-lives (if known) before Day 1, whichever was longer; use of prescription or over-the-counter medications, including herbal products (e.g., St. John's wort), with the exception of hormonal contraceptives, within 1 week of the first administration; and use of narcotics or other medications within 1 week of the first administration. Consumption of any food or beverage containing alcohol, grapefruit or grapefruit juice, apple juice or orange juice, mustard greens (such as kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard) or charcoal-grilled meat within 1 week after the first dose until the end of the study; abnormal diet (<1600 or >3500 kcal / day), significant change in dietary habits within 1 week after the first dose until the end of the study, or vegetarianism; history (including family history) or current evidence of congenital long QT syndrome or known acquired QT interval prolongation; history of liver disease and / or one or more of the following serological results are positive: a) positive hepatitis C antibody test (anti-HCV), b) positive HIV (ELISA and Western) test results, and / or c) positive hepatitis B surface antigen (HBsAg).

[0116] After the screening period, there were two evaluation phases, each consisting of two phases, for a total of four phases. Each phase consisted of a baseline visit and a single-dose treatment period, which included 48 hours of on-site observation and 72 hours of pharmacokinetic sampling. There was a washout period of at least 11 days between the four phases. The evaluation phase ended with a cohort study end visit on Day 4 of Phase 2 (for Group 1) ( Figure 5 ) and End of Cohort Study Visit on Day 4 of Period 2 (for Group 2) Figure 6 ) at the end of the second and fourth time periods. Baseline assessments will be repeated at the beginning of the second and fourth time periods. During the baseline visit, the following assessments will be performed: vital signs, weight, clinical laboratory safety tests, drug, alcohol, and cotinine screening, physical examination, urine and serum pregnancy tests (if WOCBP), and any adverse events will be recorded.

[0117] Within two hours before administration on Day 1, a pre-dose blood sample was collected to measure the presence of trodipitant and its metabolites (M2, M3, M4, and M8). Study medication was administered to participants under open-label conditions. Each participant in Group 1 ( Figure 5) received a 170 mg dose of tridipitant orally (PO) as two 85 mg tridipitant capsules at Visit 3, which could be taken with or without food, and received the alternative therapy at Visit 6. Each participant in Group 2 received a 85 mg dose of tridipitant as one 85 mg tridipitant capsule at Visit 10, which could be taken with or without food, and received the alternative therapy at Visit 13. Tridipitant capsules are white, opaque, hard gelatin capsules, 85 mg in strength. The 85 mg capsule dosage form also contains spray-dried lactose monohydrate, microcrystalline cellulose (Avicel PH102 and PH200), povidone, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate as excipients.

[0118] The subjects took the study drug between 07:00 and 09:00. Subjects who took the study drug on an empty stomach (10 hours fasting) were required to take the drug with 240 ml of room temperature tap water on an empty stomach and swallow the capsule whole without chewing. No other water was allowed from 1 hour before to 1 hour after taking the drug. Water was available at other times. Subjects who took the study drug in a fed state started eating a high-calorie, high-fat meal 30 minutes or less before taking the study drug and finished eating before taking the drug. The meal was consistent with the high-fat breakfast recommended by the U.S. Food and Drug Administration (FDA), including two eggs fried in butter, two strips of bacon, two slices of buttered toast, four ounces of fried potatoes and eight ounces of whole milk. (USDepartment 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, obtained from https: / / www.fda.gov / media / 121313 / download , p. 12, Appendix 1 (June 2022) (accessed November 11, 2022).

[0119] Food was provided 4 hours after administration, regardless of whether the participant was fed or fasting. Subsequent meals and their content were determined at the discretion of the study center and remained consistent across all participants. The following foods and beverages were prohibited with any meal during the study: alcohol, grapefruit juice, apple juice, orange juice, mustard greens (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard), and char-grilled meats.

[0120] Pharmacokinetic (PK) blood samples were collected during sessions 1-4 at the following time points: 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 (with an accuracy of + / - 5 minutes for each time point). Samples were analyzed for the following analytes: tradipitant and its metabolites M2, M3, M4, and M8. Participants left the trial center after 48 hours and returned on day 4 for a 72-hour blood sample.

[0121] End-of-study (EOS) / early discontinuation (ED) assessments were conducted after the last pharmacokinetic (PK) sample was collected on Day 4 of Period 2 for Group 1 and on Day 4 of Period 4 for Group 2; if a participant withdrew prematurely from the study, the assessment was conducted at study termination. During the EOS / ED assessment, a physical examination, vital signs and weight assessment, a 12-lead electrocardiogram, and clinical laboratory tests were performed. Adverse events and concomitant medications were recorded throughout the study.

[0122] result

[0123] Fifteen and 16 subjects were enrolled in Cohort 1 and Cohort 2, respectively, and completed both phases of the trial. These 31 subjects comprised the pharmacokinetic analysis population. Five subjects from Cohort 1 also participated in Cohort 2. The following abbreviations are used in this article:

[0124] AUC area under the plasma concentration-time curve;

[0125] AUC(0-t) is the area under the plasma concentration-time curve to the last time the concentration reaches LOQ.

[0126] AUC(inf) is the area under the plasma concentration-time curve to infinity.

[0127] CI confidence interval

[0128] Cmax maximum plasma concentration

[0129] gMean geometric mean

[0130] hr hours

[0131] LSGMR Least Squares Geometric Mean Ratio

[0132] mg milligrams

[0133] mL milliliters

[0134] ng nanogram

[0135] PK pharmacokinetics

[0136] t time

[0137] t1 / 2 elimination half-life

[0138] Tmax time to peak plasma concentration

[0139] WSCV within-subject coefficient of variation

[0140] λz elimination rate constant

[0141] Dipitant

[0142] After administration of 170 mg in the fed state, the geometric mean (gMean) plasma concentration of tredipitant ( Figures 7A-7B ) and the values ​​of Cmax, AUC(0-t), and AUC(inf) (Table 1) were significantly higher than those after oral administration under fasting conditions. The least squares geometric mean ratio (LSGMR) was 703.87% for Cmax, 328.21% for AUC(0-t), and 381.70% for AUC(inf), respectively (Table 2).

[0143] Table 1: Summary of the pharmacokinetic parameters of 170 mg of tridipitant in healthy volunteers following oral administration under fed and fasting conditions

[0144]

[0145] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0146] Table 2: Statistical comparison of pharmacokinetic parameters of 170 mg of tripitant in healthy volunteers after oral administration under fed and fasting conditions

[0147]

[0148] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0149] *Power to detect a 20% difference at α = 0.05.

[0150] The median Tmax increased from 1.50 hours under fasting conditions to 4.00 hours under fed conditions (Table 1).

[0151] The same significant increase was observed after administration of 85 mg in the fed state, as Figures 8A-8BAs shown in Table 4 (gMean concentration) and Table 3 (Cmax and AUC), the LSGMRs were 437.59%, 234.21% and 263.08%, respectively (Table 4). Administration in the fed state resulted in a 2-fold increase in Tmax (Table 3).

[0152] Table 3: Summary of the pharmacokinetic parameters of 85 mg of tridipitant in healthy volunteers following oral administration under fed and fasting conditions

[0153]

[0154] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0155] Table 4: Statistical comparison of pharmacokinetic parameters of 85 mg of tridipitant in healthy volunteers after oral administration under fed and fasting conditions

[0156]

[0157] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0158] *Power to detect a 20% difference at α = 0.05.

[0159] For both doses, postprandial administration resulted in significantly increased gMean values ​​for Cmax and AUC, and longer median Tmax, suggesting an increased extent of absorption and a decreased rate of absorption.

[0160] Metabolite M2

[0161] Consistent with the effect of fed state on the absorption of the parent compound, the geometric mean (gMean) plasma concentrations of the metabolite M2 ( Figures 9A-9B ) and Cmax, AUC(0-t), and AUC(inf) values ​​(Table 5) were significantly higher than plasma concentrations following oral administration under fasting conditions. LSGMR was 654.35% for Cmax, 352.60% for AUC(0-t), and 350.82% for AUC(inf), respectively (Table 6). When a 170 mg capsule was taken in the fed state, the median Tmax remained unchanged at 4 hours (Table 5).

[0162] The same significant increase was observed after administration of 85 mg in the fed state, as Figures 10A-10BAs shown in Table 7 (gMean concentration) and Table 7 (Cmax and AUC), the LSGMRs were 407.70%, 240.71%, and 238.83%, respectively (Table 8). When the 170 mg capsules were taken in the fed state, the median Tmax remained unchanged at 4 hours (Table 7). For both doses, gMean values ​​for Cmax and AUC increased significantly when administered in the fed state, while the median Tmax did not change, indicating an increased degree of absorption.

[0163] Table 5: Summary of the pharmacokinetic parameters of metabolite M2 following oral administration of 170 mg of tridipitant in healthy volunteers under fed and fasting conditions

[0164]

[0165] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0166] Table 6: Statistical comparison of pharmacokinetic parameters of metabolite M2 in healthy volunteers after oral administration of 170 mg of tridipitant under fed and fasting conditions

[0167]

[0168] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0169] *Power to detect a 20% difference at α = 0.05.

[0170] Table 7: Summary of the pharmacokinetic parameters of metabolite M2 following oral administration of 85 mg of tridipitant in healthy volunteers under fed and fasting conditions

[0171]

[0172] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0173] Table 8: Statistical comparison of pharmacokinetic parameters of metabolite M2 in healthy volunteers after oral administration of 85 mg of tridipitant under fed and fasting conditions

[0174]

[0175] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0176] *Power to detect a 20% difference at α = 0.05.

[0177] Metabolite M3

[0178] Consistent with the effect of fed state on the absorption of the parent compound, tridipitant, the geometric mean (gMean) plasma concentrations of the metabolite M3 ( Figures 11A-11B ) as well as Cmax, AUC(0-t), and AUC(inf) values ​​(Table 9) were significantly higher than plasma concentrations following oral administration under fasting conditions. LSGMR was 526.84% for Cmax and 356.01% for AUC(0-t) (Table 10). Median Tmax was longer when a 170 mg capsule was taken in the fed state (4 hours) compared to the fasted state (3 hours) (Table 9).

[0179] The same significant increase was observed after administration of 85 mg of tridipitant in the fed state, as Figures 12A-12B As shown in Table 11 (gMean concentration) and Table 11 (Cmax and AUC), the LSGMRs were 370.57%, 255.71%, and 263.76%, respectively (Table 12). Median Tmax was longer when the 85 mg capsule was taken in the fed state (4 hours) compared to the fasted state (3 hours) (Table 11). For both doses, gMean values ​​for Cmax and AUC were significantly increased when administered in the fed state, and the median Tmax was longer, indicating an increased extent of absorption and a decreased rate of absorption.

[0180] Table 9: Summary of the pharmacokinetic parameters of metabolite M3 following oral administration of 170 mg of tridipitant in healthy volunteers under fed and fasting conditions

[0181]

[0182] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0183] Table 10: Statistical comparison of pharmacokinetic parameters of metabolite M3 in healthy volunteers after oral administration of 170 mg of tripitant under fed and fasting conditions

[0184]

[0185] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0186] *Power to detect a 20% difference at α = 0.05.

[0187] Cannot be estimated due to missing values.

[0188] Table 11: Summary of the pharmacokinetic parameters of metabolite M3 following oral administration of 85 mg of tridipitant in healthy volunteers under fed and fasting conditions

[0189]

[0190] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0191] Table 12: Statistical comparison of pharmacokinetic parameters of metabolite M3 in healthy volunteers after oral administration of 85 mg of tridipitant under fed and fasting conditions

[0192]

[0193] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0194] *Power to detect a 20% difference at α = 0.05.

[0195] Metabolite M4

[0196] Consistent with the effect of fed state on the absorption of the parent compound, tridipitant, the geometric mean (gMean) plasma concentrations of the metabolite M4 ( Figures 13A-13B ) and Cmax, AUC(0-t), and AUC(inf) values ​​(Table 13) were significantly higher than those following oral administration of the same dose under fasting conditions. LSGMR was 547.40% for Cmax, 357.77% for AUC(0-t), and 350.82% for AUC(inf) (Table 14). Median Tmax was longer when the 170 mg capsule was taken in the fed state (6 hours) compared to the fasting state (4 hours) (Table 13).

[0197] The same significant increase was observed after administration of 85 mg of tridipitant in the fed state, as Figures 14A-14B As shown in Table 15 (gMean concentration) and Table 16 (Cmax and AUC), the LSGMR was 339.57%, 243.58%, and 239.45%, respectively (Table 16). The median Tmax was longer when the 85 mg capsule was taken in the fed state (6 hours) compared to the fasted state (4.09 hours) (Table 15). For both doses, the gMean values ​​for Cmax and AUC were significantly increased when administered in the fed state, and the median Tmax was longer, indicating an increased extent of absorption and a decreased rate of absorption.

[0198] Table 13: Summary of the pharmacokinetic parameters of metabolite M4 following oral administration of 170 mg of tridipitant in healthy volunteers under fed and fasting conditions

[0199]

[0200] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0201] Table 14: Statistical comparison of pharmacokinetic parameters of metabolite M4 in healthy volunteers after oral administration of 170 mg of tripitant under fed and fasting conditions

[0202]

[0203] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0204] *Power to detect a 20% difference at α = 0.05.

[0205] Table 15: Summary of the pharmacokinetic parameters of metabolite M4 following oral administration of 85 mg of tridipitant in healthy volunteers under fed and fasting conditions

[0206]

[0207] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0208] Table 16: Statistical comparison of pharmacokinetic parameters of metabolite M4 in healthy volunteers after oral administration of 85 mg of tripitant under fed and fasting conditions

[0209]

[0210] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0211] *Power to detect a 20% difference at α = 0.05.

[0212] Metabolite M8

[0213] Consistent with the effect of fed state on the absorption of the parent compound, tridipitant, the geometric mean (gMean) plasma concentrations of the metabolite M8 ( Figures 15A-15B ) and Cmax, AUC(0-t), and AUC(inf) values ​​(Table 17) were significantly higher than those following oral administration of the same dose under fasting conditions. LSGMR was 559.09% for Cmax, 365.76% for AUC(0-t), and 352.97% for AUC(inf) (Table 18). Median Tmax was shorter when the 170 mg capsule was taken in the fed state (8 hours) compared to the fasting state (30 hours) (Table 17).

[0214] The same significant increase was observed after administration of 85 mg in the fed state, as Figures 16A-16BAs shown in Table 19 (Cmax and AUC), the LSGMRs were 428.64%, 293.76% and 273.24% (Table 20). The median Tmax was shorter when the 85 mg capsule was taken in the fed state (8 hours) compared to the fasted state (15 hours) (Table 19).

[0215] For both doses, gMean values ​​of Cmax and AUC were significantly increased and median Tmax was shorter when administered in the fed state, indicating an increase in the extent and rate of absorption.

[0216] Table 17: Summary of the pharmacokinetic parameters of metabolite M8 following oral administration of 170 mg of tridipitant in healthy volunteers under fed and fasting conditions

[0217]

[0218] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0219] Table 18: Statistical comparison of pharmacokinetic parameters of metabolite M8 in healthy volunteers after oral administration of 170 mg of tripitant under fed and fasting conditions

[0220]

[0221] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0222] *Power to detect a 20% difference at α = 0.05.

[0223] Table 19: Summary of the pharmacokinetic parameters of metabolite M8 in healthy volunteers following oral administration of 85 mg of tridipitant in fed and fasted conditions

[0224]

[0225] **Except Tmax, geometric means [geometric %CV] (N), where medians (N) [range] are reported.

[0226] Table 20: Statistical comparison of pharmacokinetic parameters of metabolite M8 in healthy volunteers after oral administration of 85 mg of tripitant under fed and fasting conditions

[0227]

[0228] Analysis of pharmacokinetic parameters based on natural logarithm transformation.

[0229] *Power to detect a 20% difference at α = 0.05.

[0230] in conclusion

[0231] Table 21 compares the geometric means of Cmax and AUC(inf) following postprandial administration of 85 mg and 170 mg of trodipitant. Although the two doses represent different groups of subjects, the geometric mean ratios for all comparisons are close to 2.0, indicating dose proportionality of the two capsules under fed conditions.

[0232] Table 21: Comparison of pharmacokinetic parameters of trodipitant and its metabolites M2, M3, M4 and M8 after oral administration of 80 mg and 170 mg trodipitant to healthy volunteers under fed conditions.

[0233]

[0234] *Geometric mean.

[0235] Table 22 compares the geometric mean Cmax and AUC(inf) values ​​for 85 mg and 170 mg of tridipitant after a meal. Although the two doses represent different groups of subjects, the ratio of the geometric mean Cmax values ​​for tridipitant and its four metabolites is less than proportional, ranging from 1.23 to 1.64. For AUC(inf), only tridipitant was approximately proportional (ratio of 1.92), with ratios for M2, M3, M4, and M8 ranging from 1.08 to 1.78. This suggests that while the dose of the parent compound may be proportional to the exposure (AUC) under fasting conditions, this relationship is not proportional for the four metabolites.

[0236] Table 22: Comparison of pharmacokinetic parameters of trodipitant and its metabolites M2, M3, M4 and M8 after oral administration of 80 mg and 170 mg trodipitant to healthy volunteers under fasting conditions.

[0237]

[0238] *Geometric mean.

[0239] For both the 170 mg and 85 mg doses, administration in the fed state resulted in a significant increase in the gMean values ​​of trodipitant Cmax, AUC(0-t), and AUC(inf), and a longer median Tmax, indicating increased extent and decreased rate of absorption. The results for the four metabolites (M2, M3, M4, and M8) were consistent with the Cmax, AUC, and Tmax of the parent compound, with the exception of M8, whose mean Tmax decreased under fed conditions.

[0240] Based on the comparison of the two dose groups under fed conditions, the ratio of the geometric mean Cmax to AUC(inf) was close to 2.0 in all comparisons, indicating dose proportionality for both capsules. Based on the comparison of the two dose groups under fed conditions, the ratio of the geometric mean Cmax indicated less dose proportionality for trodipitant and its four metabolites. For trodipitant, the AUC(inf) was similar to the dose proportionality, but the AUC(inf) ratios for the four metabolites were smaller.

[0241] ***

[0242] As used herein, the terms "first", "second" and the like do not represent any order, quantity or importance, but are used to distinguish one element from another element, and the terms "one" and "an" herein do not represent a limit on quantity, but represent that there is at least one cited item. The modifier "about" used when representing a quantity includes the specified value, and its meaning is determined by the context (for example, including the degree of error associated with the measurement of a specific quantity). The suffix "(s)" used in this article is intended to include the singular and plural of its modifiers, thereby including one or more of the words (for example, metal includes one or more metals). The scopes disclosed herein are inclusive and can be independently combined (for example, the scope of "up to about 25 mm, or more specifically, the scope of about 5 mm to about 20 mm" includes the endpoints and all intermediate values ​​of the scope of "about 5 mm to about 25 mm", etc.).

[0243] Although various embodiments are described herein, it will be appreciated from this disclosure that various combinations, modifications, or improvements of the elements herein may be made by those skilled in the art, and all such modifications are within the scope of the present invention. Furthermore, many modifications may be made to adapt a particular situation or material to the teachings of the present invention without departing from the basic scope of the present invention. Therefore, the present invention is not limited to the particular embodiments disclosed, but includes all embodiments falling within the scope of the appended claims.

Claims

1. A method of administering tridipitant to a subject in need thereof, comprising: determining the CYP3A4 genotype of the individual; and administering tridipitant to the individual at a first dose if the individual has a CYP3A4 genotype associated with normal metabolism of tridipitant; and If the individual has a CYP3A4 genotype associated with reduced metabolism of tridipitant compared to wild type, tridipitant is administered at a second dose, wherein the second dose is less than the first dose.

2. The method according to claim 1, wherein CYP3A4 genotypes associated with reduced trodipitant metabolism compared to wild-type included at least one *22 allele.

3. The method according to claim 1, wherein CYP3A4 genotypes associated with reduced trodipitant metabolism compared to wild-type include two *22 alleles.

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

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

6. The method of claim 1, wherein: The first dose is about 100 mg to 400 mg.

7. The method of claim 1, wherein: The first dose is about 85 mg.

8. A method for determining an effective amount of tridipitant for administration to an individual in need thereof, comprising: determining a CYP3A4 genotype of the individual from a biological sample; and if the individual has a CYP3A4 genotype associated with normal metabolism of tridipitant, determining the effective amount of tridipitant to be a first dose; and If the individual has a CYP3A4 genotype associated with reduced metabolism of tridipitant compared to wild type, determining the effective amount of tridipitant to be the second dose, wherein the second dose is less than the first dose.

9. The method of claim 8, wherein: CYP3A4 genotypes associated with reduced trodipitant metabolism compared to wild-type included at least one *22 allele.

10. The method of claim 8, wherein: CYP3A4 genotypes associated with reduced trodipitant metabolism compared to wild-type include two *22 alleles.

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

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

13. The method of claim 8, wherein: The first dose is about 100 mg to 400 mg.

14. The method of claim 8, wherein: The first dose is about 85 mg.

15. A method of administering tridipitant to a subject in need thereof, comprising: A solid dosage form comprising tridipitant and one or more pharmaceutically acceptable excipients is orally administered to the subject in a fasting state.

16. The method of claim 15, further comprising: The subjects were instructed to fast for at least 30 minutes prior to administration.

17. The method of claim 15, further comprising: The subjects were instructed to fast for at least 1 hour prior to administration.

18. The method of claim 15, further comprising: The subjects were instructed to fast for at least 2 hours prior to administration.

19. The method of claim 15, further comprising: The subjects were instructed to fast for at least 4 hours prior to administration.

20. The method of claim 15, further comprising: The subjects were instructed to fast for at least 8 hours prior to administration.

21. The method of claim 15, further comprising: The subjects were instructed to fast for at least 10 hours prior to administration.

22. The method of claim 15, further comprising: The subject is instructed to fast for at least 0.5 hours to 1.5 hours prior to administration.

23. The method of claim 15, further comprising: The subjects were instructed to fast for at least 30 minutes after administration.

24. The method of claim 15, further comprising: The subjects were instructed to fast for at least 1 hour after administration.

25. The method of claim 15, further comprising: The subjects were instructed to fast for at least 2 hours after administration.

26. The method of claim 15, further comprising: The subjects were instructed to fast for at least 4 hours after administration.

27. The method of claim 15, further comprising: The subject is instructed to fast for at least 2 to 2.5 hours after administration.

28. The method of claim 15, wherein: The solid dosage form contains tredipitant in an amount of 100 mg to 400 mg.

29. The method of claim 15, wherein: The solid dosage form contains tridipitant in an amount of 150 mg to 400 mg.

30. The method of claim 15, wherein: The solid dosage form contains 170 mg of tridipitant.

31. The method of claim 15, wherein: The solid dosage form contains 85 mg of tridipitant.

32. The method of claim 15, wherein: The solid dosage forms include capsules or tablets.

33. A method of administering tridipitant to a subject in need thereof, comprising: determining the CYP3A4 genotype of the individual; and If the individual has a CYP3A4 genotype associated with normal metabolism of tridipitant, orally administering to the individual in a fasting state a solid dosage form comprising a first dose of tridipitant and one or more pharmaceutically acceptable excipients, and if the individual has a CYP3A4 genotype associated with reduced metabolism of tridipitant compared to wild type, orally administering to the individual in a fasted state a solid dosage form comprising a second dose of tridipitant and one or more pharmaceutically acceptable excipients, wherein the second dose is less than the first dose.

34. The method of claim 33, wherein: CYP3A4 genotypes associated with reduced trodipitant metabolism compared to wild-type included at least one *22 allele.

35. The method of claim 33, wherein: CYP3A4 genotypes associated with reduced trodipitant metabolism compared to wild-type include two *22 alleles.

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

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

38. The method of claim 33, wherein: The first dose is about 100 mg to 400 mg.

39. The method of claim 33, wherein: The first dose is about 85 mg.

40. The method of claim 33, further comprising: The subjects were instructed to fast for at least 30 minutes prior to administration.

41. The method of claim 33, further comprising: The subjects were instructed to fast for at least 1 hour prior to administration.

42. The method of claim 33, further comprising: The subjects were instructed to fast for at least 2 hours prior to administration.

43. The method of claim 33, further comprising: The subjects were instructed to fast for at least 4 hours prior to administration.

44. The method of claim 33, further comprising: The subjects were instructed to fast for at least 8 hours prior to administration.

45. The method of claim 33, further comprising: The subjects were instructed to fast for at least 10 hours prior to administration.

46. ​​The method of claim 33, further comprising: The subject is instructed to fast for at least 0.5 hours to 1.5 hours prior to administration.

47. The method of claim 33, further comprising: The subjects were instructed to fast for at least 30 minutes after administration.

48. The method of claim 33, further comprising: Instruct subjects to fast for at least 1 hour after administration.

49. The method of claim 33, further comprising: Instruct subjects to fast for at least 2 hours after administration.

50. The method of claim 33, further comprising: Instruct subjects to fast for at least 4 hours after administration.

51. The method of claim 33, further comprising: Instruct subjects to fast for at least 2 hours to 2.5 hours after administration.

52. The method of claim 33, wherein: The solid dosage forms include capsules or tablets.

53. A method of administering tridipitant to a subject in need thereof, comprising: determining an effective amount of tridipitant for administration to the individual, wherein the effective amount depends on whether the individual is fasting prior to administration; and Tridipitant is administered as a solid immediate-release dosage form comprising an effective amount of tridipitant and one or more pharmaceutically acceptable excipients.

54. The method of claim 53, wherein: If the subject is in a fasting state at the time of administration, the effective amount of tridipitant is a first effective amount, and wherein if the subject is in a fed state at the time of administration, the effective amount of tridipitant is a second effective amount.

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

56. The method of claim 53, wherein The individual is experiencing an acute manifestation of a disease or condition responsive to tripitant.

57. The method of claim 53, wherein: The individual is experiencing a chronic manifestation of a trodipitant-responsive disease or condition.

58. A method of determining an effective amount of tridipitant for administration to an individual in need thereof, comprising: The effective amount is determined based on whether the subject is in the fasting or fed state at the time of administration.

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