Combination Migraine Therapies Containing Atogepant

Abstract

The present disclosure provides methods for treating migraine headaches by administering atogepant or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] The present disclosure relates to medicaments and methods for treating migraine headaches. [Background technology]

[0002] Migraine is a neurological condition with high prevalence, severity and disability, and there is a large unmet need for effective treatments (Holland, PR & Goadsby, PJ Neurotherapeutics (2018)). The number of migraine sufferers worldwide exceeds 1 billion, and it is reported to be the second leading cause of disability in daily life in the 2016 Global Burden of Disease study. See GBD 2019 Diseases and Injuries Collaborators. Global Burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systemic analysis for the Global Burden of Disease Study 2019, Lancet 2020; 396: 1204-22.

[0003] Prevention is the focus of migraine treatment when attacks become frequent or disruptive to daily life. Current preventive treatments for migraine include oral medications such as valproic acid, flunarizine, topiramate, and propranolol, as well as injectable therapies such as monoclonal antibodies targeted to calcitonin gene-related peptide (CGRP). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Holland,PR& Goadsby,PJ Neurotherapeutics(2018) [Non-Patent Document 2] 2016 Global Burden of Disease study [Non-Patent Document 3] GBD 2019 Diseases and Injuries Collaborators.Global Burden of 369 diseases and injuries in 204 countries and territories,1990-2019:a systemic analysis for the Global Burden of Disease Study 2019,Lancet 2020;396:1204-22 Summary of the Invention [Problem to be solved by the invention]

[0005] There remains a need for targeted methods and dosing regimens for the use of oral CGRP therapeutics to prophylactically treat migraine headaches. [Means for solving the problem]

[0006] In an embodiment, the disclosure provides a method for prophylactically treating migraine in a patient, the patient receiving concomitant treatment with a strong CYP3A4 inhibitor, the method comprising administering 10 mg of atogepant once daily.

[0007] In an embodiment, the disclosure provides a method for prophylactic treatment of migraine in a patient, wherein the patient is receiving concomitant treatment with a moderate or strong CYP3A4 inducer, the method comprising administering 30 mg or 60 mg of atogepant once daily.

[0008] In embodiments, the disclosure provides a method for prophylactically treating migraine in a patient, the patient receiving concomitant treatment with an OATP inhibitor, the method comprising administering atogepant 10 mg or 30 mg once daily.

[0009] In embodiments, the disclosure provides a method for prophylactically treating migraine in a patient, the patient having severe renal impairment or end stage renal failure (CLcr<30 mL / min), the method comprising administering 10 mg of atogepant once daily. [Brief description of the drawings]

[0010] [Figure 1] 1 shows the mean plasma atogepant concentration-time profiles following administration of atogepant alone or in combination with a single dose of rifampin to fasting healthy participants. [Diagram 2] 1 shows the mean plasma atogepant concentration-time profiles following oral administration of atogepant alone or in combination with multiple doses of rifampin to fasting healthy participants. [Diagram 3] Mean plasma atogepant concentrations are shown following administration of 60 mg atogepant alone or in the steady-state presence of itraconazole, a strong CYP3A4 inhibitor. [Figure 4] FIG. 1 shows a semi-log plot of mean plasma atogepant concentrations after administration of 60 mg atogepant alone or in the presence of steady-state itraconazole. [Diagram 5] Figure 5A shows the mean plasma atogepant concentration-time profiles (linear scale) following a single oral dose of 60 mg atogepant in participants with mild, moderate, or severe hepatic impairment and participants with normal hepatic function (N=8 per group). Figure 5B shows the corresponding semi-log plot. Figure 5A shows the complete profile out to 72 hours, and Figure 5B shows the partial profile out to 8 hours. [Figure 6] Figure 1 shows the mean change from baseline in monthly migraine days in Study 1 (NCT03777059). [Figure 7] The distribution of changes from baseline in mean monthly migraine days (MMD) throughout the 12-week treatment period in Study 1 is shown in 2-day increments by treatment group. [Figure 8]The mean change from baseline in MMD in Study 2 (NCT02848326) is shown. [Figure 9] The distribution of mean MMD change from baseline over the 12-week treatment period in Study 2 is shown in 2-day increments by treatment group. All doses of atogepant demonstrate treatment efficacy superior to placebo within the ranges of mean MMD change from baseline. [Figure 10] Mean plasma atogepant concentration-time profiles following a single dose of one atogepant 60 mg IR tablet formulation under fed and fasted conditions (linear scale ± SD, inset semi-log scale). [Figure 11] Box plots of AUC0-t and AUC0-inf after a single administration of one tablet of atogepant 60 mg IR tablet formulation under fed and fasted conditions are shown. [Figure 12] Box plots of Cmax following single administration of one atogepant 60 mg IR tablet formulation under fed and fasted conditions. [Figure 13] The study design and dosing schedule of an open-label, single-center, multiple-dose, two-cohort, Phase 1 study to evaluate potential DDIs of atogepant and topiramate in healthy adult participants are presented. [Figure 14] Mean steady-state plasma atogepant concentrations after administration alone and in combination with topiramate are shown on linear and semi-log scales. [Figure 15] Mean (±SD) steady-state plasma atogepant concentrations when administered alone and in combination with topiramate are shown on linear and semi-log scales. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present disclosure provides a method for treating migraine in a patient in need of such treatment. In embodiments, the present disclosure provides a method for prophylactically treating a migraine patient. In embodiments, the present disclosure provides a method for prophylactically treating episodic migraine. In embodiments, the present disclosure provides a method for treating migraine (e.g., prophylactically treating episodic migraine) comprising administering a prophylactically effective amount of atogepant or a pharma- ceutically acceptable salt thereof. Atogepant's chemical name is (3'S)-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide and has the following structural formula:

[0012] [ka]

[0013] Atogepant is a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist that can be administered orally, for example, as a tablet. In embodiments, atogepant is administered for the prophylactic treatment of migraine headaches, such as episodic migraine headaches. In embodiments, atogepant is administered in a once-daily dose of 10 mg, 30 mg, or 60 mg for the prophylactic treatment of episodic migraine headaches.

[0014] After oral administration, atogepant is absorbed and reaches peak plasma concentrations in approximately 1 to 2 hours. After once-daily dosing, atogepant exhibits dose-proportional pharmacokinetics up to 170 mg and does not accumulate.

[0015] When atogepant was administered with a high-fat meal, the food effect was not significant (AUC and C max (The median time to peak plasma atogepant concentration was decreased by approximately 18% and 22%, respectively, with no effect on the median time to peak plasma atogepant concentration.) In embodiments, atogepant can be administered without regard to food.

[0016] Plasma protein binding of atogepant was concentration-independent in the range of 0.1-10 μM, and the unbound fraction of atogepant was approximately 4.7% in human plasma. The mean apparent volume of distribution (Vz / F) of atogepant after oral administration was approximately 282 L.

[0017] Atogepant is eliminated primarily through metabolism, with CYP3A4 as the primary pathway. The parent compound (atogepant) and the glucuronide metabolite (M23) were the most predominant circulating components in human plasma. The elimination half-life of atogepant is approximately 11 hours. The mean apparent oral clearance (CL / F) of atogepant is approximately 19 L / hr. In healthy male subjects, 14 Following a single oral dose of 50 mg of C-atogepant, 42% and 5% of the administered dose was recovered in the feces and urine, respectively, as unchanged atogepant.

[0018] In vitro, atogepant is not an inhibitor of CYP3A4, 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6 at clinically relevant concentrations. Atogepant does not inhibit MAO-A or UGT1A1 at clinically relevant concentrations. Atogepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

[0019] Atogepant is a substrate of P-gp, BCRP, OATP1B1, OATP1B3, and OAT1. Atogepant is not an inhibitor of P-gp, BCRP, OAT1, OAT3, NTCP, BSEP, MRP3, or MRP4 at clinically relevant concentrations. Atogepant is a weak inhibitor of OATP1B1, OATP1B3, OCT1, and MATE1.

[0020] The terms "concurrent" / "parallel" and "concurrent" / "concurrently" all include (1) simultaneous in time (e.g., at the same time point) and (2) different times during the course of a common treatment schedule.

[0021] Concomitant use of atogepant and a CYP3A4 inhibitor Coadministration of atogepant with itraconazole, a strong CYP3A4 inhibitor, resulted in a significant increase in atogepant exposure in healthy subjects. Coadministration of atogepant with itraconazole resulted in a clinically significant increase in atogepant exposure in healthy subjects (2.15-fold Cmax and 5.5-fold AUC). Population pharmacokinetic modeling suggested that coadministration of atogepant with moderate CYP3A4 inhibitors (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) or weak CYP3A4 inhibitors (e.g., cimetidine, esomeprazole) increased atogepant AUC by 1.7-fold and 1.1-fold, respectively. Changes in atogepant exposure when coadministered with weak or moderate CYP3A4 inhibitors are not expected to be clinically significant.

[0022] In embodiments, the disclosure provides methods for the prophylactic treatment of migraine (eg, prophylactic treatment of episodic migraine) when atogepant is used in combination with a strong CYP3A4 inhibitor (eg, ketoconazole, itraconazole, clarithromycin).

[0023] In an embodiment, the disclosure provides a method for prophylactically treating migraine (e.g., prophylactically treating episodic migraine) in a patient receiving concomitant treatment with a strong CYP3A4 inhibitor, the method comprising administering 10 mg of atogepant once daily. In an embodiment, the CYP3A4 inhibitor is ketoconazole, itraconazole, or clarithromycin. In an embodiment, co-administration of 10 mg of atogepant with the strong CYP3A4 inhibitor results in an increase in atogepant Cmax of less than 2.15-fold compared to administration of atogepant alone. In an embodiment, co-administration of 10 mg of atogepant with the strong CYP3A4 inhibitor (e.g., itraconazole) results in an increase in atogepant AUC of 5.5-fold or less compared to administration of atogepant alone. In an embodiment, atogepant is administered with or without food. In embodiments, the CYP3A4 inhibitor can be administered before, simultaneously with, or after administration of atogepant.

[0024] In embodiments, the disclosure provides a method for prophylactically treating migraine (e.g., prophylactically treating episodic migraine) in a patient, the method comprising administering 10 mg or 30 mg or 60 mg of atogepant once daily, and if the patient initiates concomitant treatment with a strong CYP3A4 inhibitor, adjusting the dose of atogepant to 10 mg once daily. In embodiments, the CYP3A4 inhibitor can be administered before, simultaneously with, or after administration of atogepant.

[0025] In an embodiment, the present disclosure provides a method for prophylactically treating migraine (e.g., prophylactically treating episodic migraine) in a patient receiving concomitant treatment with a moderate CYP3A4 inhibitor, the method comprising administering atogepant 10 mg, 30 mg, or 60 mg once daily. In an embodiment, the moderate CYP3A4 inhibitor is cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, and grapefruit juice. In an embodiment, co-administration of atogepant with the moderate CYP3A4 inhibitor results in an increase in atogepant AUC of about 1.7-fold or less compared to administration of atogepant alone. In an embodiment, atogepant is administered orally with or without food. In an embodiment, the CYP3A4 inhibitor can be administered before, simultaneously with, or after administration of atogepant.

[0026] In an embodiment, the disclosure provides a method for prophylactically treating migraine (e.g., prophylactically treating episodic migraine) in a patient receiving concomitant treatment with a weak CYP3A4 inhibitor, the method comprising administering 10 mg, 30 mg, or 60 mg of atogepant. In an embodiment, the weak CYP3A4 inhibitor is cimetidine or esomeprazole. In an embodiment, co-administration of 10 mg, 30 mg, or 60 mg of atogepant with the weak CYP3A4 inhibitor results in an increase in AUC of about 1.1-fold or less compared to administration of atogepant alone. In an embodiment, atogepant is administered orally with or without food. In an embodiment, the CYP3A4 inhibitor can be administered before, simultaneously with, or after administration of atogepant.

[0027] Concomitant administration of atogepant and CYP3A4 inducers Coadministration of atogepant with rifampin, a strong CYP3A4 inducer, decreased the AUC and Cmax of atogepant by 60% and 30%, respectively, in healthy subjects. Moderate inducers of CYP3A4 can decrease atogepant exposure.

[0028] In an embodiment, the present disclosure provides a method for prophylactically treating migraine (e.g., prophylactically treating episodic migraine) in a patient receiving concomitant treatment with a strong or moderate CYP3A4 inducer, the method comprising administering 30 mg or 60 mg of atogepant. In an embodiment, the strong CYP3A4 inducer is rifampin, carbamazepine, phenytoin, St. John's Wort, efavirenz, or etravirine. In an embodiment, atogepant is co-administered with the CYP3A4 inducer until steady state is reached with the CYP3A4 inducer. In an embodiment, co-administration of 30 mg or 60 mg of atogepant with the moderate or strong CYP3A4 inducer reduces atogepant AUC by less than about 60% compared to administration of atogepant alone. In embodiments, co-administration with the moderate or strong CYP3A4 inducer reduces atogepant Cmax by less than about 30% compared to administration of atogepant alone. In embodiments, atogepant is administered orally with or without food. In embodiments, the CYP3A4 inducer can be administered before, simultaneously with, or after administration of atogepant.

[0029] In embodiments, the disclosure provides a method for prophylactic treatment of migraine (e.g., prophylactic treatment of episodic migraine) in a patient receiving concomitant treatment with a weak CYP3A4 inducer, the method comprising administering 10 mg, 30 mg, or 60 mg of atogepant. In embodiments, atogepant is administered orally with or without food. In embodiments, the CYP3A4 inducer can be administered before, simultaneously with, or after administration of atogepant.

[0030] For example, in an embodiment, the disclosure provides a method for the prophylactic treatment of migraine (e.g., prophylactic treatment of episodic migraine) in a patient undergoing concurrent treatment with topiramate, a weak CYP3A4 inducer. Topiramate is a widely prescribed oral antiepileptic drug approved by the FDA and the European Medicines Agency (EMA) for the prophylactic treatment of migraine (100 mg per day in two divided doses) in individuals 12 years of age or older. Topiramate suppresses voltage-gated sodium channels, inhibits carbonic anhydrase, inhibits α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, and enhances the inhibition by γ-aminobutyric acid. Topiramate is a weak inducer of CYP3A4 activity and has a long elimination half-life of about 21 hours, while atogepant is extensively metabolized by CYP3A4 as the main pathway and CYP2D6 as the minor pathway, with an elimination half-life of about 11 hours.

[0031] In embodiments, the disclosure provides a method for treating migraine, particularly for the prophylactic treatment of migraine (e.g., prophylactic treatment of episodic migraine), the method comprising administering topiramate and atogepant. In embodiments, atogepant is administered with or without food. In certain embodiments, topiramate is administered before, simultaneously with, or after administration of atogepant. In embodiments, atogepant is administered once daily at a dose of 10 mg, or 30 mg, or 60 mg. In certain embodiments, topiramate is administered at a dose of about 1 to about 300 mg, e.g., about 25 mg to about 200 mg. In embodiments, topiramate is administered at a dose of about 25 mg, or about 50 mg, or about 100 mg, or about 200 mg. In embodiments, topiramate is administered at a dose of about 100 mg / day. In embodiments, topiramate is administered in two divided doses. In embodiments, topiramate is administered at a dose of 25 mg twice daily (e.g., morning and evening), or 25 mg in the morning and 50 mg in the evening, or 50 mg in the morning and 25 mg in the evening, or 50 mg twice daily (e.g., morning and evening). In embodiments, coadministration of topiramate and atogepant reduces atogepant AUC 0-tau,ss was reduced by approximately 25%, and Atogepant C max,ss will decrease by approximately 24%.

[0032] Concomitant use of atogepant and OATP inhibitors Coadministration of atogepant with a single dose of the OATP inhibitor rifampin increased the AUC and Cmax of atogepant by 2.85-fold and 2.23-fold, respectively, in healthy subjects.

[0033] In an embodiment, the present disclosure provides a method for prophylactically treating migraine (e.g., prophylactically treating episodic migraine) in a patient receiving concomitant treatment with an OATP inhibitor, the method comprising administering 10 mg or 30 mg of atogepant once daily. In an embodiment, administering 10 mg or 30 mg of atogepant in combination with an OATP inhibitor results in an increase in atogepant AUC of about 2.8-fold or less compared to administration of atogepant alone. In an embodiment, administering 10 mg or 30 mg of atogepant in combination with an OATP inhibitor results in an increase in atogepant Cmax of about 2.2-fold or less compared to administration of atogepant alone. In an embodiment, atogepant is administered orally with or without food. In an embodiment, the OATP inhibitor can be administered before, simultaneously with, or after administration of atogepant.

[0034] Atogepant and rifampin combination As mentioned above, atogepant is metabolized primarily by CYP3A4 and alternatively by CYP2D6, and is also a substrate for several membrane transporters, including P-gp and OATP1B1. Rifampin is an inducer of both CYP3A4 and P-gp, and is also an in vitro inhibitor of OATP.

[0035] The inventors have demonstrated that a single dose of 60 mg of atogepant combined with a single dose of 600 mg of rifampin significantly reduces the AUC 0-24 and C. max It was confirmed that the C of Atogepant increased by 2.85 times and 2.23 times, respectively. maxThese increases in C and AUC of atogepant following coadministration with a single dose of rifampin are believed to be clinically significant. max and AUC 0-24 The increase in atogepant indicates inhibition of the hepatic uptake transporter OATP by rifampin, resulting in a decrease in the hepatocyte metabolic availability of atogepant, leading to an increase in the plasma concentration of atogepant.

[0036] The present inventors further demonstrated that a single dose of 60 mg of atogepant combined with multiple doses of 600 mg of rifampin significantly increased the AUC 0-inf and AUC 0-t decreased by 61% and 60%, respectively, while C max Without wishing to be bound by theory, the C of atogepant after coadministration with multiple doses of rifampin was found to be reduced by 30%. max The decrease in AUC and AUC indicates induction of P-gp and CYP3A4, which may result in a decreased absorption rate and an increased metabolic rate of atogepant, respectively. The total body clearance was 22.8 L / h after atogepant administration alone, but increased to 58.3 L / h after atogepant administration in the setting of repeated rifampin doses. Without wishing to be bound by any particular theory, T 1 / 2 The shortening of the elimination time indicates induction of CYP3A4 by rifampin, which is thought to lead to an increase in the rate of elimination of atogepant from plasma and an increase in the slope of the terminal elimination phase. Although rifampin still tends to inhibit OATP 5 days after administration, overall, the inductive effect on CYP3A4 and P-gp exceeds the inhibition of OATP, so atogepant exposure is reduced under repeated administration of rifampin.

[0037] The present disclosure provides a method for preventing migraine in a patient, the method comprising administering atogepant 10 mg, 30 mg, or 60 mg once daily, and when the patient is co-administered with multiple doses of rifampin, the patient is administered atogepant 30 mg or 60 mg once daily. When atogepant is administered in combination with a single dose of rifampin, the AUC 0-24 and C. max 2.85-fold and 2.23-fold, respectively, whereas in an embodiment, when the patient is administered multiple doses of rifampin, 30 mg or 60 mg of ategepant is administered once a day. In an embodiment, administration of 30 mg or 60 mg of ategepant once a day in combination with multiple doses of rifampin results in a decrease in ategepant AUC of about 60% or less compared to administration of ategepant alone. In an embodiment, administration of 30 mg or 60 mg of ategepant once a day in combination with multiple doses of rifampin results in a decrease in ategepant Cmax of about 30% compared to administration of ategepant alone. In an embodiment, ategepant is administered orally with or without food. In an embodiment, rifampin can be administered before, simultaneously with, or after administration of ategepant.

[0038] In an embodiment, the disclosure provides a method for preventing migraine in a patient receiving concurrent treatment with a drug that is a strong CYP3A4 inducer and an OATP inhibitor, the method comprising administering 30 mg or 60 mg of atogepant once daily. In an embodiment, administering 30 mg or 60 mg of atogepant once daily in combination with multiple doses of a CYP3A4 inducer / OATP inhibitor results in a decrease in atogepant AUC of about 60% or less compared to administration of atogepant alone. In an embodiment, administering 30 mg or 60 mg of atogepant once daily in combination with multiple doses of a CYP3A4 inducer / OATP inhibitor results in a decrease in atogepant Cmax of about 30% or less compared to administration of atogepant alone. In an embodiment, atogepant is administered orally with or without food.

[0039] Method for the prophylactic treatment of migraine headaches in patients with renal impairment The renal elimination pathway plays a minor role in the clearance of atogepant. Using a population pharmacokinetic analysis based on estimated creatinine clearance (CLcr), we determined that there were no significant differences in the pharmacokinetics of atogepant between patients with mild or moderate renal impairment (CLcr 30-89 mL / min) and those with normal renal function (CLcr > 90 mL / min).

[0040] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine in patients with mild renal impairment (glomerular filtration rate [GFR] 60-90 mL / min), the method comprising administering 10 mg, 30 mg, or 60 mg of atogepant once daily. In embodiments, atogepant is administered orally with or without food. In embodiments, administration of 10 mg, 30 mg, or 60 mg of atogepant once daily to patients with mild renal impairment results in a reduction in atogepant C compared to patients with normal renal function. max is increased by less than about 20%, e.g., less than about 15%, or less than about 13%. In embodiments, administration of 10 mg or 30 mg or 60 mg of atogepant once daily to a patient with mild renal impairment results in an increase in the 24-hour AUC of atogepant of less than about 30%, e.g., less than about 25%, or less than about 20%.

[0041] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine in a patient with moderate renal impairment (GFR 30-60 mL / min), the method comprising administering 10 mg, 30 mg, or 60 mg of atogepant once daily. In an embodiment, atogepant is administered orally with or without food. In an embodiment, administration of 10 mg, 30 mg, or 60 mg of atogepant once daily to a patient with moderate renal impairment results in a reduction in atogepant C compared to a patient with normal renal function. max is increased by less than about 20%, e.g., less than about 15%, or less than about 13%. In embodiments, administration of 10 mg or 30 mg or 60 mg of atogepant results in an increase in the 24-hour AUC of atogepant of less than about 50%, or less than about 45%, compared to patients with normal renal function.

[0042] In embodiments, atogepant dose adjustment may be required in patients with severe renal impairment (CLcr 15-29 mL / min) or end stage renal failure (CLcr<30 mL / min). In embodiments, the present disclosure provides a method for prophylactically treating migraine in patients with severe renal impairment (CLcr 15-29 mL / min), the method comprising administering 10 mg of atogepant once daily to a patient with severe renal impairment (CLcr 15-29 mL / min). In embodiments, the present disclosure provides a method for prophylactically treating migraine in patients with end stage renal failure (CLcr<30 mL / min), the method comprising administering 10 mg of atogepant once daily to a patient with end stage renal failure. In embodiments, atogepant is administered orally with or without food.

[0043] Method for the prophylactic treatment of migraine in patients with liver dysfunction In embodiments, the present disclosure provides a method of safely administering atogepant to patients with mild or moderate hepatic impairment for the prophylactic treatment of migraine headaches, such as episodic migraine headaches. In embodiments, the hepatic impairment is pre-existing.

[0044] The term "liver impairment" refers to a scoring based on Child-Pugh scores A, B, and C. In embodiments, mild liver impairment refers to Child-Pugh classification A, moderate liver impairment refers to Child-Pugh classification B, and severe liver impairment refers to Child-Pugh classification C.

[0045] Patients with pre-existing mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment were found to have increased total atogepant exposure by 24%, 15%, and 38%, respectively.

[0046] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine in a patient with mild or moderate hepatic impairment, the method comprising administering atogepant 10 mg, 30 mg, or 60 mg once daily, in embodiments, the atogepant is administered with or without food.

[0047] In embodiments, the disclosure provides a method for the prophylactic treatment of migraine in a patient with hepatic impairment, the method comprising administering 10 mg or 30 mg or 60 mg once daily, and discontinuing atogepant administration if the patient develops severe hepatic impairment (Child-Pugh class C).

[0048] Transaminase Elevations in Patients Treated with Atogepant Compared to Placebo In embodiments, the present disclosure provides a method for prophylactic treatment of migraine (e.g., prophylactic treatment of episodic migraine), the method comprising administering atogepant, wherein the administration of atogepant does not significantly affect liver enzyme levels, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

[0049] In embodiments, the disclosure provides a method for the prophylactic treatment of migraine in a patient population, the method comprising administering atogepant 10 mg or 30 mg or 60 mg once daily to the patient population, wherein the rate of transaminase rise above 3 times the upper limit of normal (ULN) in the patient population is lower than the rate of transaminase rise above 3 times the upper limit of normal in a patient population administered a placebo. In embodiments, atogepant is administered to the patient population for at least 3 weeks, or at least about 6 weeks, or at least about 9 weeks, or at least about 12 weeks, or at least about 16 weeks, or at least about 20 weeks, or at least about 24 weeks, or at least about 52 weeks, wherein the rate of transaminase rise above 3 times the upper limit of normal (ULN) in the patient population is lower than the rate of transaminase rise above 3 times the upper limit of normal in a patient population administered a placebo.

[0050] food action As discussed above, the present disclosure provides a method for the prophylactic treatment of migraine (e.g., prophylactic treatment of episodic migraine) by administering 10 mg, 30 mg, or 60 mg of atogepant once daily to a patient in need of such treatment. In embodiments, atogepant can be administered regardless of whether the patient has eaten, which may also be expressed in terms such as "without food," "can be taken with or without food," "no food effect," and the like.

[0051] More specifically, the inventors of the present disclosure have determined that, although a statistically significant food effect on the pharmacokinetics of atogepant is demonstrated, this food effect is not clinically meaningful and patients can take atogepant with or without food, thus providing the advantage that atogepant can be administered at any time, regardless of whether the patient has recently eaten or not.

[0052] Generally, the fasted state refers to the fact that the patient has not eaten for a certain time before taking the drug, and has not eaten for a certain time after taking the drug. These times before and after taking the drug can be, for example, 2 hours to 24 hours. The fed state generally refers to the fact that the patient has eaten within a certain time period after taking a particular drug. The above times can vary, but can be, for example, a meal just before taking the drug, during taking the drug, or just after taking the drug, for example, within about 1 hour of taking the drug. The amount of food intake that corresponds to the fed state can also vary, but can generally include about 500 to about 1500 kcal of food. EXAMPLES

[0053] [Example 1] A single-center, phase 1, open-label, two-arm, two-period, single-sequence, non-randomized crossover interaction study between atogepant and rifampin was conducted in 32 healthy adult male or female participants aged 18 to 45 years.

[0054] The study consisted of a screening visit, two study periods, an end-of-treatment (EOT) visit, and a follow-up visit. As described in Table 1, participants received a total of three doses of atogepant during the first and second study periods, separated by two rest periods.

[0055] [Table 1]

[0056] Study endpoints included blood sampling to assess plasma PK of atogepant and plasma trough concentrations of rifampin.In addition, safety and tolerability of atogepant, both alone and in combination with rifampin, were monitored throughout the study by clinical assessment of AEs, vital signs, physical examination, 12-lead ECG, and laboratory tests (hematology, serum chemistry, and urinalysis).

[0057] Excluding screening, expected duration of study participation was up to 46 days (from day -1 to the follow-up visit on day 43 (± 2 days)).

[0058] The inclusion criteria were BMI of 18 kg / m 2 More than 30kg / m 2 Participants were healthy male or female participants aged 18-45 years, who were non-smokers and non-users of nicotine-containing products, and had a negative urine drug screen.

[0059] Participants were excluded from the study if, in the opinion of the investigator or his / her designee, they had any clinically significant disease state or a medical or surgical history that may have affected the absorption, distribution, biotransformation, or excretion of atogepant or rifampin.Participants also had no history of alcohol or other substance abuse within the past 5 years.

[0060] The study drugs administered (atogepant and rifampin) and the administration regimens (administration A, administration B1, and administration B2) are as follows: Treatment A: A single dose of atogepant 60 mg (one 60 mg tablet) was administered on day 1. Treatment B1: Atogepant 60 mg and rifampin 600 mg (two 300 mg capsules) were administered concomitantly on the 7th day, and rifampin 600 mg was administered alone once daily on the 8th, 9th, 10th, and 11th days. Treatment B2: Atogepant 60 mg and rifampin 600 mg were administered in combination on the 12th day, and rifampin 600 mg was administered alone on the 13th day.

[0061] The atogepant withdrawal period was 6 days between doses A and B1, and 5 days between doses B1 and B2.

[0062] The analysis populations used to analyze the data from this study were the following three populations: The safety population consisted of all participants who received at least one dose of study drug. The atogepant PK population consisted of all participants in whom atogepant PK parameters were evaluable after all doses (doses A, B1, and B2). The rifampin PK population consisted of all participants with measurable rifampin plasma concentrations.

[0063] The mean age of participants in the safety population was 31.3 years. There was a higher proportion of female participants than male participants (59.4% compared with 40.6%). White and Black or African American participants made up 50.0% and 46.9% of the safety population, respectively, with one (3.1%) being Asian. Nineteen participants (59.4%) were non-Hispanic and 13 (40.6%) were Hispanic. The mean BMI in the safety population was 25.67 kg / m 2 It was.

[0064] When atogepant was administered alone or in combination with rifampin, participants were required to fast overnight for 10 hours before dosing (starting on day -1, days 6, and 11) and to continue fasting for an additional 4 hours after dosing (days 1, 7, and 12).

[0065] When rifampin was administered alone (days 8, 9, 10, 11, and 13), food was withheld for 1 hour before and 1 hour after dosing.

[0066] All study medications were administered with approximately 240 mL of water, and participants were hydrated as desired at all times except 1 hour before and after dosing.

[0067] Blood samples for atogepant plasma PK were collected at the following times starting from the time of atogepant administration: Days 1 and 12: 0 hours (pre-dose) and 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, 36 hours, and 48 hours after dosing. Day 7: 0 hours (pre-dose) and 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, and 24 hours after dosing.

[0068] Blood samples for rifampin plasma trough concentrations were collected at the following time points: Days 11 and 12: 0 hours before rifampin administration (pre-dose).

[0069] The mean plasma atogepant concentration-time profiles are shown in Figures 1 and 2. In particular, Figure 1 shows the mean plasma atogepant concentration-time profiles after administration of atogepant alone (control, dose A) or in combination with a single dose of rifampin (study, dose B1) to fasted healthy participants. Figure 2 shows the mean plasma atogepant concentration-time profiles after oral administration of atogepant alone (control, dose A) or in combination with multiple doses of rifampin (study, dose B2) to fasted healthy participants.

[0070] The mean PK parameters of atogepant when administered alone or in combination with rifampin are summarized in Table 2.

[0071] [Table 2]

[0072] When comparing atogepant alone and in combination with single or multiple doses of rifampin (doses B1 and B2, respectively), the T max The median values ​​were similar. The apparent T of atogepant was significantly higher after atogepant alone than after combination therapy with multiple doses of rifampin. 1 / 2 The average reduction in sleep time was approximately 9 hours (2.39 hours compared to 11.4 hours).

[0073] Treatment B1 / treatment A: When a single dose of atogepant 60 mg combined with a single dose of rifampin 600 mg (test) was compared with a single dose of atogepant 60 mg (control), the AUC 0-24 and C. max The C of Atogepant was 2.85 times and 2.23 times, respectively. max These increases in AUC are considered clinically significant.

[0074] Treatment B2 / treatment A: When a single dose of atogepant 60 mg was administered in combination with multiple doses of rifampin 600 mg (study) was compared with atogepant 60 mg administered alone (control), the AUC 0-∞ and AUC 0-t decreased by 61% and 60%, respectively, while C max The C of atogepant decreased by 30%. max These decreases in AUC are considered clinically significant.

[0075] [Table 3]

[0076] [Table 4]

[0077] There was a statistically significant increase in atogepant systemic exposure (AUC 0-24 is 2.85 times, C max Rifampin is an OATP1B1 inhibitor, and atogepant metabolism depends on hepatocyte uptake of atogepant via the OATP1B1 transporter. The C max and AUC increases are likely to be clinically significant, and atogepant dose adjustments may be necessary.

[0078] There was a statistically significant decrease in systemic exposure to atogepant (AUC 0-∞ was 61%, AUC 0-t 60% are C max Rifampin is a strong CYP3A4 inducer as well as a P-gp inducer, and atogepant is extensively metabolized by CYP3A4 and is also a P-gp substrate. The C max and AUC decreases are likely to be clinically significant, and atogepant dose adjustments may be necessary.

[0079] Safety analyses were performed based on the safety population (i.e., all patients who received at least one dose of the study drug).Safety measures evaluated included TEAE records, clinical laboratory measurements, vital sign parameters, ECG results, and physical examination findings.

[0080] All 32 participants received a single dose of atogepant 60 mg on day 1 (treatment A), 31 participants received a combination of atogepant 60 mg and rifampin 600 mg on day 7 followed by rifampin 600 mg alone once daily on days 8 to 11 (treatment B1), and a combination of atogepant 60 mg and rifampin 600 mg on day 12 followed by rifampin 600 mg alone on day 13 (treatment B2). The mean treatment duration for all participants was 12.6 days.

[0081] Overall, atogepant and rifampin were well tolerated during the study. Table 5 summarizes AEs in the safety population by dosing regimen. No deaths or SAEs occurred during the study, and no participants experienced TEAEs leading to discontinuation. A total of 11 (34.4%) participants experienced TEAEs during the study, 8 (25.8%) after administration of dose B1 and 5 (16.1%) after administration of dose B2. No participants reported TEAEs after receiving dose A.

[0082] [Table 5]

[0083] The most common TEAE (occurring in at least two participants receiving a particular dose) reported after administration of B1 was headache, which occurred in two (6.5%) participants. All TEAEs reported after administration of dose B2 occurred in one (3.2%) participant each.

[0084] A total of five (15.6%) participants experienced at least one treatment-related TEAE during the study, four (12.9%) after dose B1 and two (6.5%) after dose B2. The most common treatment-related TEAE was nausea (occurring in two participants [6.3%], one after dose B1 and one after dose B2). All other treatment-related TEAEs, occurring in one participant each, were abdominal discomfort, diarrhea, vomiting, abdominal pain, arthralgia, dizziness, headache, and colored urine.

[0085] All EAEs were mild (10 [31.3%]) or moderate (1 [3.1%]) and no severe TEAEs were reported. Moderate TEAEs were nausea and vomiting, reported in one participant after dose B1.

[0086] There were no significant changes from baseline in clinical laboratory results, vital sign parameters, or ECG findings. No participant met Hy's Law criteria for clinical laboratory values.

[0087] The study drugs were a single dose of atogepant alone, or a combination of a single dose of atogepant and single or multiple doses of rifampin.

[0088] [Example 2] An open-label, single-sequence drug-drug interaction study was conducted to evaluate the effect of CYP3A4 inhibition with oral itraconazole (200 mg daily) on the pharmacokinetics of a single oral dose of atogepant (60 mg) in healthy subjects.

[0089] The primary objective of this study was to evaluate the effect of repeated doses of itraconazole on the pharmacokinetics of a single dose of atogepant. The primary endpoints were PK parameters of atogepant calculated from plasma concentrations. Secondary objectives of the study were to evaluate the safety and tolerability of atogepant and itraconazole administered alone and in combination, and to determine the correlation between atogepant concentrations in dried blood samples (DBS) (collected by fingerstick technique) and plasma. Secondary endpoints included AEs, clinical laboratory parameters, vital signs, ECG, and physical examination, as well as the correlation between atogepant concentrations in DBS and plasma.

[0090] This study was a single-center, single-sequence, open-label, two-period PK drug-drug interaction study in 40 healthy male and female subjects aged 18-45 years.

[0091] To be enrolled in this study, each subject was required to meet all of the following inclusion criteria and not meet any of the following exclusion criteria:

[0092] Selection Criteria -Be a healthy male or female aged between 18 and 45 years old. For females, a negative serum pregnancy test result at screening and a negative serum or urine pregnancy test result on day -1. Men must use effective contraception throughout the study and agree not to impregnate their partner, or be sterilized at least one year prior. Women of childbearing potential must agree to use effective contraception throughout the entire study period and to avoid becoming pregnant. - You are a non-smoker (you have never smoked or have not smoked within the past two years). Body mass index (BMI) of 18 kg / m 2 More than 30kg / m 2 The results were as follows. - Sitting pulse rate between 60 beats per minute (bpm) and 100 bpm during vital sign assessment at screening.

[0093] Exclusion criteria Known hypersensitivity to atogepant or other CGRP receptor antagonists or to itraconazole. -Has a clinically significant disease state in the opinion of the investigator. Sitting systolic blood pressure (SBP) ≥ 140mmHg or ≤ 90mmHg, or sitting diastolic blood pressure (DBP) ≥ 90mmHg or ≤ 60mmHg at screening. Abnormal ECG results or investigator-diagnosed QT prolongation (QTcF ≥ 450 msec or uncorrected QT ≥ 500 msec) considered to be potentially clinically significant (PCS). - Positive test result for anti-human immunodeficiency virus type 1 or type 2 drugs, hepatitis B surface antigen, or anti-hepatitis C virus drugs at screening. · Abnormal and clinically significant results of physical examination, medical history, serum chemistry, hematology, coagulation, or urinalysis. · History of alcohol or other substance abuse within the past 5 years. - Positive test result for benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, phencyclidine, or cotinine at Screening or Day -1. Participating in another clinical trial using an experimental drug that requires repeated blood or plasma sampling within 60 days of IP dosing. Participating in a blood or plasma donation program within 60 or 30 days, respectively, of IP administration. Consumption of caffeine within 48 hours prior to IP dosing, consumption of grapefruit-containing products or cruciferous vegetables (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard) within 14 days, or consumption of alcohol within 72 hours. -Have a medical or surgical history that may affect the absorption, distribution, biotransformation, or excretion of atogepant or itraconazole. -Taking any concomitant medication (including over-the-counter drugs) within 14 days prior to IP administration, or taking any hormone preparations within 30 days prior to IP administration. -Previously taking atogepant or previously participating in a clinical trial of atogepant or MK-8031. -You are breastfeeding.

[0094] Subjects who met the inclusion and exclusion criteria were assigned to a single fixed dose sequence, dose A followed by dose B, with a 7-day washout period between doses. Treatment A: Atogepant 60 mg (tablet) was administered orally once under fasting conditions on day 1. Administration B Days 8 to 14: Itraconazole 200 mg (tablet) was orally administered once daily under fed conditions. Day 15: Itraconazole 200 mg was administered in combination with atogepant 60 mg (tablet) under fasting conditions. Days 16-17: Itraconazole 200 mg (tablet) was administered once daily under fed conditions.

[0095] In this study, atogepant was administered under fasting conditions. Itraconazole is more bioavailable when administered with food. Therefore, to maximize the CYP3A4 inhibitory effect, itraconazole was administered with food on all itraconazole dosing days except day 15, when both itraconazole and atogepant were administered under fasting conditions. 1 / 2 Because of the long duration (34-42 hours), administration of itraconazole in the fasting state on day 15 was unlikely to affect the CYP3A4 inhibitory effect.

[0096] Total study participation for each subject was approximately 48 days (days -1 to 47), excluding the screening visit. The study included an 8-night hospital stay.

[0097] The mean age of participants was 34.8 years, ranging from 19 to 45 years. Eighteen (45%) subjects were male and 22 (55%) were female. A total of 33 (82.5%) subjects were Caucasian, and 7 (17.5%) were Black or African American. Overall, 37 (92.5%) were Hispanic or Latino, and 3 (7.5%) were non-Hispanic or non-Latino. The mean (SD) BMI was 27.41 (2.47) kg / m 2 It was.

[0098] Mean plasma atogepant concentrations after administration of 60 mg atogepant alone or in the presence of steady-state itraconazole are shown in Figure 3. A semi-log plot of mean plasma atogepant concentrations is shown in Figure 4. Mean (SD) PK parameters and results of statistical analysis are shown in Table 6.

[0099] [Table 6]

[0100] Atogepant C max The RR and AUC were increased by 2.15-fold and 5.5-fold, respectively, due to inhibition of CYP3A4 by itraconazole. Because this increase in atogepant exposure due to CYP3A4 inhibition is likely to be clinically significant, dose adjustment of atogepant may be necessary when coadministered with a strong CYP3A4 inhibitor.

[0101] The total body clearance of atogepant was 19.2 L / h after administration alone, but decreased to 3.46 L / h after administration in the presence of itraconazole at steady state. 1 / 2 The mean mean time to death was 11.2 hours after administration of the drug alone, but was increased to 14.9 hours by inhibition of CYP3A4 with itraconazole.

[0102] Overall, each dose was well tolerated. Five TEAEs were reported (two subjects [atogepant alone] experienced dizziness, two subjects [itraconazole alone] experienced headache, and one subject [itraconazole alone] experienced constipation). None of these TEAEs were reported as SAEs, and all TEAEs were mild in intensity. No TEAEs led to permanent discontinuation of study drug. No deaths occurred during the study. No post-baseline laboratory findings, vital signs, or ECGs were PCS during the study.

[0103] Overall, itraconazole at steady state had a clinically significant effect on atogepant pharmacokinetics. These results suggest that CYP3A4 inhibition by itraconazole or other strong CYP3A4 inhibitors results in a clinically significant increase in atogepant exposure. Atogepant dose reduction may be necessary when coadministered with strong CYP3A4 inhibitors. Each dosing regimen was well tolerated in healthy subjects.

[0104] [Example 3] A multicenter, nonrandomized, open-label, parallel-group, single-dose study was conducted to evaluate the PK, safety, and tolerability profile of atogepant after a single oral dose of 60 mg atogepant in participants with hepatic impairment and matched healthy participants with normal hepatic function. Primary outcome measures were PK parameters of atogepant calculated from plasma concentrations. Safety measures included AEs, clinical laboratory measurements, vital sign parameters, electrocardiogram results, and physical examination findings.

[0105] In this study, participants with normal hepatic function and participants with hepatic impairment (mild, moderate, or severe according to the Child-Pugh classification) received a single oral dose of atogepant 60 mg tablet with 240 mL of water under fasting conditions at the study site on day 1. PK blood samples were collected up to 72 hours after dosing. The total study participation period for each participant was 5 days (days -1 to 4), excluding the screening visit. Participants were admitted to the hospital on day -1 and were to remain admitted until day 4. Participants with moderate hepatic impairment were enrolled after four participants with mild hepatic impairment had completed the study, and participants with severe hepatic impairment were enrolled after four participants with moderate hepatic impairment had completed the study. Participants with normal hepatic function were recruited after all patients with hepatic impairment had been enrolled in the study. The safety and tolerability of atogepant was confirmed in each group before enrolling the next group.

[0106] Participants attended an EOS visit at or within 7 days of the final PK sample collection on Day 4. Participants also attended a safety follow-up visit on Day 30 for safety assessments.

[0107] The planned enrollment was 32 participants, including 24 participants with liver dysfunction (8 mild, 8 moderate, and 8 severe) and 8 participants with normal liver function. All participants were aged 18-80 years and had a BMI of 18 kg / m2 or greater. 2 More than 42kg / m 2The following criteria were met: sitting pulse rate ≥50 bpm ≤100 bpm, and QTcF <470 msec. Participants with liver dysfunction had to have a Child-Pugh score ≤12 and were excluded if their sitting systolic blood pressure was ≥165 mmHg or ≤95 mmHg, or if their sitting diastolic blood pressure was ≥100 mmHg or ≤50 mmHg at screening. Participants with normal liver function were excluded if their sitting systolic blood pressure was ≥140 mmHg or ≤90 mmHg, or if their sitting diastolic blood pressure was ≥90 mmHg or ≤50 mmHg at screening.

[0108] Participants were enrolled in four groups: Group I (mild liver impairment), Group II (moderate liver impairment), Group III (severe liver impairment), and Group IV (normal liver function). Participants with normal liver function were recruited after enrolling participants with liver impairment in the study, so that participants could be matched as closely as possible between groups by age range, weight range, and gender. Participants were matched according to age range (≤5 years difference between the means of the normal group and the liver dysfunction groups in all three groups), weight range (≤20% deviation between the means of the normal group and the liver dysfunction groups in all three groups), and gender (maximally matching the ratios of the normal group and the liver dysfunction groups in all three groups).

[0109] A total of 32 participants were enrolled: 8 with normal liver function, 8 with mild liver impairment, 8 with moderate liver impairment, and 8 with severe liver impairment. All participants completed the study through the safety follow-up period. No participants discontinued early.

[0110] The mean age of the safety population was 58.8 years (range 45-72 years), two-thirds of the population was male, the majority of participants (87.5%) were white, and the mean BMI was 30.72 kg / m 2Demographic characteristics were similar across the four liver function groups, except for race; in the moderate liver impairment group, three-quarters of participants were non-Hispanic / non-Latino, whereas in the other liver function groups, non-Hispanic / non-Latino participants made up a quarter to half of participants in each group. The differences in racial distribution observed across groups are unlikely to have influenced the results of the study.

[0111] None of the participants in the normal liver function group had a history of hepatic and biliary disorders, compared with 6 of 8 participants in the mild liver impairment cohort, 8 of 8 in the moderate liver impairment cohort, and 8 of 8 in the severe liver impairment cohort.

[0112] Participants were given a single oral dose of atogepant 60 mg tablet. Each participant received only one dose of the study intervention. Participants were administered atogepant tablets with 240 mL of water under fasting conditions at the study site. After administration, participants continued to fast for 4 hours and were asked to maintain an awake, upright sitting position.

[0113] From 14 days prior to Day 1 until completion of all study procedures, participants were advised to refrain from consuming grapefruit, grapefruit juice, and cruciferous vegetables (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard). From 48 hours prior to administration of the study intervention until completion of all study procedures, participants were advised to refrain from consuming xanthine-containing compounds (caffeine-containing products, including but not limited to coffee, tea, soft drinks, energy sports drinks, and chocolate). No alcoholic beverages were permitted from 72 hours prior to administration until completion of PK blood sample collection, and participants with alcoholic cirrhosis were advised to abstain from alcohol for at least 1 week prior to administration of the study intervention and throughout the entire study period. Participants were advised to refrain from strenuous activity at all time points during the study period.

[0114] Beginning on day 1, samples for plasma atogepant concentrations were collected at 0 hours (pre-dose) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours after dosing.

[0115] The mean plasma atogepant concentration-time profiles in participants with various degrees of hepatic impairment and normal hepatic function are shown on a linear scale in Figure 5A. The corresponding semi-log plots are shown in Figure 5B. The mean PK parameters of atogepant when administered to participants with various degrees of hepatic impairment and normal hepatic function are summarized in Table 7.

[0116] [Table 7]

[0117] T in participants with mild, moderate, or severe liver impairment and those with normal liver function max The median differences were 0, 0.25, and 0.75 hours, respectively. The mean terminal elimination half-life of atogepant was similar in participants with hepatic impairment and those with normal hepatic function.

[0118] Table 8 shows statistical comparisons of PK parameters (including geometric mean ratios and 90% CI) between participants with various degrees of hepatic impairment and those with normal hepatic function.

[0119] [Table 8]

[0120] Compared with participants with normal liver function, participants with mild liver impairment had a significantly higher C max The C-terminal region of the endothelial cell wall was 9% higher and the AUC was 24% higher. Compared with participants with normal liver function, participants with moderate liver impairment had a C max The AUC was 14%-15% higher in participants with severe hepatic impairment than in those with atogepant C. maxand a 38% increase in atogepant AUC.

[0121] Beginning on day 1, blood samples for protein binding were collected from all participants at time 0 (pre-dose) and 2 hours post-dose. A known amount of atogepant was exogenously spiked into pre-dose samples collected from each participant prior to dosing. Direct measurement of atogepant concentration in blood samples was used to determine the percentage of atogepant bound in samples collected at 2 hours. The percentage of atogepant bound is summarized in Table 9.

[0122] [Table 9]

[0123] Plasma protein binding did not differ substantially between participants with hepatic impairment and those with normal hepatic function. Following a single oral dose of 60 mg atogepant in participants with mild, moderate, or severe hepatic impairment, the percentage of atogepant bound to plasma proteins was 97.4%, 97.1%, and 95.3%, respectively, and 98.2% in participants with normal hepatic function. Plasma protein binding was similar across all hepatic impairment groups and in participants with normal hepatic function.

[0124] Overall, no clinically meaningful changes in the PK of atogepant were observed in participants with mild, moderate, or severe hepatic impairment. Peak plasma atogepant concentrations were similar in participants with mild, moderate, or severe hepatic impairment compared with participants with normal hepatic function (+9%, -12%, and -4%, respectively). The overall extent of atogepant systemic exposure (AUC) was slightly higher (14%-38%) in participants with hepatic impairment compared with participants with normal hepatic function, but these changes are unlikely to be clinically meaningful.

[0125] Atogepant was well tolerated in participants across all hepatic function groups. One AE was reported during the study, which was mild and transient. No SAEs or AEs leading to early discontinuation were reported, and no participants died. No clinically meaningful changes in laboratory parameters, vital signs, or ECG values ​​were observed in any hepatic function group. No participants met potential High's Law criteria. No safety issues were identified when a single dose of atogepant 60 mg was administered to participants with hepatic impairment.

[0126] [Example 4] Population pharmacokinetic modeling was performed to evaluate coadministration of atogepant with moderate CYP3A4 inhibitors (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) or weak CYP3A4 inhibitors (e.g., cimetidine, esomeprazole). Modeling suggested that moderate CYP3A4 inhibitors would increase atogepant AUC by 1.7-fold and weak CYP3A4 inhibitors would increase atogepant AUC by 1.1-fold. Changes in atogepant exposure when coadministered with weak or moderate CYP3A4 inhibitors are not expected to be clinically significant.

[0127] [Example 5] We conducted a phase 1, open-label, two-arm, single-sequence, non-randomized, crossover, drug-drug interaction study to evaluate the effect of multiple doses of esomeprazole magnesium 40 mg on the pharmacokinetics (PK) and safety of a single dose of coadministered atogepant 60 mg in healthy adults.

[0128] In this study, healthy adult participants received a single oral dose of atogepant 60 mg on day 1, followed by esomeprazole 40 mg once daily on days 7-13, coadministered with a single dose of atogepant on day 12. Samples for atogepant PK analysis were collected on days 1 and 12. PK parameters calculated from plasma atogepant concentrations were peak plasma concentration (C max ), C max Arrival time (t max), from 0 to 5 hours (AUC 0-t ) and from time 0 to infinity (AUC 0-∞ ) was the area under the plasma concentration-time curve. A mixed-effects model was used to compare PK parameters of atogepant administered alone and in combination with esomeprazole. Statistical significance was achieved if the 90% confidence interval (CI) of the geometric least squares mean ratio (GMR) of PK parameter values ​​of atogepant administered alone versus in combination with esomeprazole was in the range of 80% to 125%.

[0129] Thirty-two participants (mean age 30.8 years, 50% male) were enrolled, and 29 (90.6%) completed the study. max The median time was 1.51 hours for atogepant alone, but was 3.00 hours for esomeprazole, a 1.5 hour delay. The GMR (90% CI) was max was 76.63 (69.19–86.11), and AUC 0-t was 91.61 (93.67-100.29), and the AUC 0-∞ is 92.04 (94.12~100.71), and C max Only the change in CI was statistically significant. Treatment-emergent adverse events were generally infrequent and mild in intensity, except for one report each of presyncope (moderate) and elective termination of pregnancy (severe).

[0130] When coadministered with esomeprazole, the absorption rate of atogepant was decreased (C max decreased by 23%, and t max Atogepant 60 mg alone or in combination with esomeprazole magnesium 40 mg was safe and well tolerated in healthy participants.

[0131] [Example 6] We conducted a phase 1, single-center, single-sequence, open-label, two-arm, drug-drug interaction study to evaluate the effect of P-glycoprotein (P-gp) inhibition with quinidine gluconate on the pharmacokinetics (PK) and safety of atogepant. Healthy adults received atogepant 60 mg on day 1, quinidine gluconate 324 mg twice daily on day 8, and quinidine gluconate 648 mg twice daily on days 9–12, with atogepant 60 mg on day 11. Plasma samples were collected on days 1 and 11.

[0132] The calculated PK parameters of atogepant were peak plasma concentration (C max ), C max Arrival time (t max ), and from time 0 to time t (AUC 0-t ) and up to infinity (AUC 0-∞ ) was the area under the plasma concentration-time curve. A mixed-effects model was used to compare the PK parameters of atogepant administered alone versus in combination with quinidine gluconate. Statistical significance was achieved if the 90% confidence interval (Ci) of the geometric least squares mean ratio (GMR) of the PK parameter values ​​of atogepant administered alone versus in combination with quinidine gluconate was within the range of 80% to 125%. Safety evaluation included clinical laboratory values, vital signs, electrocardiograms, and treatment-related adverse events (TEAEs).

[0133] Of the 33 participants enrolled (mean age 30.3 years, 72.7% male), 23 (69.7%) completed the study. Ten discontinued due to treatment-emergent adverse events (TEAEs, both of which were QT prolongation during quinidine gluconate administration). max The median was 1.50 hours regardless of whether quinidine gluconate was administered. The GMR (90% CI) was max was 104.41 (89.17-122.25), and the AUC 0-t was 120.49 (110.21-142.88), and the AUC 0-∞The change in AUC was 125.91 (110.56-143.40), and the change was statistically significant. Most TEAEs were related to quinidine gluconate administration.

[0134] When administered in combination with quinidine gluconate, the C max There was a 4.4% increase in RR and an approximately 25% increase in AUC. However, these changes are not expected to be clinically significant. Atogepant 60 mg was safe and well tolerated in healthy participants when administered alone or in combination with quinidine gluconate.

[0135] [Example 7] The efficacy of atogepant for the preventive treatment of episodic migraine in adults was demonstrated in two randomized, multicenter, double-blind, placebo-controlled trials (Study 1 and Study 2). Patients with at least a 1-year history of migraine with or without aura according to the International Classification of Headache Disorders (ICHD-3) diagnostic criteria were enrolled in the studies.

[0136] In study 1 (NCT03777059), 910 patients were randomized 1:1:1:1 to receive atogepant 10 mg (N = 222), atogepant 30 mg (N = 230), atogepant 60 mg (N = 235), or placebo (N = 223) once daily for 12 weeks. In study 2 (NCT02848326), 652 patients were randomized 1:2:2:2 to receive atogepant 10 mg (N = 94), atogepant 30 mg (N = 185), atogepant 60 mg (N = 187), or placebo (N = 186) once daily for 12 weeks. In both studies, patients were allowed to use acute headache medications (i.e., triptans, ergotamine derivatives, NSAIDs, acetaminophen, and opioids) as needed. Concomitant use of medications acting on the CGRP pathway was not allowed for either acute or prophylactic treatment of migraine. Patients who had suffered a myocardial infarction, stroke, or transient ischemic attack within 6 months prior to screening were excluded from the study.

[0137] Test 1 The primary efficacy endpoint was the change from baseline in the mean number of monthly migraine days (MMD) over the 12-week treatment period. Secondary endpoints included the change from baseline in the mean number of monthly headache days, the change from baseline in the mean number of monthly days of acute medication use, the proportion of patients achieving at least a 50% reduction from baseline in the mean MMD (3-month average), the change from baseline in the mean monthly score in the Performance of Daily Activities (PDA) domain of the Activity Impairment in Migraine-Diary (AIM-D), the change from baseline in the mean monthly score in the Physical Impairment (PI) domain of the AIM-D, and the change from baseline in the Role Function-Restrictive (RFR) domain score of the Migraine Specific Quality of Life Questionnaire version 2.1 (MSQv2.1) at week 12.

[0138] The AIM-D assesses the difficulty of migraine in carrying out daily activities (PDA domain) and disability (PI domain) on a scale of 0 to 100. Higher scores indicate greater impact of migraine, and a decrease from baseline indicates improvement. The MSQv2.1 Role Limitations in Functioning (RFR) domain score assesses how frequently migraine has affected functioning related to daily social and work-related activities over the past 4 weeks on a scale of 0 to 100. Higher scores indicate less impact of migraine on daily activities, and an increase from baseline indicates improvement.

[0139] Patients had a mean age of 42 years (range 18-73 years), 89% were female, 83% were white, 14% were black, and 9% were Hispanic or Latino. Mean migraine frequency at baseline was approximately 8 migraine days per month and was similar between treatment groups. A total of 805 (88%) patients completed the 12-week double-blind study period. Primary efficacy results from Study 1 are summarized in Table 10.

[0140] [Table 10]

[0141] The mean change from baseline in MMD in Study 1 is shown in Figure 6. Figure 7 shows the distribution of the change from baseline in mean monthly migraine days (MMD) over the 12-week treatment period by treatment group in 2-day increments. All doses of atogepant show a treatment effect superior to placebo within the range of mean change from baseline in MMD.

[0142] Test 2 The primary efficacy endpoint was the change from baseline in mean monthly number of migraine days over the 12-week treatment period.

[0143] Patients had a mean age of 40 years (range: 18-74 years), 87% were female, 76% were white, 20% were black, and 15% were Hispanic or Latino. Mean migraine frequency at baseline was approximately 8 migraine days per month. A total of 541 (83%) patients completed the 12-week double-blind study period.

[0144] In Study 2, as summarized in Table 11, all three atogepant groups experienced a significant reduction in the mean number of monthly migraine days over the 12-week treatment period compared with placebo.

[0145] [Table 11]

[0146] Figure 8 shows the mean change from baseline in MMD in Study 2. Patients receiving atogepant had a greater mean decrease from baseline in MMD over the 12-week treatment period compared to patients receiving placebo. Figure 9 shows the distribution of mean change from baseline in MMD over the 12-week treatment period in 2-day increments by treatment group. All doses of atogepant show a treatment effect superior to placebo for the range of change from baseline in MMD.

[0147] [Example 8] The safety of atogepant was evaluated in 1958 migraine patients who received at least one dose of atogepant. Of these, 839 were exposed to atogepant once daily for at least 6 months, and 487 were exposed to atogepant once daily for 12 months. In the 12-week placebo-controlled clinical trials (Study 1 and Study 2 described above in Example 7), 314 patients received at least one dose of atogepant 10 mg once daily, 411 patients received at least one dose of atogepant 30 mg once daily, 417 patients received at least one dose of atogepant 60 mg once daily, and 408 patients received placebo. Approximate numbers were 88% female, 80% white, 17% black, and 12% Hispanic or Latino. The mean age at study entry was 41 years (range 18-74 years).

[0148] The most common adverse reactions (incidence greater than placebo and at least 4%) were nausea, constipation, and fatigue.

[0149] Adverse events occurring during Study 1 and Study 2 are summarized in Table 12.

[0150] [Table 12]

[0151] The most common adverse reactions leading to discontinuation in Studies 1 and 2 were constipation (0.5%), nausea (0.5%), and fatigue / somnolence (0.5%).

[0152] Elevated liver enzymes In Studies 1 and 2, the incidence of transaminase elevations greater than 3 times the upper limit of normal was similar in atogepant-treated (1.0%) and placebo-treated (1.8%) patients. Transaminase elevations greater than 3 times the upper limit of normal were transiently associated with atogepant treatment in some cases, but these were asymptomatic and resolved within 8 weeks of discontinuation. There were no cases of severe liver injury or jaundice.

[0153] weight loss In Studies 1 and 2, the percentage of patients who lost at least 7% body weight at any time point was 2.8% in the placebo group, 3.8% in the atogepant 10 mg group, 3.2% in the atogepant 30 mg group, and 4.9% in the atogepant 60 mg group.

[0154] [Example 9] We conducted a single-center, randomized, open-label, single-dose, two-period crossover study to evaluate the effect of a high-fat meal on the systemic exposure of atogepant after a single dose of immediate-release (IR) tablets in healthy adult participants.Secondary objectives were to evaluate secondary PK parameters of atogepant after a single dose of the IR tablet formulation in healthy participants under fasted and fed conditions and to evaluate the safety and tolerability profile of atogepant after a single dose in healthy adult participants under fed and fasted conditions.

[0155] Twenty healthy adult male and female participants, aged 18-45 years, received a single dose of atogepant 60 mg after an overnight fast or after a high-fat meal (provided 30 min prior to dosing), with a 7-day washout period between interventions. Plasma samples were collected pre-dose and at timed intervals up to 48 h post-dose. Plasma atogepant concentrations were measured using a validated LC-MS / MS assay, and pharmacokinetic (PK) parameters were calculated using WinNonlin. A linear mixed-effects model with sequence, study intervention, and dosing phase as fixed effects and participant nested within sequence as a random effect was used to calculate the atogepant PK parameter, AUC 0-t , AUC0-inf , and C max The natural log-transformed values ​​of 100 mg / kg / day were compared. Safety was monitored by ECG, vital signs, clinical laboratory values, and adverse events.

[0156] Participants were randomly assigned to receive study intervention A (a single dose of atogepant 60 mg, IR formulation, one atogepant 60 mg tablet, fed conditions) or study intervention B (a single dose of atogepant 60 mg, IR formulation, one atogepant 60 mg tablet, fasted conditions).

[0157] Screening occurred within 21 days prior to dosing (days -21 to -1). The study intervention period was scheduled for a total of 11 days (days -1 to 10), with a follow-up visit on day 38 (±3) (30 [±3] days after the last dose on day 8) for serum chemistry analysis. Beginning on days 1 (period 1) and 8 (period 2), PK blood samples were collected for analysis of plasma atogepant concentrations at 0 h (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 h post-dose.

[0158] Overall, 20 participants were randomized to receive study interventions A and B in one of two sequences, with at least a 7-day washout period between each study intervention, as shown in Table 13. Nineteen participants (95.0%) completed the study, and one (5.0%) discontinued on Day 7 (Period 2) due to a major protocol deviation.

[0159] [Table 13]

[0160] Participants were healthy men or women aged 18 to 45 years and with a body mass index of 18 kg / m 2 More than 30kg / m 2≤ 18 years and had a sitting pulse rate of 40 bpm to 100 bpm during vital signs assessment at the screening visit. Participants were additionally required to be nonsmokers and nonusers of nicotine-containing products (never smoked or used nicotine-containing products, or had not smoked or used nicotine-containing products, including e-cigarettes, within the past 6 months prior to study intervention). Twenty healthy participants with a mean age of 31.9 years (range 23-44 years) were enrolled. The majority of participants were male (13 of 20 participants, 65.0%). Participants were Black or African American (11 of 20 participants, 55.0%), White (8 of 20 participants, 40.0%), and multiracial (1 of 20 participants, 5.0%). Mean (SD) body weight was 72.95 (9.264) kg, and mean (SD) body mass index was 24.15 (2.368) kg / m 2 Demographic and baseline characteristics were comparable between sequences and identical in the PK and safety populations.

[0161] Plasma atogepant concentration data were analyzed for 19 and 20 participants undergoing the study intervention under fed and fasted conditions, respectively.

[0162] The mean plasma atogepant concentration-time profiles following a single dose of one tablet of atogepant 60 mg IR formulation under fed (study intervention A) and fasted (study intervention B) conditions are shown in Figure 10 (linear scale ± SD, inset semi-log scale). Plasma atogepant PK parameters are summarized in Table 14. max The mean AUC and AUC were lower when atogepant was administered under fed conditions than under fasted conditions, but the T and AUC were significantly higher for the two study interventions. max and T lag The median values ​​are the same, t t1 / 2 , CL / F, and V z The mean values ​​of / F were similar. Box plots of plasma PK parameters of atogepant are shown in Figure 11 (AUC 0-t and AUC 0-inf ) and Fig. 12(C max ) as shown in

[0163] [Table 14]

[0164] [Table 15]

[0165] The pharmacokinetics of atogepant 60 mg IR tablet formulation demonstrated a food effect. The food effect was statistically significant but mild. Administration of atogepant 60 mg IR tablet formulation under fed conditions reduced AUC by approximately 18% compared to administration under fasted conditions, and C max The median difference between matched pairs was about 22%. max was delayed by 0.5 hours. The mild food effect on atogepant PK is not considered clinically significant.

[0166] A single dose of atogepant 60 mg IR formulation was safe and well tolerated in healthy participants in this study when administered under both fed and fasted conditions. No clinically meaningful differences in safety or tolerability were observed following a single dose of atogepant 60 mg IR formulation under fed compared to fasted conditions.

[0167] Overall, seven (35.0%) participants experienced treatment-emergent AEs (TEAEs). Of these, three (15%) experienced four TEAEs that were deemed related to the study intervention. The most frequently reported TEAEs were arthralgia and back pain (two participants each, 10.0%). Of the seven participants who reported TEAEs, six TEAEs were deemed mild in severity, and one participant experienced alanine aminotransferase increase and aspartate aminotransferase increase TEAEs during follow-up, which were deemed moderate in severity, recorded as adverse events of special interest, and considered unrelated to the study intervention. No deaths or severe or serious TEAEs were reported. No participants experienced a TEAE that led to discontinuation from the study. All TEAEs were resolved / resolved by follow-up visits.

[0168] Changes from baseline in mean laboratory tests, vital signs, and safety 12-lead electrocardiogram (ECG) parameters were not clinically meaningful. Overall, eight participants had potentially clinically significant laboratory values ​​at end of treatment (EOD), and no participants had liver function test results that met the criteria for potential High's Law cases. No participants had vital signs or 12-lead ECG results that met the criteria for potentially clinically significant changes during the study.

[0169] [Example 10] We conducted an open-label, single-center, multiple-dose, two-cohort, phase 1 study to evaluate the potential for PKDDIs of atogepant and topiramate in healthy adult participants. Eligible participants were enrolled in cohort 1 to evaluate the effect of topiramate 100 mg twice daily on the PK of atogepant 650 mg once daily, and in cohort 2 to evaluate the effect of atogepant 60 mg once daily on the PK of topiramate 100 mg twice daily. Participants in cohort 1 received atogepant alone on days 1-7 and atogepant and topiramate on days 8-17. Participants in cohort 2 received topiramate alone on days 1-10 and topiramate and atogepant on days 11-17. The study design is shown in Figure 13.

[0170] The duration of the study was 25 days (± 2 days) from day -1 to the follow-up visit, excluding the screening period. The screening period was up to 21 days before day 1, and the intervention period was a total of 19 days, with an end-of-treatment visit on the final day. Cerebrospinal fluid (CSF) samples for atogepant concentration were collected by lumbar puncture in a subset of participants who consented in cohort 1. A single CSF sample was collected from each participant in the CSF-collecting subset 2 or 6 hours after the morning dose on day 6 in cohort 1. A follow-up visit was conducted on day 24 (7 [± 2] days after the last dose of study drug), and laboratory tests were performed.

[0171] Eligible participants were healthy adults aged 18–45 years, non-smokers, and had a body mass index of 18 kg / m 2 More than 30kg / m 2 and a sitting pulse rate between 45 and 100 beats per minute. Participants were excluded if they had clinically significant abnormal electrocardiogram (ECG) results or QT prolongation (QTcF ≥450 msec in men and ≥470 msec in women) or if they had a medical or surgical history that might affect the absorption, distribution, biotransformation, or excretion of atogepant or topiramate.

[0172] The primary endpoint was the area under the plasma concentration-time curve (AUC) during the dosing interval at steady state for atogepant and topiramate when administered in combination and alone. 0-tau,ss ) and the maximum plasma drug concentration at steady state (C max,ss Other PK parameters were the time to reach the maximum plasma drug concentration at steady state (T max,ss ), mean plasma drug concentration at steady state (C avg,ss ), and the minimum steady-state plasma drug concentration (C min,ss The safety and tolerability of atogepant, topiramate, and the combination were monitored throughout the study by time-specific clinical assessment of adverse events (AEs), vital sign measurements, evaluation of 12-lead ECGs, and laboratory tests (hematology, clinical chemistry, coagulation, and urinalysis).

[0173] The safety population included 28 participants in cohort 1 (28 received atogepant alone, 26 received atogepant and topiramate in combination, and 24 were included in the CSF-collected subset) and 25 participants in cohort 2 (25 received topiramate alone and 24 received topiramate and atogepant in combination). The PK analysis populations for atogepant alone and atogepant + topiramate included 25 and 21 participants, respectively. The PK analysis populations for topiramate alone and topiramate + atogepant included 24 and 22 participants, respectively. A total of 21 participants in cohort 1 and 22 participants in cohort 2 completed the study. Ten participants discontinued the study, eight due to AEs, one for study drug non-compliance, and one for other reasons (non-compliance with investigator instructions). Baseline demographics were similar between the two cohorts, as shown in Table 16.

[0174] [Table 16]

[0175] The mean (standard deviation [SD]) steady-state plasma concentrations of atogepant after administration alone and in combination with topiramate are shown in Figure 14. As demonstrated by these data, coadministration of atogepant with topiramate results in slightly lower plasma atogepant concentrations compared to administration of atogepant alone. PK parameters of atogepant administered alone and in combination with topiramate are summarized in Table 17. Coadministration of atogepant with topiramate results in a higher C max,ss Although the T max,ss There was no change in the median

[0176] [Table 17]

[0177] As a result of GMR analysis, as shown in Table 18, when atogepant was administered in combination with topiramate, the AUC 0-tau,ss and C.max,ss were found to decrease by 25% and 24%, respectively. AUC 0-tau,ss and C. max,ss The GMR and lower limit of 90% CI for atogepant were both <0.80, suggesting a statistically significant decrease in atogepant exposure when coadministered with topiramate.

[0178] [Table 18]

[0179] The mean (SD) steady-state plasma concentrations of topiramate after administration alone and in combination with atogepant are shown in Figure 15. When coadministered with atogepant, plasma topiramate concentrations were slightly lower compared to topiramate alone. Topiramate PK parameters are summarized in Table 19. Overall, topiramate PK parameters were similar with or without coadministration of atogepant, but when coadministered with atogepant, the T of topiramate was significantly higher. max,ss The median delay was 0.5 hours. As a result of the GMR analysis, as shown in Table 20, the AUC 0-tau,ss and C. max,ss It was found that the rates decreased by 5% and 6%, respectively. max The GMR and AUC values ​​and their 90% CIs were in the range of 0.80 to 1.25, indicating that no DDIs would occur.

[0180] [Table 19]

[0181] [Table 20]

[0182] Topiramate AUC 0-tau,ss and C max,ss was similar when coadministered with atogepant compared with topiramate alone, but the AUC 0-tau,ssand C max,ss were decreased by 25% and 24%, respectively, due to the weak induction of CYP3A4 by topiramate, however, these changes are expected to be of minimal clinical significance and therefore no dose adjustments are likely necessary for coadministration of atogepant with weak CYP3A4 inducers.

[0183] For cohort 1 participants, the mean (SD) duration of exposure was 7.9 (0.42) days for atogepant alone and 8.8 (2.79) days for the combination of atogepant and topiramate, for a total of 15.1 (3.62) days. For cohort 2 participants, the mean (SD) duration of exposure was 10.0 (0.20) days for topiramate alone and 6.7 (1.23) days for the combination of topiramate and atogepant, for a total of 16.4 (1.96) days. In total, 24 (85.7%) cohort 1 participants and 19 (76.0%) cohort 2 participants reported at least one treatment-emergent adverse event (TEAE). TEAEs in the safety population are summarized in Table 6.

[0184] [Table 21]

[0185] The most commonly reported adverse events were nausea and constipation. In cohort 1, nausea was reported by six participants receiving atogepant alone and two participants receiving atogepant and topiramate. In cohort 2, nausea was reported by three participants receiving topiramate alone and none receiving topiramate and atogepant. In cohort 1, constipation was reported by three participants receiving atogepant alone and none receiving atogepant and topiramate. In cohort 2, constipation was reported by two participants receiving topiramate alone and two participants receiving topiramate and atogepant.

[0186] Five participants experienced TEAEs leading to discontinuation during atogepant monotherapy. One participant reported elevated aspartate aminotransferase / alanine aminotransferase, and one reported confusion and insomnia, and discontinued during the atogepant monotherapy period. Two participants who experienced TEAEs during atogepant monotherapy (one who experienced nausea and procedural pain [post-lumbar puncture neck pain], and one who experienced post-lumbar puncture syndrome) were unable to complete atogepant and discontinued during the atogepant and topiramate cotherapy period. One additional participant experienced a TEAE of nausea during atogepant monotherapy and a TEAE of muscle weakness during the atogepant and topiramate cotherapy period, and this participant discontinued during the cotherapy period.

[0187] The incidence of treatment-related TEAEs was similar between treatment interventions, and no serious AEs or deaths occurred during the study.Laboratory tests, vital signs, and ECG assessments revealed no clinically significant findings, and no participants met the criteria for potential High's Law cases (aminotransferases >3x upper limit of normal [ULN], total bilirubin ≥2x ULN, and alkaline phosphatase <2x ULN).

[0188] Atogepant and topiramate, either alone or in combination, are safe and well tolerated in healthy adults.

Claims

1. A pharmaceutical composition comprising atogepant or a pharmaceutically acceptable salt thereof, the pharmaceutical composition is for use in the prophylactic treatment of patients receiving concomitant treatment with a strong CYP3A4 inhibitor; The pharmaceutical composition, wherein the atogepant or a pharmaceutically acceptable salt thereof is formulated to administer 10 mg of atogepant once daily.

2. As a result of coadministration of atogepant and the strong CYP3A4 inhibitor, the C ｍａｘ The pharmaceutical composition of claim 1, wherein the IL-16 receptor agonist activity is increased by less than 2.15-fold compared to administration of atogepant alone.

3. 2. The pharmaceutical composition of claim 1, wherein the combined administration of atogepant and the strong CYP3A4 inhibitor results in an increase in the AUC of atogepant of about 5.5-fold compared to administration of atogepant alone.

4. 2. The pharmaceutical composition of claim 1, wherein the CYP3A4 inhibitor is selected from the group consisting of ketoconazole, itraconazole, or clarithromycin.

5. 2. The pharmaceutical composition of claim 1, wherein the CYP3A4 inhibitor is itraconazole.

6. A pharmaceutical composition comprising atogepant or a pharmaceutically acceptable salt thereof, the pharmaceutical composition is for use in the prophylactic treatment of migraine in patients receiving concomitant treatment with a moderate CYP3A4 inhibitor; The pharmaceutical composition, wherein the atogepant or a pharmaceutically acceptable salt thereof is formulated to administer atogepant in an amount of 10 mg, 30 mg, or 60 mg once daily.

7. 7. The pharmaceutical composition of claim 6, wherein the moderate CYP3A4 inhibitor is selected from the group consisting of cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, and grapefruit juice.

8. 7. The pharmaceutical composition of claim 6, wherein co-administration of atogepant and the moderate CYP3A4 inhibitor results in an increase in the AUC of atogepant of about 1.7-fold compared to administration of atogepant alone.

9. A pharmaceutical composition comprising atogepant or a pharmaceutically acceptable salt thereof, the pharmaceutical composition is for use in the prophylactic treatment of migraine in patients receiving concomitant treatment with a weak CYP3A4 inhibitor; The pharmaceutical composition, wherein the atogepant or a pharmaceutically acceptable salt thereof is formulated to administer atogepant in an amount of 10 mg, 30 mg, or 60 mg once daily.

10. 10. The pharmaceutical composition of claim 9, wherein the weak CYP3A4 inhibitor is cimetidine or esomeprazole.

11. 10. The pharmaceutical composition of claim 9, wherein co-administration of 10 mg, 30 mg, or 60 mg of atogepant with the CYP3A4 inhibitor results in an increase in the AUC of atogepant of about 1.1-fold compared to administration of atogepant alone.

12. A pharmaceutical composition comprising atogepant or a pharmaceutically acceptable salt thereof, the pharmaceutical composition is for use in the prophylactic treatment of migraine in a patient receiving treatment with a CYP3A4 inducer; The atogepant or a pharmaceutically acceptable salt thereof is formulated to administer atogepant in an amount of 30 mg or 60 mg.

13. 13. The pharmaceutical composition of claim 12, wherein the CYP3A4 inducer is selected from the group consisting of rifampin, carbamazepine, phenytoin, St. John's wort, efavirenz, or etravirine.

14. 13. The pharmaceutical composition of claim 12, wherein atogepant is administered when the CYP3A4 inducer has reached steady state.

15. 15. The pharmaceutical composition of claim 14, wherein when atogepant is administered in combination with the moderate or strong CYP3A4 inducer, the AUC of atogepant is reduced by about 60% compared to when atogepant is administered alone.

16. The pharmaceutical composition described in claim 12, wherein the CYP3A4 inducer is a weak CYP3A4 inducer.

17. The pharmaceutical composition described in claim 12, wherein the CYP3A4 inducer is a moderate CYP3A4 inducer.

18. The pharmaceutical composition described in claim 12, wherein the CYP3A4 inducer is a strong CYP3A4 inducer.

19. A pharmaceutical composition comprising atogepant or a pharmaceutically acceptable salt thereof, the pharmaceutical composition is for use in the prophylactic treatment of migraine in a patient receiving treatment with an OATP inhibitor; The pharmaceutical composition, wherein the atogepant or a pharmaceutically acceptable salt thereof is formulated to administer atogepant in an amount of 10 mg or 30 mg once daily.

20. 20. The pharmaceutical composition of claim 19, wherein co-administration of atogepant with the OATP inhibitor results in an increase in Cmax of atogepant of about 2.2-fold compared to administration of atogepant alone.

21. A pharmaceutical composition comprising atogepant or a pharmaceutically acceptable salt thereof, the pharmaceutical composition is for use in the prophylactic treatment of migraine in a patient; the atogepant or a pharmaceutically acceptable salt thereof is formulated to administer atogepant in an amount of 10 mg, 30 mg, or 60 mg once daily; When rifampin is repeatedly administered to the patient, the dose of atogepant is adjusted to 30 mg or 60 mg once a day.

22. 22. The pharmaceutical composition of claim 21, wherein administering atogepant in combination with multiple doses of rifampin results in a decrease in Cmax of atogepant of about 30% compared to administering atogepant alone.

23. A pharmaceutical composition comprising atogepant or a pharmaceutically acceptable salt thereof, the pharmaceutical composition is for use in the prophylactic treatment of migraine in patients with severe renal impairment or end-stage renal failure; The pharmaceutical composition, wherein the atogepant or a pharmaceutically acceptable salt thereof is formulated to administer 10 mg of atogepant once daily.

24. A pharmaceutical composition comprising atogepant or a pharmaceutically acceptable salt thereof, The pharmaceutical composition is for use in the prophylactic treatment of migraine in patients with mild or moderate hepatic impairment, The pharmaceutical composition, wherein the atogepant or a pharmaceutically acceptable salt thereof is formulated to administer atogepant in an amount of 10 mg, 30 mg, or 60 mg once daily.

25. Use of atogepant in the manufacture of a medicament for the prophylactic treatment of migraine in a patient receiving concomitant therapy with a CYP3A4 inhibitor, comprising: The atogepant is formulated to administer atogepant in an amount of 10 mg, 30 mg, or 60 mg once daily.

26. Use of atogepant in the manufacture of a medicament for the prophylactic treatment of migraine in a patient receiving concomitant therapy with a CYP3A4 inducer, comprising: The atogepant is formulated to administer atogepant in an amount of 30 mg or 60 mg once daily.

27. ​​Use of atogepant in the manufacture of a medicament for the prophylactic treatment of migraine in patients with severe renal impairment or end-stage renal failure, comprising: The atogepant is formulated to administer atogepant in an amount of 10 mg once daily.

28. Use of atogepant in the manufacture of a medicament for the prophylactic treatment of migraine in patients with mild or moderate hepatic impairment, comprising: The atogepant or a pharmaceutically acceptable salt thereof is formulated to administer atogepant in an amount of 10 mg, 30 mg, or 60 mg once daily.

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