Rimegepant 75 mg in Subjects With Hepatic Impairment: Results of a Phase 1, Open‐Label, Single‐Dose, Parallel‐Group Study

Rimegepant is a small‐molecule calcitonin gene–related peptide receptor antagonist (gepant) with demonstrated efficacy and safety in the acute and preventive treatment of migraine. Here, we report the pharmacokinetics and safety of a single 75‐mg oral dose of rimegepant in subjects with severe, moderate, or mild hepatic impairment and matched healthy subjects from an open‐label, single‐dose, 4‐group phase 1 study. Thirty‐six subjects aged 41‐71 years were enrolled, including 6 each with severe, moderate, or mild hepatic impairment and 18 healthy subjects. All subjects completed the study. A <20% increase in total and unbound pharmacokinetics was observed in subjects with mild hepatic impairment and ≤65% increase with moderate hepatic impairment versus matched healthy controls. Total and unbound systemic exposure increased 2.0‐ and 3.9‐fold in the severe hepatic impairment group. In subjects with severe hepatic impairment, geometric mean ratios (severe impairment/controls) for total concentrations were 202.2% for area under the plasma concentration–time curve from time 0 to the last quantifiable concentration, 202.2% for area under the plasma concentration–time curve from time 0 to infinity, and 189.1% for maximum observed plasma concentration. Corresponding geometric mean ratios using unbound concentrations were 388.8% and 388.7%, respectively. Three (8.3%) subjects reported 4 treatment‐emergent adverse events. Rimegepant is not recommended for use in adults with severe hepatic impairment.

Migraine is a chronic neurobiological disorder with an overall prevalence of ≈15% (20.7% in women and 9.7% in men). 1 It is associated with cardiovascular disease, psychiatric disease, and sleep disordersand causes significant disability worldwide. 1,2 Rates of dissatisfaction with older migraine therapies have been reported by ≈50% of patients. 3 Accordingly, the need for new options to treat acute migraine attacks is a high priority, as many recommended therapies are often not effective in all patients, may have contraindications related to cardiovascular conditions in some individuals, and may be poorly tolerated in others. 4 Calcitonin gene-related peptide (CGRP) is an inflammatory mediator and a potent vasodilator associated with increased CGRP blood levels in people with migraine. [5][6][7] Small-molecule CGRP receptor antagonists (gepants) are relatively new drugs for the acute and preventive treatment of migraine. [8][9][10][11] Treatment with a CGRP receptor antagonist is believed to impact migraine pathophysiology by (1) blocking neurogenic inflammation, (2) reducing artery dilation, and (3) inhibiting pain transmission. 8,[10][11][12] This new class of antimigraine treatments (gepants) with new mechanisms to abort or prevent a migraine attack is devoid of the cardiovascular effects of triptans, providing a new approach for those with cardiovascular conditions or risk factors that may contraindicate triptan use. [13][14][15][16] The pharmacokinetics of many orally administered medications for the acute treatment of migraine, including nonsteroidal anti-inflammatory drugs 17 and triptans, 18,19 can be significantly affected by mild or moderate hepatic impairment. Severe hepatic impairment is often a contraindication for migraine medications. 20,21 Furthermore, several first-generation gepants with daily dosing have been associated with elevated levels of alanine aminotransferase (ALT) and signals of drug-induced liver injury, which led to termination of drug development. [22][23][24][25] Rimegepant (formerly known as BMS-927711 and BHV-3000) is an orally administered small-molecule CGRP receptor antagonist, second-generation gepant, with a novel mechanism that targets the underlying pathophysiology of migraine without causing vasoconstriction. 10,12,26 The pharmacokinetics of rimegepant were investigated in healthy male subjects following oral administration of [ 14 C]-rimegepant (data on file, Biohaven Pharmaceutical, Inc, which was acquired by Pfizer Inc. in 2022). Rimegepant pharmacokinetics are characterized by an absolute oral bioavailability of ≈64% with a maximum observed plasma concentration (C max ) achieved after 1.5 hours and plasma protein binding of ≈96%. Metabolism resulted in the formation of several inactive metabolites, and 77% of the dose is eliminated unchanged in feces and urine (twothirds of which is excreted in feces, which also includes unabsorbed drug based on the rimegepant bioavailability of 64%) with an average elimination half-life of ≈11 hours in patients with normal renal and hepatic function. 5,27 Rimegepant is primarily metabolized by cytochrome P450 (CYP) 3A4 and, to a lesser extent, by CYP2C9. 27 This is supported by in vivo studies that determined that coadministration of strong inhibitors of CYP3A4 (eg, itraconazole) resulted in significant increases in rimegepant exposure (area under the plasma concentration-time curve [AUC] increased 4-fold and C max 1.5-fold). Thus, it is recommended to avoid coadministration of rimegepant with strong CYP3A4 inhibitors and to administer the next dose of rimegepant at least 48 hours following coadministration with a moderate CYP3A inhibitor (eg, fluconazole). Inhibition of CYP2C9 only is not expected to significantly increase rimegepant exposure. Conversely, in vitro studies found that rimegepant exposure can be substantially reduced following coadministration with CYP3A4 inducers, such as rifampin. 27 Rimegepant is also a substrate of the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters in vitro; however, it is not a substrate of the organic anion transporting polypeptides 1B1 and 1B3. 27 A recent study in healthy subjects found that single doses of cyclosporine (strong P-gp and BCRP inhibitor) and quinidine (strong P-gp inhibitor) similarly increased oral rimegepant exposures (>50%, <2-fold). 28 Because cyclosporine and quinidine coadministration induced a similar effect on rimegepant exposure, the influence of BCRP inhibition on rimegepant exposure is minimal.
The efficacy and safety of rimegepant in the acute treatment of a single migraine attack was established in several phase 2b/3 randomized, placebo-controlled trials, with a sustained effect up to 48 hours. [29][30][31][32] Elevations in liver transaminases were reported infrequently (<4%), were comparable between the rimegepant and placebo groups, and mostly of mild severity (serum aspartate aminotransferase [AST] or ALT ≤3 upper limit of normal [ULN] or total bilirubin ≤2 ULN). [30][31][32] In 1 study, 1 participant in the rimegepant and placebo group had a transaminase concentration >3 × ULN; no participant in either group had elevations in bilirubin >2 × ULN. 33 Rimegepant is also effective for the preventive treatment of migraine. 33 The aim of this study was to evaluate the pharmacokinetics, safety, and tolerability profiles following a single 75-mg rimegepant oral dose in subjects with normal hepatic function and with mild, moderate, or severe hepatic impairment.

Study Design
This was a 2-center, phase 1, open-label, single-dose, 4-group, pharmacokinetic study in adult subjects with varying degrees of hepatic dysfunction and healthy volunteers who received a single oral 75-mg dose of rimegepant (Biohaven Pharmaceuticals, Inc., New Haven, CT, USA, which was acquired by Pfizer Inc. in 2022). The dose selected was based on the efficacy data from a phase 2b/3 study, 33 which was the dose used in all phase 3 studies. 30 Approximately 36 adult subjects were planned for enrollment, including 18 healthy subjects with normal hepatic function and at least 6 subjects each with mild, moderate, and severe hepatic impairment. Subjects with hepatic impairment were assigned to a group based on Child-Pugh score: mild hepatic impairment (5-6 points), moderate hepatic impairment (7-9 points), and severe hepatic impairment (10-15 points). The healthy subjects were matched with the subjects with hepatic impairment by age (±10 years), body mass index (±15%), and sex to the extent possible.
The study was guided on the basis of the ethical principles of Good Clinical Practice, the International Council for Harmonization Harmonized Tripartite Guideline, and all local laws and regulations. The study protocol and any amendments were reviewed and approved by the Institutional Review Board/Independent Ethics Committee for each site before initiation of the study, and subjects provided written informed consent.

Participants
Adult men or women aged 18-80 years (inclusive) with a body mass index of 18.0-40.0 kg/m 2 (inclusive) and body weight ≥50.0 kg for men and ≥45.0 kg for women were eligible for enrollment. All subjects were to be clinically stable including hepatic function; have a score of 0 on the Sheehan Suicidality Tracking Scale (S-STS) 34,35 ; and have no history of suicidal tendency, disposition to seizures, state of confusion, or clinically relevant psychiatric diseases.
Women were eligible for enrollment if they were not pregnant, lactating, or of reproductive potential.
Matched control subjects were determined by a health care professional to be healthy on the basis of findings from a medical history, physical examination, laboratory values, and electrocardiogram (ECG) within 4 weeks before dosing, including the absence of a clinically significant history of lactic acidosis and severe hepatomegaly with steatosis. In addition, subjects with normal hepatic function were nonsmokers (no use of tobacco products within 3 months before screening).
Subjects with hepatic impairment as assessed by Child-Pugh classification score were nonsmokers and/or light smokers (up to 5 cigarettes/day or equivalent). Hepatic impairment included those with documented history of cirrhosis diagnosed by ultrasonography, computed tomography scan, liver biopsy, or magnetic resonance imaging.
Key exclusion criteria for all individuals included history of clinically significant illness or surgery within 4 weeks before dosing; significant drug use or regular alcohol consumption within 6 months before the study; a positive result on drug/alcohol screening; and use of any drugs known to be strong inducers or strong inhibitors of hepatic drug metabolism within 30 days before study drug administration.
For subjects with normal hepatic function, other reasons for exclusion were a current diagnosis of viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, nonalcoholic fatty liver disease, alcoholic liver disease, or any other liver disease; a positive test for hepatitis B antigen or hepatitis C virus or HIV at screening; current or recent (within 3 months of study drug administration) gastrointestinal (GI) disease or GI surgery interfering with physiological absorption and motility; or use of medications other than topical products without significant systemic absorption.
For subjects with hepatic impairment, key exclusion criteria included hepatocellular carcinoma or acute hepatic disease from infection or drug toxicity; stage 3 or 4 encephalopathy; presence of surgically created or transjugular intrahepatic portal systemic shunts; estimated glomerular filtration rate <50 mL/min/1.73 m 2 at screening; clinically significant history or presence of any GI pathology, unresolved GI symptoms, or renal disease; use of concomitant medications other than those essential for the management of hepatic impairment and treatment of concomitant stable medical conditions; or concomitant treatment with interferon or other prohibited medications within 30 days of study drug administration.

Study Procedures
Subjects were to be confined at the research facility from the morning of study day −1 until after the 96-hour postdose blood draw (if normal hepatic function) or after the 120-hour postdose blood draw (if hepatic impairment). On study day 1, rimegepant was administered as a single oral dose under fasting conditions (at least 10 hours before dosing and 2 hours after dosing). For healthy subjects with normal hepatic function, a total of 20 blood samples were collected for quantitation of total rimegepant in plasma at 0 hours (before dosing) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours after dosing. For subjects with hepatic impairment, a total of 21 blood samples were drawn from each subject for quantitation of total rimegepant at the same time points as for healthy subjects and then at 120 hours after dosing. Quantitation of unbound rimegepant was calculated using the total and unbound plasma concentrations of rimegepant determined from samples collected at 1, 2, 12, and 24 hours after dosing.
At baseline (screening visit and/or study day −1), a physical examination, vital signs measurement, 12lead ECG, S-STS, routine laboratory tests (biochemistry, serology, hematology, coagulation, urinalysis, and serum cystatin C) were performed. In addition, a serum pregnancy test was performed at screening and on study day −1; a urine drug screen, a urine cotinine test (for healthy subjects only), and an alcohol breath test were performed at screening and before dosing.

Assessments
Pharmacokinetics. Single-dose pharmacokinetic parameters were estimated from the individual plasma rimegepant concentration-time profiles using noncompartmental analysis by Phoenix WinNonlin version 6.4 (Certara USA, Princeton, NJ, USA). Primary pharmacokinetic parameters included C max , area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable concentration time point (AUC 0-t ), and AUC from time 0 to infinity (AUC 0-inf ). Secondary end points were time to maximum plasma concentration (t max ), terminal elimination rate constant (K el ), apparent terminal elimination half-life (t 1/2el ), residual area, and apparent total body clearance (CL/F). The unbound fraction was calculated using the total and unbound plasma concentrations of rimegepant generated 1, 2, 12, and 24 hours after dosing. Subsequently, unbound AUC 0-t , unbound AUC 0-inf , and unbound C max were estimated.
Safety. Subjects were closely monitored for adverse events throughout the study. The incidence of adverse events was tabulated, and all adverse events were reviewed for their relation to rimegepant and clinical importance. Blood samples for clinical laboratory testing, including liver function tests, were collected at screening, on study day −1, on study day 1, and before study discharge. In addition, 12-lead ECG, vital signs, and physical examinations were performed before dosing and at the time of study discharge. S-STS was performed at screening and at study exit. A serum pregnancy test was performed on study day -1, and a urine pregnancy test was performed at study exit.

Bioanalytical Methods
Total and unbound (free) rimegepant was quantitatively determined in human dipotassium ethylenediaminetetraacetic acid plasma samples using a validated method by ultra-performance liquid chromatography with tandem mass spectrometry detection (inVentiv Health Clinique, Inc. (a Syneos Health group company, Québec, QC, Canada). The quantifiable range was 0.5 to 1000 ng/mL (1.0 to 500 ng/mL for unbound). The internal standard was BMS-927711-04. The validation was performed using an API 5000 liquid chromatography-tandem mass spectrometry system with Analyst software, version 1.6.1 or higher (SCIEX, Framingham, MA, USA). The precision of rimegepant calibration standards ranged from −2.39% to 5.20% (−1.90% to 0.85% unbound); the between-run accuracy bias ranged from −4.26% to 1.48% (−1.74% to 0.76% unbound), and the within-run accuracy bias ranged from −2.94% to 3.73% (−1.56% to −0.40% unbound). The accuracy and precision of quality control samples was ≤15% (≤20% at the lower limit of quantitation), and calibration curves for the liquid chromatography-tandem mass spectrometry bioanalytical assay were within acceptable limits. Additional details for analysis of rimegepant in plasma have been previously reported. 28 For plasma protein binding, the analysis of total rimegepant in human dipotassium ethylenediaminetetraacetic acid plasma was performed using the above bioanalytical method. However, the analysis of free (unbound) rimegepant was performed using an ultrafiltration method. 36

Statistical Analysis
Individual and descriptive rimegepant plasma concentration-time data were presented for all participants by hepatic function group in a tabular form and displayed graphically by participant group. Descriptive statistics (arithmetic and geometric means, standard deviation, coefficient of variation, minimum, maximum, and median) are presented for all the pharmacokinetic parameters including C max , t max , AUC 0-t , AUC 0-inf , K el , and t 1/2el . Descriptive summaries were also provided for unbound rimegepant C max and AUC.
For plasma rimegepant, using generalized linear model procedures in SAS version 9.4 (SAS Institute, Cary, NC, USA), an analysis of variance (ANOVA) was performed on total untransformed K el and t 1/2el and on total and unbound log-transformed AUC 0-t , AUC 0-inf , and C max at the alpha level of 0.05. Factors incorporated in the model included group (control [normal hepatic function] and mild, moderate, and severe hepatic impairment) as a fixed effect. Each statistical comparison (ie, mild vs control, moderate vs control, and severe vs control) was done separately, and only the matching controls of the appropriate group (controls for mild, moderate, and severe) were used for each of the comparisons. Estimates for missing data were not extrapolated or interpolated. The ratios (mild/control, moderate/control, and severe/control), based on geometric least square means, and 90% geometric confidence intervals were calculated according to ANOVA results for AUC 0-t , AUC 0-inf , and C max .
Relationships between the derived Child-Pugh total score and rimegepant pharmacokinetic parameters, based on total rimegepant plasma concentrations, were explored using a regression analysis for AUC 0-t , AUC 0-inf , C max , and CL/F on derived Child-Pugh total score, with Child-Pugh total score as the independent variable and the pharmacokinetic parameter as the dependent variable. A graphical description of the relationship between the Child-Pugh classification scores and primary rimegepant pharmacokinetic parameters was presented. Safety data were summarized using descriptive statistics.

Study Population
Of the 131 subjects who were screened, 65 (49.6%) were screen failures. Fifty-four (41.2%) of the screened  subjects were enrolled in the study. As planned, 36 subjects were dosed with rimegepant and completed the study. No subject was withdrawn from the study. The first subject was enrolled on September 5, 2017, and the last subject was completed on February 19, 2018. All 36 subjects were included in the safety and pharmacokinetic population analyses. Demographic characteristics were generally well balanced between each hepatic impairment group and matched control group ( Table 1). The overall mean (standard deviation) age for the safety population was 55.1 (6.8) years, 94.4% of subjects were men, and most subjects were White (91.7%). Hepatic impairment was defined at screening by Child-Pugh scores of 6 points for all 6 subjects with mild disease, 7 points (n = 4) or 8 points (n = 2) for subjects with moderate disease, and 10 points (n = 2) or 11 points (n = 4) for subjects with severe disease. Eight subjects had positive results on hepatitis C virus antibody testing at screening, including 4 subjects with mild hepatic impairment and 2 subjects each with moderate and severe hepatic impairment.

Pharmacokinetics
Total Rimegepant. Single-dose total rimegepant mean plasma concentration-time profiles (semilogarithmic scales) in subjects with mild, moderate, and severe hepatic impairment compared with matched healthy volunteers are shown in Figure 1A-C. Median t max of rimegepant ranged from 1.3 to 2.3 hours among the 3 hepatic impairment groups, similar to matched controls (Table 2). However, subjects with moderate and severe hepatic impairment had longer (50%) median t 1/2el (14-15 hours) compared with subjects with mild hepatic impairment (10 hours) (   compared with 12.7 hours among matched controls. However, ANOVA revealed no significant differences in untransformed K el or t 1/2el in subjects with mild, moderate, or severe hepatic impairment compared with matched controls. Among subjects with mild or moderate hepatic impairment, administration of a single 75mg dose of rimegepant was not associated with notable differences in AUC and C max versus matched controls ( Table 2, Figures 1 and 2). On the contrary, subjects with severe hepatic impairment had 2-fold increases in AUC and C max versus matched controls following a single rimegepant 75-mg dose (Table 2, Figure 1C). Statistical comparisons of the pharmacokinetic parameters for subjects with varying degrees of hepatic impairment and matched control groups including the ratios of geometric least square means following administration of a single 75-mg dose of rimegepant revealed no significant differences in AUC or C max for the mild and moderate hepatic impairment groups compared with the matched control groups (Table 3). There was a 2-fold increase in AUC and C max in the severe hepatic impairment group compared with the matched control group, with ratios for the severe hepatic impairment group compared with the matched control group of 202% for AUC (P < .001) and 189% for C max (P = .009).
Unbound Rimegepant. For unbound rimegepant, systemic exposure was higher in the severe hepatic   impairment groups versus the matched controls, whereas <20% to ≤65% increases were observed between the mild and moderate hepatic impairments versus the matched controls (Table 2). When compared with matched subjects with normal hepatic function, the unbound geometric mean AUC and C max were increased by 3.9-fold and 3.6-fold, respectively, in subjects with severe hepatic impairment; by 65% and 33%, respectively, in subjects with moderate hepatic impair-ment; and by 8% and 19%, respectively, in subjects with mild hepatic impairment (Table 3).

Relationship Between Extent of Hepatic Impairment and Rimegepant Exposure
Relationships between the derived Child-Pugh total score and rimegepant pharmacokinetic parameters, based on total plasma concentrations, were explored using a regression analysis for AUC 0-t , AUC 0-inf , C max , and CL/F on derived Child-Pugh total score, with Child-Pugh total score as the independent variable and the pharmacokinetic parameter as the dependent variable. A positive correlation was observed between Child-Pugh total score and AUC 0-t (r 2 = 0.48), AUC 0-inf (r 2 = 0.48), and C max (r 2 = 0.55) ( Table 4, Figure 2A-C). A nonsignificant negative relationship between Child-Pugh score and CL/F was observed (data not shown).

Safety and Tolerability
A single 75-mg oral dose of rimegepant was well tolerated in healthy adult subjects and in subjects with mild, moderate, and severe hepatic impairment. No deaths, serious adverse events, or adverse events leading to discontinuation were reported during the study. A total of 3 (8.3%) subjects reported 4 treatment-emergent adverse events, which were all mild in intensity. The 4 events included presyncope, procedural dizziness, and pruritus in 2 subjects with normal hepatic function and sinus tachycardia (noted on ECG) in 1 subject with severe hepatic impairment. The treatment-emergent adverse event of sinus tachycardia was judged by the investigator to be possibly related to study treatment and resolved within 5 hours without treatment.
No clinically meaningful changes from baseline in clinical laboratory values, vital signs, ECGs, or the S-STS were identified in this study. Abnormalities of liver chemistries (ALT, AST, alkaline phosphatase, and/or bilirubin) seen in the hepatic impairment groups were consistent with these subjects' underlying condition. No elevations in liver chemistries were observed in the 18 healthy control subjects.

Discussion
Rimegepant is the first migraine agent approved for both the acute and preventive treatment of migraine. Because rimegepant is primarily metabolized by hepatic CYP isoenzymes (CYP3A4), 27 this study evaluated rimegepant's disposition following single 75-mg doses in healthy adult subjects with normal hepatic function and subjects with mild, moderate, or severe hepatic impairment. Overall, administration of a single 75-mg dose of rimegepant to subjects with mild or moderate hepatic impairment did not result in appreciable differences in total systemic exposure compared with matched controls. Although t max was generally similar across all hepatic impairment groups, systemic exposure of total (bound) rimegepant was significantly (2-fold) higher in subjects with severe hepatic impairment, as supported by significantly higher geometric least square mean ratios of 202% for AUC and 189% for C max, compared to healthy adult controls. The more than doubling of rimegepant exposure, using total plasma concentrations, was significantly correlated with higher Child-Pugh total scores, indicating subjects with higher Child-Pugh scores tended to have higher exposures and higher maximum rimegepant concentrations. Regardless of hepatic impairment status, a single oral 75-mg dose of rimegepant was safe and well tolerated in all participants.
Systemic exposure of the free (unbound) fraction of rimegepant was increased in subjects with hepatic impairment. The unbound geometric mean ratios of AUC and C max in subjects with moderate hepatic impairment versus matched control subjects with normal hepatic function were increased by 65% and 33%, respectively, and by 8% and 19%, respectively, in those with mild hepatic impairment; considering the variability associated with rimegepant free fraction, a <2-fold increase in the unbound AUC and C max of rimegepant in moderate hepatic impairment is not likely to have appreciable impact on the safety of rimegepant. However, the unbound geometric mean ratios of AUC and C max in subjects with severe hepatic impairment were ≥3.9and ≥3.6-fold higher, respectively, versus subjects with normal hepatic function, providing further evidence that the increases in exposure in hepatic impairment are of a clinically relevant magnitude. Rimegepant is not recommended for administration in subjects with severe hepatic impairment.
Rimegepant's safety and tolerability profile has been reported in several phase 2 and phase 3 studies in individuals with migraine. [29][30][31][32] In a meta-analysis of pooled 3827 patients from 4 multicentered randomized controlled studies, the overall adverse event profile following a single 75-mg dose of rimegepant was similar to placebo. 37 Safety outcomes, including nausea, urinary tract infection, dizziness, and elevated ALT/AST, were not significantly different between rimegepant and placebo. In this study, no serious safety or tolerability issues following administration of a single oral dose of rimegepant were reported among participants with hepatic impairment. The use of 75-mg rimegepant was not associated with any specific adverse events. Although 1 participant with severe hepatic impairment reported a transient, nonserious event of sinus tachycardia, this event resolved without any intervention. Overall, this study provides additional support that a single 75-mg dose of rimegepant can be used safely in patients with migraine and mild or moderate hepatic impairment.

Conclusions
A <20% increase in the total and unbound exposures of a single 75-mg dose of rimegepant was observed in adults with mild hepatic impairment, and a ≤65% increase was observed in those with moderate hepatic impairment compared with the matched healthy controls. In contrast, unbound systemic exposure increased up to 3.9-fold among adults with severe hepatic impairment, providing evidence that the increases in exposure with severe hepatic impairment are of a clinically relevant magnitude. Rimegepant is not recommended for administration to individuals with severe hepatic im-pairment. In this single-dose study, 75-mg oral doses of rimegepant were safe and well-tolerated when administered to adults with hepatic impairment.