Rimegepant 75 mg in Subjects with Hepatic Impairment: Results of a Phase 1, Open-label, Single-dose, Parallel-group Study Robert Croop, MD 1 ; Joseph Stringfellow, MS 2 ; Andrea Ivans, MHS 1 ; Vladimir Coric, MD 1 1 Biohaven Pharmaceuticals, Inc., New Haven, CT; 2 DataCeutics, Inc., Pottstown, PA Poster No. P241LB References: 1. Lipton RB et al. Cephalalgia. 2018;38(1 suppl):123-55 (abstract MTIS2018-171); 2. Lipton RB et al. AAN 2019 Emerging Science presentation (Data Blitz #005, Poster #075); 3. Coric V et al. Psychiatry (Edgmont). 2009;6:26–31. Disclosures This study was sponsored by Biohaven Pharmaceuticals. RC, AI, and VC are employed by and own stock/stock options in Biohaven Pharmaceuticals. • The pharmacokinetics (PK) of many orally administered medications for the acute treatment of migraine, including nonsteroidal anti-inflammatory drugs and triptans, can be significantly affected by mild or moderate hepatic impairment; severe impairment is usually a contraindication • Rimegepant is an orally administered small molecule calcitonin gene-related peptide receptor antagonist that has demonstrated efficacy and safety in the acute treatment of migraine in 3 separate Phase 3 clinical trials 1,2 • The effects of hepatic impairment on the PK of rimegepant have not been assessed • The objective of this study was to determine the effect of various categories of severity of hepatic impairment on the PK of rimegepant following a single 75-mg dose in subjects with normal hepatic function and with mild, moderate, or severe hepatic impairment Objective • This was a 2-center, Phase 1, open-label, single-dose, 4-group PK study Methods • Subjects included adult nonsmokers aged ≥18 and ≤80 years, with body mass index (BMI) ≥18.0 and ≤ 40.0 kg/m 2 weight ≥50.0 kg (males) and ≥45.0 kg (females); and a score of 0 on the Sheehan Suicidality Tracking Scale (S-STS) 3 • Healthy volunteers were matched with subjects with hepatic impairment according to sex, age (±10 years), and BMI (±15%) to the extent possible • Subjects were assigned to groups according to their degree of hepatic impairment based on Child-Pugh score (Table 1) Subjects • Primary PK endpoints: area under the curve from time 0 to the last quantifiable concentration time point (AUC) 0-t , AUC from time 0 to infinity (AUC 0-inf ), and maximum observed plasma concentration (C max ) calculated for rimegepant • Safety assessments: AEs, ECGs, vital signs, physical measurements, routine laboratory tests, including liver function tests Assessments • For plasma rimegepant, analysis of variance (ANOVA) was performed on untransformed K el and T 1/2 el and on log (ln)-transformed AUC 0-t , AUC 0-inf , and C max at the alpha level of .05 • Ratios (mild/control, moderate/control, severe/control) and 90% geometric confidence intervals (CIs) were calculated according to ANOVA results for AUC 0-t , AUC 0-inf , and C max ; coefficient of variation was also estimated • Rimegepant T max was analyzed nonparametrically (Hodges-Lehmann) with point estimates and 90% CIs for the median differences of T max between groups (mild- control, moderate-control, and severe-control) Statistical Analysis Introduction Group N Hepatic Impairment Child-Pugh Score, points 1 18 Healthy subjects/Normal Control 2 6 Mild 5-6 3 6 Moderate 7-9 4 6 Severe 10-15 Table 1. Subjects Grouped by Degree of Hepatic Impairment • Subjects were confined at the research facility from the morning of Day −1 until after the 96-hour (Group 1) or the 120-hour postdose blood draw (Groups 2, 3, and 4) Mild Moderate Severe Parameter Mean±SD CV% Control (N = 6) Impairment (N = 6) Control (N = 6) Impairment (N = 6) Control (N = 6) Impairment (N = 6) AUC 0-t (hr*ng/mL) 4677.18 ±524.52 11.21 4305.24 ±2363.69 54.90 3879.40 ±1105.39 28.49 4348.12 ±1911.11 43.95 4002.12 ±779.46 19.48 8728.28 ±2601.48 31.43 AUC 0-inf (hr*ng/mL) 4693.36 ±523.84 11.16 4327.62 ±2364.16 54.63 3899.31 ±1107.77 28.41 4365.51 ±1908.00 43.71 4019.71 ±772.81 19.23 8323.15 ±2641.58 31.74 C max (ng/mL) 614.69 ±155.83 25.35 591.35 ±218.90 37.02 565.09 ±151.87 26.87 597.05 ±406.85 68.14 715.97 ±200.70 28.03 1367.50 ±487.66 35.66 Conclusions • Exposure to rimegepant 75 mg oral tablet was similar among subjects with mild or moderate hepatic impairment and matched controls • Among subjects with severe hepatic impairment, AUC and C max were increased by approximately 2-fold versus matched controls • Rimegepant was well tolerated in healthy adults and in subjects with mild, moderate, or severe hepatic impairment Results cont. • 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 • Three (8.3%) subjects reported at least 1 treatment-emergent adverse event (TEAE): 2 in the control group and 1 in the group with severe hepatic impairment • No event was reported in more than 1 subject • All events were reported as mild in intensity • One TEAE of sinus tachycardia (noted on ECG) in 1 subject with severe hepatic impairment was mild in intensity, judged by the investigator to be possibly related to study treatment, and resolved within 5 hours without treatment • There were no clinically meaningful changes from baseline in clinical laboratory values, vital signs, ECGs, or the S-STS • Abnormalities of liver function parameters seen in the hepatic impairment groups were consistent with these subjects’ underlying condition Safety Pharmacokinetics • For the secondary PK endpoints, shown in Table 3, there were no significant differences in untransformed K el or T ½ el in subjects with mild, moderate, or severe hepatic impairment compared with matched controls • Using the nonparametric Hodges-Lehmann method, the 90% CIs (interval midpoints) for the difference in T max between subjects with severe hepatic impairment and matched controls were: – −1.483 to .017 (−.733 hours) for subjects with mild hepatic impairment – −.983 to 1.033 (.025 hours) for subjects with moderate hepatic impairment – −1.517 to −.483 (−1 hours) for subjects with severe hepatic impairment Table 3. Secondary Pharmacokinetic Endpoints Results • All 36 enrolled subjects were dosed, completed the study, and evaluated for safety and PK • The overall median age was 55.1 years; 94.4% of subjects were male, and 91.7% were White Subjects Pharmacokinetics • Among subjects with severe hepatic impairment: – Administration of rimegepant 75 mg resulted in approximately 2-fold increases in AUC and C max versus matched controls (Figure 1 and Table 2) – The ratio for ln-transformed AUC 0-t was 202.25 (P<.001), for ln-transformed AUC 0-inf was 202.21 (P<.001), and for ln-transformed C max was 189.14 (P=.009) versus matched controls • Among subjects with mild or moderate hepatic impairment, administration of a single 75 mg dose of rimegepant did not result in notable differences in AUC and C max versus matched controls (Table 2, Figures 2 and 3) Figure 1a. Mean Plasma Concentrations, Severe Impairment, Linear Scale Figure 1b. Mean Plasma Concentrations, Severe Impairment, Semi-log Scale Mild Moderate Severe Parameter Control (N = 6) Impairment (N = 6) Control (N = 6) Impairment (N = 6) Control (N = 6) Impairment (N = 6) T max (hr), median Min–Max 2.734 1.967–3.983 1.750 1.000–3.000 1.984 1.467–4.950 2.250 1.000–8.000 2.000 1.500–3.133 1.250 1.000–2.000 T 1/2 el (hr), median Min–Max 11.546 9.042–13.678 10.448 5.451–26.195 14.291 7.205–18.248 14.489 7.520–19.442 10.942 8.456–21.418 15.743 5.943–16.376 K el , median Min–Max .0602 .0507–.0767 .0667 .0265–.1272 .0493 .0380–.0962 .0483 .0357–.0922 .0637 .0324–.0820 .0441 .0423–.1166 Results cont. Pharmacokinetics Table 2. Pharmacokinetic Parameters, Mild, Moderate, and Severe Impairment Figure 2. Mean Plasma Concentrations, Moderate Impairment, Linear Scale Figure 3. Mean Plasma Concentrations, Mild Impairment, Linear Scale American Headache Society 61 st Annual Scientific Meeting | July 11-14, 2019 | Philadelphia, PA To download a copy of this poster, scan QR code. Rimegepant is an investigational new drug, not approved or authorized for marketing in the U.S. or any country for any indication or treatment of any disease or condition. This material is being made available through Biohaven’s Medical Affairs Department.
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Rimegepant 75 mg in Subjects with Hepatic Impairment: Results of a Phase 1, Open-label, Single-dose, Parallel-group StudyRobert Croop, MD1; Joseph Stringfellow, MS2; Andrea Ivans, MHS1; Vladimir Coric, MD1
1 Biohaven Pharmaceuticals, Inc., New Haven, CT; 2 DataCeutics, Inc., Pottstown, PA
Poster No. P241LB
References: 1. Lipton RB et al. Cephalalgia. 2018;38(1 suppl):123-55 (abstract MTIS2018-171); 2. Lipton RB et al. AAN 2019 Emerging Science presentation (Data Blitz #005, Poster #075); 3. Coric V et al. Psychiatry (Edgmont). 2009;6:26–31.Disclosures This study was sponsored by Biohaven Pharmaceuticals. RC, AI, and VC are employed by and own stock/stock options in Biohaven Pharmaceuticals.
• The pharmacokinetics (PK) of many orally administered medications for the acute treatment of migraine, including nonsteroidal anti-inflammatory drugs and triptans, can be significantly affected by mild or moderate hepatic impairment; severe impairment is usually a contraindication
• Rimegepant is an orally administered small molecule calcitonin gene-related peptide receptor antagonist that has demonstrated efficacy and safety in the acute treatment of migraine in 3 separate Phase 3 clinical trials1,2
• The effects of hepatic impairment on the PK of rimegepant have not been assessed
• The objective of this study was to determine the effect of various categories of severity of hepatic impairment on the PK of rimegepant following a single 75-mg dose in subjects with normal hepatic function and with mild, moderate, or severe hepatic impairment
Objective
• This was a 2-center, Phase 1, open-label, single-dose, 4-group PK study Methods
• Subjects included adult nonsmokers aged ≥18 and ≤80 years, with body mass index (BMI) ≥18.0 and ≤ 40.0 kg/m2 weight ≥50.0 kg (males) and ≥45.0 kg (females); and a score of 0 on the Sheehan Suicidality Tracking Scale (S-STS)3
• Healthy volunteers were matched with subjects with hepatic impairment according to sex, age (±10 years), and BMI (±15%) to the extent possible
• Subjects were assigned to groups according to their degree of hepatic impairment based on Child-Pugh score (Table 1)
Subjects
• Primary PK endpoints: area under the curve from time 0 to the last quantifiable concentration time point (AUC)0-t, AUC from time 0 to infinity (AUC0-inf), and maximum observed plasma concentration (Cmax) calculated for rimegepant
• Safety assessments: AEs, ECGs, vital signs, physical measurements, routine laboratory tests, including liver function tests
Assessments
• For plasma rimegepant, analysis of variance (ANOVA) was performed on untransformed Kel and T1/2 el and on log (ln)-transformed AUC0-t, AUC0-inf, and Cmax at the alpha level of .05
• Ratios (mild/control, moderate/control, severe/control) and 90% geometric confidence intervals (CIs) were calculated according to ANOVA results for AUC0-t, AUC0-inf, and Cmax; coefficient of variation was also estimated
• Rimegepant Tmax was analyzed nonparametrically (Hodges-Lehmann) with point estimates and 90% CIs for the median differences of Tmax between groups (mild-control, moderate-control, and severe-control)
Statistical Analysis
Introduction
Group N Hepatic Impairment Child-Pugh Score, points1 18 Healthy subjects/Normal Control2 6 Mild 5-63 6 Moderate 7-94 6 Severe 10-15
Table 1. Subjects Grouped by Degree of Hepatic Impairment
• Subjects were confined at the research facility from the morning of Day −1 until after the 96-hour (Group 1) or the 120-hour postdose blood draw (Groups 2, 3, and 4)
Mild Moderate SevereParameter
Mean±SD CV%
Control (N = 6)
Impairment(N = 6)
Control (N = 6)
Impairment (N = 6)
Control(N = 6)
Impairment (N = 6)
AUC0-t (hr*ng/mL)4677.18±524.52
11.21
4305.24±2363.69
54.90
3879.40±1105.39
28.49
4348.12±1911.11
43.95
4002.12±779.4619.48
8728.28±2601.48
31.43
AUC0-inf (hr*ng/mL)4693.36±523.84
11.16
4327.62±2364.16
54.63
3899.31±1107.77
28.41
4365.51±1908.00
43.71
4019.71±772.8119.23
8323.15±2641.58
31.74
Cmax (ng/mL)614.69±155.8325.35
591.35±218.9037.02
565.09±151.8726.87
597.05±406.8568.14
715.97±200.7028.03
1367.50±487.6635.66
Conclusions• Exposure to rimegepant 75 mg oral tablet was similar among subjects
with mild or moderate hepatic impairment and matched controls• Among subjects with severe hepatic impairment, AUC and Cmax were
increased by approximately 2-fold versus matched controls• Rimegepant was well tolerated in healthy adults and in subjects with
mild, moderate, or severe hepatic impairment
Results cont.
• 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
• Three (8.3%) subjects reported at least 1 treatment-emergent adverse event (TEAE): 2 in the control group and 1 in the group with severe hepatic impairment
• No event was reported in more than 1 subject• All events were reported as mild in intensity• One TEAE of sinus tachycardia (noted on ECG) in 1 subject with severe hepatic
impairment was mild in intensity, judged by the investigator to be possibly related to study treatment, and resolved within 5 hours without treatment
• There were no clinically meaningful changes from baseline in clinical laboratory values, vital signs, ECGs, or the S-STS
• Abnormalities of liver function parameters seen in the hepatic impairment groups were consistent with these subjects’ underlying condition
Safety
Pharmacokinetics• For the secondary PK endpoints, shown in Table 3, there were no significant
differences in untransformed Kel or T½ el in subjects with mild, moderate, or severe hepatic impairment compared with matched controls
• Using the nonparametric Hodges-Lehmann method, the 90% CIs (interval midpoints) for the difference in Tmax between subjects with severe hepatic impairment and matched controls were:– −1.483 to .017 (−.733 hours) for subjects with mild hepatic impairment– −.983 to 1.033 (.025 hours) for subjects with moderate hepatic impairment– −1.517 to −.483 (−1 hours) for subjects with severe hepatic impairment
Table 3. Secondary Pharmacokinetic Endpoints
Results
• All 36 enrolled subjects were dosed, completed the study, and evaluated for safety and PK
• The overall median age was 55.1 years; 94.4% of subjects were male, and 91.7% were White
Subjects
Pharmacokinetics• Among subjects with severe hepatic impairment:
– Administration of rimegepant 75 mg resulted in approximately 2-fold increases in AUC and Cmax versus matched controls (Figure 1 and Table 2)
– The ratio for ln-transformed AUC0-t was 202.25 (P<.001), for ln-transformed AUC0-inf was 202.21 (P<.001), and for ln-transformed Cmax was 189.14 (P=.009) versus matched controls
• Among subjects with mild or moderate hepatic impairment, administration of a single 75 mg dose of rimegepant did not result in notable differences in AUC and Cmax versus matched controls (Table 2, Figures 2 and 3)
Figure 1a. Mean Plasma Concentrations, Severe Impairment, Linear Scale
Figure 1b. Mean Plasma Concentrations, Severe Impairment, Semi-log Scale
Mild Moderate Severe
Parameter Control (N = 6)
Impairment(N = 6)
Control (N = 6)
Impairment (N = 6)
Control(N = 6)
Impairment (N = 6)
Tmax (hr), median Min–Max
2.7341.967–3.983
1.7501.000–3.000
1.9841.467–4.950
2.2501.000–8.000
2.0001.500–3.133
1.2501.000–2.000
T1/2 el (hr), median Min–Max
11.5469.042–13.678
10.4485.451–26.195
14.2917.205–18.248
14.4897.520–19.442
10.9428.456–21.418
15.7435.943–16.376
Kel , median Min–Max
.0602.0507–.0767
.0667.0265–.1272
.0493.0380–.0962
.0483.0357–.0922
.0637.0324–.0820
.0441.0423–.1166
Results cont.PharmacokineticsTable 2. Pharmacokinetic Parameters, Mild, Moderate, and Severe Impairment
Figure 2. Mean Plasma Concentrations, Moderate Impairment, Linear Scale
Figure 3. Mean Plasma Concentrations, Mild Impairment, Linear Scale
American Headache Society 61st Annual Scientific Meeting | July 11-14, 2019 | Philadelphia, PA To download a copy of this poster, scan QR code.
Rimegepant is an investigational new drug, not approved or authorized for marketingin the U.S. or any country for any indication or treatment of any disease or condition.This material is being made available through Biohaven’s Medical Affairs Department.
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