A Phase 1 Study to Evaluate the Bioequivalence of Oral Tablet … · 2018-09-21 · A Phase 1 Study...
1
References: 1. Dahlöf C et al. J Headache Pain. 2004;5:115-122.; 2. Lipton RB et al. Headache. 1999;39(s2):S20-S26.; 3. Lipton RB et al. Headache. 2002;42 Suppl 1:3-9.; 4. Malik SN et al. Headache. 2006;46(5):773-780.; 5. Mitsikostas DD et al. J Headache Pain. 2017;18(1):102.; 6. Loder E et al. Headache. 2001;41(8):745-753.; 7. Dowson AJ et al. Curr Med Res Opin. 2005;21 Suppl 3:S13-17.; 8. Dowson AJ et al. Int J Clin Pract. 2003;57(7):573-576.; 9. Delini-Stula A et al. Int J Psychiatry Clin Pract. 2009;13(2):109-116. Acknowledgments RC, AI, DS, JH, BAM, JS, CJ, and VC are employees and stockholders in Biohaven Pharmaceuticals; J-AM, RL, and MT are employees of Syneos Health; RBL has received honoraria and research support from Biohaven Pharmaceuticals; he is also a stockholder • Patient preference is an important component of drug selection in the acute treatment of migraine 1 • In some patients, the affinity for a particular type of migraine treatment does not completely align with standard efficacy endpoints, such as pain relief, 1 that might be expected to predict preference • This helps to explain why a rapid onset of relief is consistently ranked among the most important attributes of acute migraine medications 2-4 • When offered a choice between delivery systems for acute treatment, the vast majority of patients with headache conditions (~90%) prefer oral formulations 5 • Because of the convenience and perceived rapid onset of action with Orally Dissolving Tablet (ODT) formulations, patients with migraine have been shown to prefer them to traditional oral tablets 6-8 • Adherence to drug therapy is generally poor in migraine, 5 and drug delivery via ODT may improve patient adherence to prescribed regimens 9 • Following oral administration, ODTs are rapidly dissolved and absorbed without the need for additional fluid, which facilitates easy administration of acute treatment to headache patients • Rimegepant is an orally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine • Two formulations of rimegepant are being developed: – A conventional oral tablet – An ODT utilizing the Zydis ® fast-dissolve technology • Two Phase 3 clinical trials of rimegepant oral tablet for the acute treatment of migraine have been completed (Study 301, NCT03235479; Study 302, NCT03237845) • A pharmacokinetic (PK) comparison of rimegepant ODT versus rimegepant tablet is required to characterize their individual PK profiles and ascertain bioequivalence Introduction Objectives • A total of 35 subjects was enrolled, and 34 subjects (97.1%) completed the study • The demographic characteristics of the study population are shown in Table 1 Results Characteristic Age, years, mean (SD) 37.7 (9.5) Sex, n (%) Male 28 (80.0) Female 7 (20.0) Race, n (%) White 28 (80.0) Non-White 7 (20.0) BMI, kg/m 2 25.85 Weight, kg 76.6 Conclusions • This study demonstrates that, based on the rate and extent of absorption, rimegepant ODT administered sublingually and rimegepant oral tablet are bioequivalent • Rimegepant ODT and rimegepant oral tablet were well tolerated • The earlier T max seen with rimegepant ODT versus oral tablet is a PK advantage that might translate into an earlier onset of action for this fast-dissolving ODT formulation • The results of a Phase 3 clinical trial of rimegepant ODT for the acute treatment of migraine are pending (Study 303, NCT03461757) 17 th Biennial Migraine Trust International Symposium | 6-9 September 2018 | London, UK To download a copy of this poster, scan code. A Phase 1 Study to Evaluate the Bioequivalence of Oral Tablet and Orally Dissolving Tablet Formulations of Rimegepant, a Small Molecule CGRP Receptor Antagonist Robert Croop, MD 1 ; Andrea Ivans, MHS 1 ; David Stock, PhD 1 ; Jennifer Hould, BA 1 ; Beth A. Morris, BA 1 ; Joe Stringfellow, MS 1 ; Christopher M. Jensen, PharmD 1 ; Julie-Alexandra Moulin, MSc 2 ; Richard Larouche, BPharm, MD 2 ; Mario Tanguay, BPharm, PhD 2 ; Vladimir Coric, MD 1 ; Richard B. Lipton, MD 3 1 Biohaven Pharmaceuticals, New Haven, CT, USA; 2 Syneos Health, Quebec, Canada; 3 Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA • The objectives of this study were to: – Compare the rate and extent of absorption of rimegepant ODT administered sublingually versus rimegepant oral tablet administered as 1 x 75 mg in healthy, fasted volunteers – Assess the safety, tolerability, and PK of rimegepant ODT and rimegepant oral tablet Methods • This was a single-center, Phase 1, open-label, randomized 4-period bioequivalence study • Subjects were screened within 28 days of the administration of study medications Subjects • The study population included members of the community at large who were recruited via advertisements in various media (eg, radio, newspaper, online) • Healthy adult nonsmokers, aged 18 to 55 years, with BMI between 18.5 and 30.0 kg/m 2 and weight of at least 50.0 kg for males and 45.0 kg for females were eligible to participate • Any subject with a medical history, concurrent illness, or any physical or laboratory test finding that was likely to interfere with successful completion of the dosing procedure or analysis of results was excluded Safety • Seventeen subjects experienced adverse events (AEs) • Most AEs were mild, required no treatment, and did not result in withdrawal from the study • The only AEs reported by more than 1 subject were constipation (n=6); increased level of alanine transaminase (n=3, none >3x ULN); heart rate increase (n=2); headache (n=2); cold symptoms (n=2); and back pain (n=2) • One subject discontinued due to a moderate AE (external otitis), which was considered unrelated to treatment • No severe or serious AEs were reported Treatments • Subjects were given the 2 following treatments twice: – 75 mg rimegepant ODT administered sublingually held under the tongue until fully dissolved then swallowed without water – 75 mg rimegepant oral tablet swallowed with water • Doses were administered after a 10-hour overnight fast • Treatments were separated by washouts of at least 5 days Assessments • For analysis of the PK parameters AUC 0-t , AUC 0-inf , C max , and T max , blood samples were collected at baseline, 5, 10, 20, 30, 40, 50 minutes and 1, 1.5, 2, 2.5, 5, 8, 12, 24, 48, and 72 hours • Following analyses of AUC 0-t , AUC 0-inf , and C max — the primary PK endpoints — the formulations were considered bioequivalent if the 90% CI for the ratio of geometric means was within 80% to 125% Pharmacokinetic and Statistical Analyses • The PK analysis was performed using Phoenix ® WinNonlin ® • Inferential statistical analyses were performed using ln-transformed data and the MIXED procedure in SAS ® Zydis is a registered trademark of R.P. Scherer Technologies, Inc. Table 1. Demographics (N=35) PK Parameter Ratio a (%) 90% CI b (%) Lower Upper Ln(AUC 0-t ) 96.79 92.63 101.15 Ln(AUC 0-inf ) 96.81 92.66 101.14 Ln(C max ) 104.65 97.04 112.84 PK, pharmacokinetic; CI, confidence interval a Calculated using least squares means according to the formula: e (DIFFERENCE) X 100 b 90% Geometric Confidence Interval using ln-transformed data Table 2. Bioequivalence of Rimegepant ODT and Rimegepant Oral Tablet Subjects Pharmacokinetics • Statistical comparisons of the ln-transformed AUC 0-t , AUC 0-inf , and C max of rimegepant ODT administered sublingually versus rimegepant tablet showed that all 90% CIs of geometric mean ratios were within the predefined range (80%-125%) for bioequivalence (Table 2) • Median T max was 1.5 hours for rimegepant ODT administered sublingually versus 2 hours for rimegepant oral tablet • A statistical comparison, using Proc Mixed, found the least-squares means (standard errors) for rimegepant ODT and oral tablet to be 1.48 (0.098) hours and 1.92 (0.163) hours, respectively • The difference in time to peak concentration, 0.44 hours (26 minutes), was statistically significant (P=0.0021) Poster No. MTIS2018-170 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 for informational purposes only.
Transcript of A Phase 1 Study to Evaluate the Bioequivalence of Oral Tablet … · 2018-09-21 · A Phase 1 Study...
References: 1. Dahlöf C et al. J Headache Pain. 2004;5:115-122.; 2. Lipton RB et al. Headache. 1999;39(s2):S20-S26.; 3. Lipton RB et al. Headache. 2002;42 Suppl 1:3-9.; 4. Malik SN et al. Headache.2006;46(5):773-780.; 5. Mitsikostas DD et al. J Headache Pain. 2017;18(1):102.; 6. Loder E et al. Headache. 2001;41(8):745-753.; 7. Dowson AJ et al. Curr Med Res Opin. 2005;21 Suppl 3:S13-17.; 8. Dowson AJ et al. Int J Clin Pract. 2003;57(7):573-576.; 9. Delini-Stula A et al. Int J Psychiatry Clin Pract. 2009;13(2):109-116. Acknowledgments RC, AI, DS, JH, BAM, JS, CJ, and VC are employees and stockholders in Biohaven Pharmaceuticals; J-AM, RL, and MT are employees of Syneos Health; RBL has received honoraria and research support from Biohaven Pharmaceuticals; he is also a stockholder
• Patient preference is an important component of drug selection in the acute treatmentof migraine1
• In some patients, the affinity for a particular type of migraine treatment does notcompletely align with standard efficacy endpoints, such as pain relief,1 that might beexpected to predict preference
• This helps to explain why a rapid onset of relief is consistently ranked among the mostimportant attributes of acute migraine medications2-4
• When offered a choice between delivery systems for acute treatment, the vast majorityof patients with headache conditions (~90%) prefer oral formulations5
• Because of the convenience and perceived rapid onset of action with Orally DissolvingTablet (ODT) formulations, patients with migraine have been shown to prefer them totraditional oral tablets6-8
• Adherence to drug therapy is generally poor in migraine,5 and drug delivery via ODTmay improve patient adherence to prescribed regimens9
• Following oral administration, ODTs are rapidly dissolved and absorbed without theneed for additional fluid, which facilitates easy administration of acute treatment toheadache patients
• Rimegepant is an orally administered small molecule calcitonin gene-related peptide(CGRP) receptor antagonist in development for the acute treatment of migraine
• Two formulations of rimegepant are being developed:– A conventional oral tablet– An ODT utilizing the Zydis® fast-dissolve technology
• Two Phase 3 clinical trials of rimegepant oral tablet for the acute treatment of migrainehave been completed (Study 301, NCT03235479; Study 302, NCT03237845)
• A pharmacokinetic (PK) comparison of rimegepant ODT versus rimegepant tablet isrequired to characterize their individual PK profiles and ascertain bioequivalence
Introduction
Objectives
• A total of 35 subjects was enrolled, and 34 subjects (97.1%) completed the study• The demographic characteristics of the study population are shown in Table 1
Results
Characteristic
Age, years, mean (SD) 37.7 (9.5)Sex, n (%)
Male 28 (80.0)Female 7 (20.0)
Race, n (%)White 28 (80.0)Non-White 7 (20.0)
BMI, kg/m2 25.85Weight, kg 76.6
Conclusions• This study demonstrates that, based on the rate and extent of absorption,
rimegepant ODT administered sublingually and rimegepant oral tablet arebioequivalent
• Rimegepant ODT and rimegepant oral tablet were well tolerated• The earlier Tmax seen with rimegepant ODT versus oral tablet is a PK
advantage that might translate into an earlier onset of action for this fast-dissolving ODT formulation
• The results of a Phase 3 clinical trial of rimegepant ODT for the acutetreatment of migraine are pending (Study 303, NCT03461757)
17th Biennial Migraine Trust International Symposium | 6-9 September 2018 | London, UK To download a copy of this poster, scan code.
A Phase 1 Study to Evaluate the Bioequivalence of Oral Tablet and Orally Dissolving Tablet Formulations of Rimegepant, a Small Molecule CGRP Receptor AntagonistRobert Croop, MD1; Andrea Ivans, MHS1; David Stock, PhD1; Jennifer Hould, BA1; Beth A. Morris, BA1; Joe Stringfellow, MS1; Christopher M. Jensen, PharmD1; Julie-Alexandra Moulin, MSc2; Richard Larouche, BPharm, MD2; Mario Tanguay, BPharm, PhD2; Vladimir Coric, MD1; Richard B. Lipton, MD31Biohaven Pharmaceuticals, New Haven, CT, USA; 2Syneos Health, Quebec, Canada; 3Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA
• The objectives of this study were to:– Compare the rate and extent of absorption of rimegepant ODT administered
sublingually versus rimegepant oral tablet administered as 1 x 75 mg in healthy,fasted volunteers
– Assess the safety, tolerability, and PK of rimegepant ODT and rimegepant oral tablet
Methods• This was a single-center, Phase 1, open-label, randomized 4-period bioequivalence
study• Subjects were screened within 28 days of the administration of study medications
Subjects• The study population included members of the community at large who were recruited
via advertisements in various media (eg, radio, newspaper, online)• Healthy adult nonsmokers, aged 18 to 55 years, with BMI between 18.5 and 30.0 kg/m2
and weight of at least 50.0 kg for males and 45.0 kg for females were eligible toparticipate
• Any subject with a medical history, concurrent illness, or any physical or laboratory testfinding that was likely to interfere with successful completion of the dosing procedureor analysis of results was excluded
Safety• Seventeen subjects experienced adverse events (AEs)• Most AEs were mild, required no treatment, and did not result in withdrawal from the
study• The only AEs reported by more than 1 subject were constipation (n=6); increased level
of alanine transaminase (n=3, none >3x ULN); heart rate increase (n=2); headache(n=2); cold symptoms (n=2); and back pain (n=2)
• One subject discontinued due to a moderate AE (external otitis), which was consideredunrelated to treatment
• No severe or serious AEs were reported
Treatments• Subjects were given the 2 following treatments twice:
– 75 mg rimegepant ODT administered sublingually held under the tongue until fullydissolved then swallowed without water
– 75 mg rimegepant oral tablet swallowed with water• Doses were administered after a 10-hour overnight fast• Treatments were separated by washouts of at least 5 days
Assessments• For analysis of the PK parameters AUC0-t, AUC0-inf, Cmax, and Tmax, blood samples were
collected at baseline, 5, 10, 20, 30, 40, 50 minutes and 1, 1.5, 2, 2.5, 5, 8, 12, 24, 48, and 72 hours
• Following analyses of AUC0-t, AUC0-inf, and Cmax — the primary PK endpoints — theformulations were considered bioequivalent if the 90% CI for the ratio of geometric means was within 80% to 125%
Pharmacokinetic and Statistical Analyses• The PK analysis was performed using Phoenix® WinNonlin®
• Inferential statistical analyses were performed using ln-transformed data and the MIXEDprocedure in SAS®
Zydis is a registered trademark of R.P. Scherer Technologies, Inc.
Table 1. Demographics (N=35)
PK Parameter Ratioa (%) 90% CIb (%)
Lower Upper
Ln(AUC0-t) 96.79 92.63 101.15
Ln(AUC0-inf) 96.81 92.66 101.14
Ln(Cmax) 104.65 97.04 112.84PK, pharmacokinetic; CI, confidence intervalaCalculated using least squares means according to the formula: e(DIFFERENCE) X 100b90% Geometric Confidence Interval using ln-transformed data
Table 2. Bioequivalence of Rimegepant ODT and Rimegepant Oral Tablet
Subjects
Pharmacokinetics• Statistical comparisons of the ln-transformed AUC0-t, AUC0-inf, and Cmax of rimegepant
ODT administered sublingually versus rimegepant tablet showed that all 90% CIs of geometric mean ratios were within the predefined range (80%-125%) for bioequivalence (Table 2)
• Median Tmax was 1.5 hours for rimegepant ODT administered sublingually versus2 hours for rimegepant oral tablet
• A statistical comparison, using Proc Mixed, found the least-squares means (standarderrors) for rimegepant ODT and oral tablet to be 1.48 (0.098) hours and 1.92 (0.163)hours, respectively
• The difference in time to peak concentration, 0.44 hours (26 minutes), was statisticallysignificant (P=0.0021)
Poster No. MTIS2018-170
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 for informational purposes only.
![BeST - Bioequivalence Study Templatestudy carried out to evaluate the bioequivalence of two medicinal products. The bioequivalence studies are strictly regulated [1] and are therefore](https://static.fdocuments.us/doc/165x107/5ed9f97c28db2d5ca2492e81/best-bioequivalence-study-template-study-carried-out-to-evaluate-the-bioequivalence.jpg)