Research Fellow Pfizer, Inc. Groton, Connecticut, United States
Background: Rimegepant orally disintegrating tablet (ODT) is a calcitonin gene-related peptide receptor antagonist indicated for treatment of migraine in adults. A capsule (free base form), a conventional tablet, and the ODT (both tablets were hemisulfate sesquihydrate [HS] salt forms and are bioequivalent) were used during clinical development. This study used a physiologically-based pharmacokinetic (PBPK) model to assess the impact of increasing gastric pH on rimegepant ODT pharmacokinetics (PK). Methods: A combination of in vitro data and clinical PK data obtained following administration of 10 to 75 mg single dose rimegepant in healthy subjects was used to develop the PBPK model. Rimegepant absorption was predicted using an advanced dissolution absorption and metabolism (ADAM) model using the in vitro pH solubility profile for both the free base and the HS salt form, dissolution, and permeability data as input. The ADAM model also incorporated a P-glycoprotein component to account for the observed dose-dependent increase in fraction absorbed (fa) with increasing dose. The PBPK model for the free base form was verified using observed clinical drug-drug interaction data with famotidine, a gastric pH modifying agent. The PBPK model was applied to assess the effect of increased gastric pH on rimegepant PK for the HS salt form. Results: Increasing gastric pH values to 7.0 resulted in a significant effect on PK of the free-base form, with predicted ratios (pH 7 vs pH 1.5) for AUC and Cmax of 0.33 and 0.26, respectively, consistent with the observed ratios of 0.43 and 0.26. In contrast, a small effect on drug PK due to elevating gastric pH was predicted for the HS salt form, with ratios (pH 7 vs pH 1.5) for AUC and Cmax of 0.74 and 0.67, respectively (Table). Further sensitivity analysis of gastric pH in the range of 1.5 to 7.0 showed a significant decrease in predicted fa of the free base from 0.69 to 0.28; whereas the decrease in predicted fa of the HS salt form was from 0.65 to 0.51 in the same pH range. Conclusion: Rimegepant ODT (HS salt form) bioavailability is not sensitive to gastric pH elevations. Thus, clinically significant drug-drug interaction with pH modifying agents is not expected. These results were accepted by the European Medicines Agency and were used to inform the Summary of Product Characteristics.
