Assessment of the Potential for Drug–Drug Interactions Between INP104 and Gepants for Migraine Management Using a Model-based Approach (P12-12.008)

Abstract

<h3>Objective:</h3> To predict whether coadministration of INP104 and gepants for migraine management results in potential drug–drug interactions (DDIs). <h3>Background:</h3> Nasally administered dihydroergotamine mesylate (DHE; INP104) and orally administered gepants are approved migraine therapies. DHE has broad receptor coverage (serotonergic, adrenergic, and dopaminergic), while gepants are calcitonin gene-related peptide (CGRP) receptor antagonists. It is likely that INP104 and gepants will be coadministered; however, no clinical studies investigating possible DDIs between these agents exist. <h3>Design/Methods:</h3> This was a critical evaluation for potential pharmacokinetic or pharmacodynamic DDIs between INP104 and atogepant, rimegepant, or ubrogepant. Quantitative predictions were assessed according to methods/criteria from current regulatory authority guidelines on in vitro DDIs. These predictions and their ability to sufficiently rule out clinically relevant interactions based on available data from applicable documents and publications were assessed. Whether DHE is an inhibitor/inducer of DDIs or is inhibited/induced by DDIs was also investigated. <h3>Results:</h3> All three gepants are principally cleared by hepatic metabolism and are sensitive substrates of CYP3A4, suggesting that gepant pharmacokinetics is potentially influenced by CYP3A4 inhibitors/inducers. DHE is not an in vitro inhibitor of CYP3A4 activity. Clinically relevant in vivo DDIs arising from inhibition of hepatic/gastrointestinal CYP3A4 by DHE can be excluded. DHE is principally cleared by hepatic metabolism and is considered a CYP3A4 substrate; coadministration of potent CYP3A4 inhibitors with DHE is contraindicated. None of the three gepants is a potent inhibitor/inducer of CYP3A4. Data exclude clinically relevant DDIs from hepatic/gastrointestinal metabolic inhibition by gepants or from nasal metabolic inhibition of DHE. No clinically relevant DDIs from inhibition of, or being a substrate for, transporter proteins by gepants or DHE are anticipated because of limited data, but cannot be excluded. <h3>Conclusions:</h3> Based on available data, no DDIs of clinical concern are predicted when recommended clinical doses of INP104 and gepants are coadministered. <b>Disclosure:</b> Dr. Ray has received personal compensation for serving as an employee of Impel Pharmaceuticals. Dr. Ray has stock in Impel Pharmaceuticals. Brad Torphy has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Amgen. Brad Torphy has received personal compensation in the range of $0-$499 for serving as a Consultant for Novartis. Brad Torphy has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Impel. Brad Torphy has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Teva. Brad Torphy has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbvie. Brad Torphy has received personal compensation in the range of $100,000-$499,999 for serving on a Speakers Bureau for Abbvie. Brad Torphy has received personal compensation in the range of $100,000-$499,999 for serving on a Speakers Bureau for Amgen. Brad Torphy has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biohaven. Brad Torphy has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Impel. Brad Torphy has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Lilly. Brad Torphy has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Lundbeck. Brad Torphy has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Teva. The institution of Brad Torphy has received research support from Amgen. The institution of Brad Torphy has received research support from Teva. The institution of Brad Torphy has received research support from Theranica. The institution of Brad Torphy has received research support from Abbvie. Dr. Joshi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Joshi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Dr. Joshi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lilly. Dr. Joshi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. Dr. Joshi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Currax. Dr. Joshi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Relivion. Dr. Joshi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nerivio. Dr. Joshi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Axiome. Dr. Joshi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biohaven. Dr. Joshi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck. Dr. Joshi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Abbvie. Dr. Joshi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Amgen. Dr. Joshi has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Lilly. Dr. Joshi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Teva. Dr. Joshi has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Impel. Dr. Joshi has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Biohaven. The institution of Dr. Joshi has received research support from Lilly . The institution of Dr. Joshi has received research support from Biohaven. The institution of Dr. Joshi has received research support from Amgen. Dr. Vann has received personal compensation for serving as an employee of Impel Neuropharma. Dr. Vann has received personal compensation for serving as an employee of Biogen. Mr. Downing has received personal compensation for serving as an employee of Impel Pharmaceuticals . Ms. Fonseca has received personal compensation for serving as an employee of Impel Pharmaceuticals. Ms. Fonseca has stock in Impel Pharmaceuticals. Dr. Shrewsbury has received personal compensation for serving as an employee of Impel NeuroPharma. Dr. Shrewsbury has received stock or an ownership interest from Impel NeuroPharma. Dr. Aurora has received personal compensation for serving as an employee of Impel Neuropharma. Dr. Aurora has stock in Impel Neurpharma.