Reduced hepatic impairment study to evaluate pharmacokinetics and safety of zavegepant and to inform dosing recommendation for hepatic impairment

Abstract Zavegepant, a high‐affinity, selective, small‐molecule calcitonin gene‐related peptide (CGRP) receptor antagonist, is approved in the United States for acute treatment of migraine in adults. The effects of moderate hepatic impairment (8 participants with Child‐Pugh score 7–9 points) on the pharmacokinetics of a single 10‐mg intranasal dose of zavegepant versus eight matched participants with normal hepatic function were evaluated in a phase I study. Pharmacokinetic sampling determined total and unbound plasma zavegepant concentrations. Moderate hepatic impairment increased the exposure of total zavegepant (~2‐fold increase in AUC 0–inf and 16% increase in C max ) versus normal hepatic function, which is not considered clinically meaningful. The geometric least squares mean ratios (moderate impairment/normal) of plasma zavegepant AUC 0−inf and C max were 193% (90% confidence interval CI: 112, 333; p = 0.051) and 116% (90% CI: 69, 195; p = 0.630), respectively. The geometric mean fraction unbound of zavegepant was similar for participants with moderate hepatic impairment (0.13; coefficient of variation CV 13.71%) versus those with normal hepatic function (0.11; CV 21.43%). Similar exposure findings were observed with unbound zavegepant versus normal hepatic function (~2.3‐fold increase in AUC 0−inf and 39% increase in C max ). One treatment‐emergent adverse event (mild, treatment‐related headache) was reported in a participant with normal hepatic function. No dosage adjustment of intranasal zavegepant is required in adults with mild or moderate hepatic impairment.