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

Rajinder BhardwajMary K DonohueJennifer MadoniaBeth A MorrisThomas C MarburyKyle T MatschkeRobert CroopRichard BertzJing Liu
Published in: Clinical and translational science (2024)
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.
Keyphrases
  • small molecule
  • high intensity
  • emergency department
  • magnetic resonance
  • dna methylation
  • liver failure
  • mechanical ventilation
  • genome wide analysis