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Clinical Trial
. 2024 Jul;17(7):e13813.
doi: 10.1111/cts.13813.

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

Rajinder Bhardwaj  1 , Mary K Donohue  2 , Jennifer Madonia  2 , Beth Morris  2 , Thomas C Marbury  3 , Kyle T Matschke  4 , Robert Croop  2 , Richard Bertz  2 , Jing Liu  5
Affiliations
Clinical Trial

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

Rajinder Bhardwaj et al. Clin Transl Sci. 2024 Jul.

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 AUC0-inf and 16% increase in Cmax) versus normal hepatic function, which is not considered clinically meaningful. The geometric least squares mean ratios (moderate impairment/normal) of plasma zavegepant AUC0-inf and Cmax 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 AUC0-inf and 39% increase in Cmax). 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.

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Conflict of interest statement

R.B. is an employee of Certara who was a paid consultant to Biohaven, acquired by Pfizer in October 2022, for this study. M.K.D., J.M., B.M., R.B. are current or former employees of Biohaven, acquired by Pfizer in October 2022, for this study. R.C. was an employee of Biohaven Pharmaceuticals, owns stock in Biohaven Ltd, was an employee of Pfizer, has received research payments from Pfizer, and provides services to Collima LLC, which has had consulting agreements with Pfizer, Aptose Biosciences Inc., Manistee Therapeutics, and Vida Ventures Management Co., LLC. T.C.M. is an employee and equity owner of Orlando Clinical Research Center. K.T.M., J.L. are employed by and hold stock/options in Pfizer.

Figures

FIGURE 1
FIGURE 1
Linear plasma zavegepant (total) mean concentration–time profiles following a single intranasal 10 mg dose. Zavegepant concentrations are shown on a semilogarithmic scale insert for subjects with moderate hepatic impairment versus subjects with normal hepatic function. h, hours.
FIGURE 2
FIGURE 2
(a–c) Exposure–hepatic function relationships between zavegepant pharmacokinetic parameters versus albumin, total bilirubin, and aPTT at baseline. aPTT, activated partial thromboplastin time; AUC, area under the concentration–time curve; AUC0−t, AUC from time zero to the last non‐zero concentration; AUC0−inf, AUC from time zero to infinity; CI, confidence interval; Cmax, maximum serum concentration.
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