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

作者信息

Bhardwaj Rajinder, Donohue Mary K, Madonia Jennifer, Morris Beth, Marbury Thomas C, Matschke Kyle T, Croop Robert, Bertz Richard, Liu Jing

机构信息

Certara USA, Princeton, New Jersey, USA.

Biohaven Pharmaceuticals, Inc., New Haven, Connecticut, USA.

出版信息

Clin Transl Sci. 2024 Jul;17(7):e13813. doi: 10.1111/cts.13813.


DOI:10.1111/cts.13813
PMID:39014555
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11252018/
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 and 16% increase in C) versus normal hepatic function, which is not considered clinically meaningful. The geometric least squares mean ratios (moderate impairment/normal) of plasma zavegepant AUC and C 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 and 39% increase in C). 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.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d63e/11252018/98ac04e260c1/CTS-17-e13813-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d63e/11252018/95fb23dd82e1/CTS-17-e13813-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d63e/11252018/98ac04e260c1/CTS-17-e13813-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d63e/11252018/95fb23dd82e1/CTS-17-e13813-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d63e/11252018/98ac04e260c1/CTS-17-e13813-g002.jpg

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

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引用本文的文献

[1]
Adverse events associated with gepants: a pharmacovigilance analysis based on the FDA adverse event reporting system.

J Headache Pain. 2025-6-23

[2]
Clinical evaluation of zavegepant for the acute treatment of migraine.

J Manag Care Spec Pharm. 2025-6

[3]
Population pharmacokinetic modeling of zavegepant, a calcitonin gene-related peptide receptor antagonist, in healthy adults and patients with migraine.

CPT Pharmacometrics Syst Pharmacol. 2025-1

本文引用的文献

[1]
Zavegepant: First Approval.

Drugs. 2023-6

[2]
Migraine: from pathophysiology to treatment.

J Neurol. 2023-7

[3]
Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial.

Lancet Neurol. 2023-3

[4]
Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial.

Headache. 2022-10

[5]
Design and conduct considerations for studies in patients with hepatic impairment.

Clin Transl Sci. 2023-1

[6]
Gepants - a long way to cure: a narrative review.

Neurol Sci. 2022-9

[7]
New Generation Gepants: Migraine Acute and Preventive Medications.

J Clin Med. 2022-3-16

[8]
The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice.

Headache. 2022-1

[9]
The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice.

Headache. 2021-7

[10]
Calcitonin gene-related peptide (CGRP)-targeted therapies as preventive and acute treatments for migraine-The monoclonal antibodies and gepants.

Prog Brain Res. 2020

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