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Papers of the Week


Papers: 2 Nov 2024 - 8 Nov 2024


2024 Nov 03


CPT Pharmacometrics Syst Pharmacol


39492601

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

Authors

Comisar CM, Francis J, Hughes JH, Bhardwaj R, Bertz R, Liu J

Abstract

Zavegepant (ZAVZPRET™) is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist available for acute treatment of migraine in adults. A population pharmacokinetic analysis was performed to describe zavegepant plasma concentration-time course, characterize bioavailability, and identify covariates affecting zavegepant exposure. The model was developed and validated using data from 10 phase I clinical studies, wherein zavegepant was administered intravenously, intranasally, or orally to healthy adults and patients with migraine. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling. A three-compartment model with first-order elimination from the central compartment, and sequential zero- and first-order absorption best described the observed plasma concentration-time course of zavegepant. Bioavailability was 5.1% and 0.65% for intranasal and oral treatment, respectively; absorption rate constants were 5.8 and 0.8 h, respectively. Body weight-based empirical allometric scaling was applied using standard exponents (0.75 for clearance and 1 for volume of distribution). Age (range 18-71 years), race, ethnicity, sex, renal function, and co-administration of oral contraceptives or sumatriptan did not significantly change zavegepant pharmacokinetics. Moderate hepatic impairment (Child-Pugh score 7-9) or co-administration of rifampin decreased elimination clearance of oral zavegepant by ~40%. The zavegepant population pharmacokinetic model adequately characterized zavegepant concentration-time profiles, the bioavailability of intranasal and oral zavegepant, as well as the effect of intrinsic and extrinsic factors on zavegepant pharmacokinetics.