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

CPT Pharmacometrics Syst Pharmacol. 2025 Jan;14(1):179-191. doi: 10.1002/psp4.13257. Epub 2024 Nov 3.

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-1, 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.

MeSH terms

  • Administration, Intranasal
  • Administration, Intravenous
  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Azepines / administration & dosage
  • Azepines / pharmacokinetics
  • Biological Availability*
  • Calcitonin Gene-Related Peptide Receptor Antagonists* / administration & dosage
  • Calcitonin Gene-Related Peptide Receptor Antagonists* / pharmacokinetics
  • Clinical Trials, Phase I as Topic
  • Female
  • Humans
  • Male
  • Middle Aged
  • Migraine Disorders* / drug therapy
  • Models, Biological*
  • Young Adult

Substances

  • Azepines
  • Calcitonin Gene-Related Peptide Receptor Antagonists