Population pharmacokinetic modeling of zavegepant, a calcitonin gene‐related peptide receptor antagonist, in healthy adults and patients with migraine
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, characte...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13257 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841555910142459904 |
|---|---|
| author | Craig M. Comisar Jose Francis Jim H. Hughes Rajinder Bhardwaj Richard Bertz Jing Liu |
| author_facet | Craig M. Comisar Jose Francis Jim H. Hughes Rajinder Bhardwaj Richard Bertz Jing Liu |
| author_sort | Craig M. Comisar |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8eac1e56628e4a00961142140027c66f |
| institution | Kabale University |
| issn | 2163-8306 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj-art-8eac1e56628e4a00961142140027c66f2025-01-07T20:49:00ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062025-01-0114117919110.1002/psp4.13257Population pharmacokinetic modeling of zavegepant, a calcitonin gene‐related peptide receptor antagonist, in healthy adults and patients with migraineCraig M. Comisar0Jose Francis1Jim H. Hughes2Rajinder Bhardwaj3Richard Bertz4Jing Liu5Certara Inc. Princeton New Jersey USACertara Inc. Princeton New Jersey USAPfizer Inc. Groton Connecticut USACertara Inc. Princeton New Jersey USABiohaven Pharmaceuticals Inc. New Haven Connecticut USAPfizer Inc. Groton Connecticut USAAbstract 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.https://doi.org/10.1002/psp4.13257 |
| spellingShingle | Craig M. Comisar Jose Francis Jim H. Hughes Rajinder Bhardwaj Richard Bertz Jing Liu Population pharmacokinetic modeling of zavegepant, a calcitonin gene‐related peptide receptor antagonist, in healthy adults and patients with migraine CPT: Pharmacometrics & Systems Pharmacology |
| title | Population pharmacokinetic modeling of zavegepant, a calcitonin gene‐related peptide receptor antagonist, in healthy adults and patients with migraine |
| title_full | Population pharmacokinetic modeling of zavegepant, a calcitonin gene‐related peptide receptor antagonist, in healthy adults and patients with migraine |
| title_fullStr | Population pharmacokinetic modeling of zavegepant, a calcitonin gene‐related peptide receptor antagonist, in healthy adults and patients with migraine |
| title_full_unstemmed | Population pharmacokinetic modeling of zavegepant, a calcitonin gene‐related peptide receptor antagonist, in healthy adults and patients with migraine |
| title_short | Population pharmacokinetic modeling of zavegepant, a calcitonin gene‐related peptide receptor antagonist, in healthy adults and patients with migraine |
| title_sort | population pharmacokinetic modeling of zavegepant a calcitonin gene related peptide receptor antagonist in healthy adults and patients with migraine |
| url | https://doi.org/10.1002/psp4.13257 |
| work_keys_str_mv | AT craigmcomisar populationpharmacokineticmodelingofzavegepantacalcitoningenerelatedpeptidereceptorantagonistinhealthyadultsandpatientswithmigraine AT josefrancis populationpharmacokineticmodelingofzavegepantacalcitoningenerelatedpeptidereceptorantagonistinhealthyadultsandpatientswithmigraine AT jimhhughes populationpharmacokineticmodelingofzavegepantacalcitoningenerelatedpeptidereceptorantagonistinhealthyadultsandpatientswithmigraine AT rajinderbhardwaj populationpharmacokineticmodelingofzavegepantacalcitoningenerelatedpeptidereceptorantagonistinhealthyadultsandpatientswithmigraine AT richardbertz populationpharmacokineticmodelingofzavegepantacalcitoningenerelatedpeptidereceptorantagonistinhealthyadultsandpatientswithmigraine AT jingliu populationpharmacokineticmodelingofzavegepantacalcitoningenerelatedpeptidereceptorantagonistinhealthyadultsandpatientswithmigraine |