Population Pharmacokinetics of Atogepant for the Prevention of Migraine
Abstract
Background and objective: Atogepant is an oral calcitonin gene-related peptide receptor antagonist developed for the preventive treatment of migraine. This work aimed to develop a population pharmacokinetic (popPK) model to support dosage regimen selection during the clinical development of atogepant in patients with episodic migraine (EM) or chronic migraine (CM) and to guide the dosing recommendations for regulatory approval.
Methods: Pharmacokinetic data collected from 12 phase 1 studies, 1 phase 2b/3 study, and 1 phase 3 study in healthy participants and patients with EM were used to develop a popPK model that was externally validated with data from a CM phase 3 study and a phase 3 study in patients with EM for whom two to four classes of conventional oral preventive treatments have failed. The model was built and evaluated using nonlinear mixed-effect modeling and diagnostic assessments.
Results: The final model featured three disposition compartments, with linear elimination from the central compartment and a sequential zero-/first-order lagged absorption process. Formulation, dose, food status, liver function, concomitant medication, and body weight were each found to have a statistically significant influence on atogepant's pharmacokinetics. Absorption was affected by dose and formulation, the apparent central volume of distribution (V1/F) increased with body weight, relative bioavailability (Frel) modestly increased with dose, and a high-fat meal lengthened…
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Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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