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 (F_rel) modestly increased with dose, and a high-fat meal lengthened absorption lag time. Severe hepatic impairment and coadministration of itraconazole, quinidine, or a single rifampin dose decreased apparent clearance (CL/F) by ~37% and ~66%, ~29%, and ~13%, respectively, while coadministration of multiple rifampin doses increased CL/F by 1.82-fold. F_rel increased by 1.95 and 2.4 fold with coadministration of itraconazole and a single rifampin dose, respectively, and decreased by ~25% with multiple rifampin doses. Mild/moderate renal impairment, coadministration of breast cancer resistance protein (BCRP) inhibitors, BCRP substrates and statins, age, and sex had no clinically relevant effect on atogepant pharmacokinetics. No statistically significant differences were observed in atogepant's pharmacokinetics between healthy participants and patients with migraine.

Conclusions: The pharmacokinetics of atogepant are similar in healthy participants and patients with CM or EM. Dose adjustments owing to intrinsic factors of age, sex, race, and body weight, or owing to concomitant medications consisting of P-glycoprotein (P-gp) inhibitors, BCRP inhibitors, oral contraceptive components (ethinyl estradiol and levonorgestrel), famotidine, esomeprazole, sumatriptan, acetaminophen, and naproxen are not necessary. Atogepant's popPK model provides a valuable tool for evaluating specific questions for patients, healthcare providers, and regulatory agencies. Integration into other modeling approaches has also aided in model-informed drug development decisions.

Clinical trial registration: NCT03855137 (EudraCT number: 2018-004337-32).

Fig. 1

Goodness-of-fit plots for the final episodic migraine Phase 3 Model (left) and the external validation for the chronic migraine data (right). The upper panels depict observed and predicted concentrations on the normal scale, whereas the middle plots show log–log concentrations. The lower panels present conditional weighted residuals over PRED and time. Magenta line, Loess smooth (95% confidence interval is green shaded area); Black line, line of identity; PRED, population predictions; IPRED, individual predictions. Note: 1 nM of atogepant is equal to 0.6035 ng/mL

Fig. 2

Prediction-corrected visual predictive checks by study for the Phase 3 Model. Circles: observations; solid blue line: median of the observed atogepant concentrations; dashed lines: 2.5th and 97.5th percentiles of the observed atogepant concentrations; shaded areas: the 95% CI around the prediction-corrected median (green area), and 2.5th and 97.5th percentiles of the simulated concentrations (gray areas). See Supplementary Table S1 for study details

Fig. 3

Visual predictive checks by atogepant dosing regimen for the Phase 3 Model. External validation with a the PROGRESS study chronic migraine population and b the ELEVATE study episodic migraine population. Patients with episodic migraine in the PROGRESS study were previously failed by two to four conventional oral preventive treatments. Circles: observations; solid black line: median of the observed atogepant concentrations; solid green line: median of the simulated atogepant concentrations; dashed lines: 2.5th and 97.5th percentiles of the observed atogepant concentrations; shaded areas: 95% CI around the median (green area) and 2.5th and 97.5th percentiles of the simulated concentrations (gray areas). BID, twice daily; QD, once daily

Fig. 4

Forest plots for patients from the EM phase 2b/3 study (CGP-MD-01), EM phase 3 ADVANCE study, and the CM phase 3 PROGRESS study. Dots and error bars represent the geometric mean ratio and corresponding 95% CI of model-predicted 60 mg steady-state exposures relative to reference groups. The vertical black line shows the exposure ratio of 1 relative to the reference group. AUC24, area under the plasma concentration–time curve from time 0 to 24 h; BCRP, breast cancer resistance protein; C_max, maximum plasma concentration