Clinical pharmacokinetics · 2025
Population Pharmacokinetics of Atogepant for the Prevention of Migraine.
Клиническое исследование I фазыКлиническое исследование II фазыКлиническое исследование III фазыСтатьяВалидационное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Schlachter Louisa, Stodtmann Sven, Voelkner Alexander, Jonsson Fredrik, Lagraauw Hendrik Maxime, Boinpally Ramesh R
Аннотация
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 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. Frel 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).
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 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. Frel 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).