Evaluation of the Pharmacokinetic Interaction and Safety of Atogepant Co-Administered with Acetaminophen or Naproxen in Healthy Participants: A Randomized Trial.

BACKGROUND: Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for preventive treatment of migraine.

OBJECTIVE: To evaluate potential pharmacokinetic drug-drug interactions (DDIs), safety and tolerability of atogepant co-administered with acetaminophen or naproxen in healthy participants.

METHODS: This open-label, randomized, five-way crossover, single-center, phase 1 DDI trial randomized healthy adult participants to one of ten intervention sequences to receive single-dose 60 mg atogepant, 1000 mg acetaminophen, 500 mg naproxen, or co-administrations of atogepant with acetaminophen or naproxen, with 7-day washout periods between interventions. Potential DDIs were assessed using geometric mean ratios and 90% confidence intervals (CIs) calculated from maximum plasma drug concentrations (Cmax ) and area under the plasma drug concentration-time curves (AUCs) for co-administered medications versus medications administered alone. Secondary pharmacokinetic parameters [time to Cmax (tmax ), terminal elimination half-life (t1/2 ), volume of distribution during terminal phase (VZ /F), total body clearance (CL/F)], and safety were evaluated.

RESULTS: Forty participants enrolled; 35 (87.5%) completed the trial. Atogepant Cmax was unchanged, AUC0-t and AUC0-∞ both increased 13%, and tmax and t1/2 were unchanged when co-administered with acetaminophen; and acetaminophen Cmax decreased 11%, AUC0-t and AUC0-∞ both decreased 6%, and tmax and t1/2 were unchanged when co-administered with atogepant. Atogepant mean (SD) Vz /F and CL/F were 369.45 (255.68) L and 18.88 (9.28) L/h, respectively, when administered alone and 297.56 (196.01) L and 16.33 (6.11) L/h when co-administered with acetaminophen. Atogepant Cmax was unchanged, AUC0-t and AUC0-∞ both decreased 1%, and tmax and t1/2 were unchanged when co-administered with naproxen; and naproxen Cmax decreased 6%, AUC0-t and AUC0-∞ both decreased 2%, and tmax and t1/2 were unchanged when co-administered with atogepant. Atogepant mean (SD) Vz /F and CL/F were 359.61 (247.99) L and 18.80 (7.78) L/h, respectively, when co-administered with naproxen. Treatment-emergent adverse events (TEAEs) occurred at rates of 5.6-21.1% across interventions. The most commonly reported TEAEs were oropharyngeal pain (n = 2, with atogepant; not treatment related) and nausea (n = 2, with atogepant/acetaminophen; treatment related).

CONCLUSION: Co-administration of 60 mg atogepant with 1000 mg acetaminophen or 500 mg naproxen was safe and well tolerated in healthy participants, and no DDIs were observed.