Pharmacokinetics and Safety of Atogepant Co‐administered with Quinidine Gluconate in Healthy Participants: A Phase 1, Open‐Label, Drug‐Drug Interaction Study

Abstract

AbstractAtogepant, an oral calcitonin gene‐related peptide receptor antagonist, is approved for the preventive treatment of migraine. Atogepant is a substrate of P‐glycoprotein (P‐gp), breast cancer resistance protein, organic anion transporting polypeptide transporters, and cytochrome P450 (CYP)3A4 and 2D6. Quinidine is a strong P‐gp and CYP2D6 inhibitor. A phase 1 open‐label study evaluated the effect of P‐gp and CYP2D6 inhibition by quinidine on the pharmacokinetics of atogepant, and the safety and tolerability of atogepant and quinidine gluconate (QG) when co‐administered and when given alone in 33 healthy adults. There was no significant change in the atogepant maximum plasma concentration with QG co‐administration. The overall systemic exposure, the area under the plasma concentration‐time curve (from time 0 to time t or to infinity), of atogepant increased by 25% when co‐administered with QG. However, such an increase was not considered clinically relevant. Atogepant did not alter the mean plasma concentration of quinidine at steady state. The incidence of treatment‐emergent adverse events (TEAEs) was highest when QG was administered alone (42.4%), which was primarily due to QT prolongation. Most TEAEs reported were mild in severity and resolved within 1‐2 days. Co‐administration of atogepant with QG did not result in any unexpected tolerability findings in this phase 1 study in healthy participants. The increase in atogepant exposure during QG co‐administration could be due to inhibition of CYP2D6 (a minor contributor to atogepant clearance) as well as inhibition of P‐gp.