Effects of CYP3A4 inhibition/induction and OATP inhibition on the pharmacokinetics of atogepant in healthy adults

Aim: Atogepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is a substrate of OATP and metabolized by CYP3A4. Effect of multiple-dose itraconazole (strong CYP3A4 inhibitor), singledose rifampin (strong OATP inhibitor) and multiple-dose rifampin (strong CYP3A4 inducer) on singledose pharmacokinetics (PK) and safety of atogepant were assessed. Methods: Two phase I, open-label, single-center, crossover trials enrolled healthy adults. Results: C-max and AUC of atogepant increased when co-administered with itraconazole. Atogepant systemic exposure increased following co-administration with single-dose rifampin. Atogepant systemic exposure decreased with co-administration of multipledose rifampin. Treatment emergent adverse events (TEAEs) were predominantly mild or moderate, and included constipation, dizziness, headache and nauseas. Conclusion: Systemic exposure of atogepant increased significantly when co-administered with a strong CYP3A4 or OATP inhibitor and decreased significantly when co-administered with a strong CYP3A4 inducer. Plain language summary: Calcitonin gene-related peptide (CGRP) is involved in migraines, a neurological disorder with severe headache and sensory disturbances. A medication called atogepant is a CGRP receptor antagonist that can block the effect of CGRP and is approved by the FDA for the preventive treatment of migraines. If you take a drug, such as itraconazole, a strong inhibitor of an enzyme called CYP3A4, that metabolizes atogepant, at the same time as atogepant, it can increase the amount of atogepant in your body. OATPs are membrane transport proteins that facilitate liver uptake of atogepant. If you take a drug that is an OATP inhibitor with atogepant, it can increase the amount of atogepant in your body. However, if you take a CYP3A4 inducer such as rifampin, which increases the activity of CYP3A4, it can decrease the amount of atogepant in your body. Your doctor may adjust the dose of atogepant accordingly.