Physiologically Based Pharmacokinetic Modeling to Assess Transporter-Mediated Drug-Drug Interactions in Support of...

Zavegepant nasal spray, a calcitonin gene-related peptide receptor antagonist indicated for acute treatment of migraine with or without aura in adults, is a substrate for organic anion transporting polypeptide 1B3 (OATP1B3), Na⁺/taurocholate cotransporting polypeptide (NTCP), P-glycoprotein (P-gp), and cytochrome P450 3A4 (CYP3A4). In clinical drug-drug interaction (DDI) studies, oral zavegepant exposure increased in the presence of multiple-dose (MD) rifampin or itraconazole; however, no interaction was observed between intranasal (IN) zavegepant and itraconazole. A physiologically based pharmacokinetic (PBPK) model was developed and validated using in vitro, human mass balance, and observed clinical zavegepant pharmacokinetic data and was employed to assess clinical DDI mechanisms and further support zavegepant nasal spray labeling recommendations. PBPK modeling indicated that DDI observed between itraconazole and oral zavegepant is primarily driven by intestinal P-gp inhibition, and observed DDI with MD rifampin primarily results from hepatic uptake inhibition. Modeling predicted an increase in plasma exposure (AUC ratio [AUCR] = 2.39) of IN zavegepant with single-dose (SD) rifampin; IN zavegepant plasma exposure was also predicted to increase with MD rifampin (AUCR = 2.11). Predicted IN zavegepant exposure change with SD cyclosporine A was 1.58-fold (AUCR) when assuming 90:10 proportion for OATP1B3:NTCP contribution to hepatic uptake. CYP3A inducers, carbamazepine and efavirenz, were predicted to have minimal effect on IN zavegepant PK. Overall, PBPK modeling and observed PK data support that CYP3A/P-gp inhibitors and inducers do not produce clinically relevant modulation in IN zavegepant plasma exposure; however, OATP1B3/NTCP inhibitors can significantly increase IN zavegepant exposure, and coadministration should be avoided.