PII-176 - PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING FOR ASSESSMENT OF THE DRUG-DRUG INTERACTION POTENTIAL OF ZAVEGEPANT

A. Ke¹, E. Callegari², R. Bhardwaj¹, M. Varma², C. Muto², R. Bertz³, V. Sahasrabudhe², J. Liu²; ¹Certara USA, ²Pfizer, Inc., ³Biohaven Pharmaceuticals.

Background: Zavegepant 10 mg nasal spray is a calcitonin gene-related peptide receptor antagonist indicated for acute treatment of migraine in adults. Zavegepant is a cytochrome P450 3A4 (CYP3A4), P-glycoprotein (P-gp), organic anion transporting polypeptide 1B3 (OATP1B3), and Na+/taurocholate cotransporting polypeptide (NTCP) substrate in vitro. Physiologically-based pharmacokinetic (PBPK) modeling was used to assess drug-drug interaction (DDI) of zavegepant with rifampin and other potential concomitant medications.

Methods: A combination of in vitro, human mass balance, and clinical zavegepant PK data was used for PBPK model development. Observed oral and intranasal (IN) zavegepant DDI with itraconazole (strong CYP3A4 and P-gp inhibitor) and observed oral zavegepant DDI with multiple-dose (MD) rifampin (strong CYP3A inducer; OATP1B3 and NTCP inhibitor) were used to estimate the contribution of P-gp (intestine and liver) and hepatic uptake transporters, respectively, and were incorporated into the model. Models predicted DDI of IN zavegepant with single-dose (SD) or MD rifampin, cyclosporine A (OATP1B3, NTCP, and P-gp inhibitor), and moderate (efavirenz) or strong (carbamazepine) CYP3A4 and/or P-gp inducers.

Results: The PBPK model indicated that DDI observed between itraconazole and oral zavegepant is primarily through P-gp inhibition and the observed DDI with MD rifampin is predominantly due to inhibition of hepatic uptake transport. Predicted DDI effects for IN zavegepant with SD rifampin were 2.39 for AUC ratio (AUCR) and 1.70 for Cmax ratio (CmaxR; Table). Predicted effects for IN zavegepant with MD rifampin were 2.11 for AUCR and 1.67 for CmaxR. Predicted effects for IN zavegepant with SD cyclosporine A were 1.58 for AUCR and 1.23 for CmaxR, with greatest DDI assuming a 90:10 ratio of OATP1B3:NTCP contribution. Predicted induction effects on IN zavegepant were negligible ( < 10%) for carbamazepine and efavirenz.

Conclusion: PBPK modeling and observed clinical PK data support zavegepant nasal spray labeling recommendations that CYP3A4 inhibitors/inducers or P-gp inhibitors do not have a clinically relevant effect on zavegepant exposure. OATP1B3/NTCP inhibitors may result in a significant increase in zavegepant exposure and co-administration should be avoided.