Physiologically-based Pharmacokinetic Modeling for Assessment of the Drug-drug Interaction Potential of Zavegepant
Alice Ke1, Ernesto Callegari2, Rajinder Bhardwaj1, Manthena Varma2, Chieko Muto3, Richard Bertz4, Vaishali Sahasrabudhe2, Jing Liu2
1Certara USA, 2Pfizer Inc, 3Pfizer R&D Japan, 4Biohaven Pharmaceuticals
Objective:
To assess drug-drug interaction (DDI) of zavegepant with rifampin and other medications using physiologically-based pharmacokinetic (PBPK) modeling.
Background:
Zavegepant 10 mg nasal spray, a calcitonin gene-related peptide receptor antagonist indicated for acute treatment of migraine, 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.
Design/Methods:
In vitro, human mass balance, and clinical zavegepant pharmacokinetic data was used for model development. Observed oral and intranasal 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 incorporated into the model. Models predicted DDI of intranasal 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:
Modeling indicated that DDI observed between itraconazole and oral zavegepant is primarily through P-gp inhibition and observed DDI with MD rifampin is predominantly due to inhibition of hepatic uptake transport. Predicted DDI effects for intranasal zavegepant with SD rifampin were 2.39 for AUC ratio (AUCR) and 1.70 for Cmax ratio (CmaxR). Predicted effects for intranasal zavegepant with MD rifampin were 2.11 for AUCR and 1.67 for CmaxR. Predicted effects for intranasal 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 intranasal zavegepant were negligible (<10%) for carbamazepine and efavirenz.
Conclusions:
PBPK modeling and observed clinical pharmacokinetic data support zavegepant labeling recommendations that CYP3A4 inhibitors/inducers or P-gp inhibitors do not have clinically relevant effects on zavegepant exposure. OATP1B3/NTCP inhibitors may significantly increase zavegepant exposure and co-administration should be avoided.