Abstract Details

Title Physiologically-based Pharmacokinetic Modeling for Assessment of the Drug-drug Interaction Potential of Zavegepant

Topic Headache

Presentation(s) P9 - Poster Session 9 (8:00 AM-9:00 AM)

Poster/Presentation
Number 12-006

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 C_max ratio (C_maxR). Predicted effects for intranasal zavegepant with MD rifampin were 2.11 for AUCR and 1.67 for C_maxR. Predicted effects for intranasal zavegepant with SD cyclosporine A were 1.58 for AUCR and 1.23 for C_maxR, 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.

Authors/Disclosures
David Semel PRESENTER	David Semel has received personal compensation for serving as an employee of pfizer.
Alice Ke	No disclosure on file
Ernesto Callegari (Pfizer)	No disclosure on file
Rajinder Bhardwaj (Certara)	The institution of Rajinder Bhardwaj has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Biohaven .
Manthena Varma	No disclosure on file
Chieko Muto (Pfizer R&D Japan)	No disclosure on file
Richard Bertz (Biohaven Pharmaceuticals)	Richard Bertz has received personal compensation for serving as an employee of Biohaven Pharmaceuticals. Richard Bertz has stock in Biohaven Pharmaceuticals.
Vaishali Sahasrabudhe (Pfizer, Inc)	No disclosure on file
Jing Liu	Jing Liu has received personal compensation for serving as an employee of Pfizer, Inc.. Jing Liu has stock in Pfizer, Inc. .

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