PBPK Model Simulation of CYP3A4 and Transporter Mediated Drug-drug Interactions Involving Erythromycin

Conference: AAPS
Software: GastroPlus®
Division: Simulations Plus


Purpose: Erythromycin, a macrolide antibiotic, is cleared primarily by cytochrome P450-3A4 metabolism to the N-demethylated metabolite and C-formaldehyde. Its uptake into hepatocytes is mediated by organic anion transporting polypeptides (OATPs), and it is effluxed by P-glycoprotein (P-gp). A total of 478 interactions with other drugs have been reported. For example, increased exposure of 100 – 400 % for simvastatin, midazolam, sildenafil, everolimus, and cyclosporine has been reported. This study employed dynamic drug-drug interaction (DOI) simulations to study both metabolic and transporter-related DDIs. Midazolam, talinolol, and digoxin were chosen as model compounds to study these interactions.

Methods: Physiologically Based Pharmacokinetic (PBPK) models were developed with GastroPlus™ (Simulations Plus, Inc.) for the perpetrator, erythromycin, and for the victim drugs, midazolam, talinolol, and digoxin using literature data. In vitro enzyme and transporter inhibition constants for midazolam, talinolol, and digoxin were obtained from literature data. Drug-drug interactions were predicted using dynamic simulations within the DOI Module in GastroPlus.

American Association of Pharmaceutical Scientists (AAPS), October 14-18, 2012, Chicago, IL

Harisha Atluri, Grazyna Fraczkiewicz, Viera Lukacova, Michael B. Bolger, Walter S. Woltosz