Physiologically Based Pharmacokinetic Modeling of Quinidine to Establish a CYP3A4, P-gp and CYP2D6 Drug-Drug-Gene Interaction Network.

Abstract

The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) and is therefore recommended for use in clinical drug-drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P-gp, it is susceptible to DDIs involving these proteins. Physiologically based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion (ADME) processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug-drug(-gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P-gp perpetrators as well as CYP2D6 and P-gp victims. The quinidine parent-metabolite model including 3-hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1-600 mg). The model covers efflux transport via P-gp and metabolic transformation to either 3-hydroxyquinidine or unspecified metabolites via CYP3A4. The 3-hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with >90% of predicted pharmacokinetic parameters within two-fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with >90% of predicted DD(G)I pharmacokinetic parameter ratios within two-fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims and targets, to support investigations of DD(G)Is.