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Quantitative Prediction of Repaglinide-Rifampicin Complex Drug Interactions Using Dynamic and Static Mechanistic Models: Delineating Differential CYP3A4 Induction and OATP1B1 Inhibition Potential of Rifampicin.

Drug Metab Dispos. 2013 Feb 7;

Authors: Varma MV, Lin J, Bi YA, Rotter CJ, Fahmi OA, Lam J, El-Kattan AF, Goosen TC, Lai Y


Repaglinide is mainly metabolized by cytochrome-P-450 (CYP)2C8 and CYP3A4, and is also a substrate to hepatic uptake transporter, organic anion transporting polypeptide (OATP)1B1. The purpose of this study is to predict the "dosing-time" dependent pharmacokinetic interactions of repaglinide with rifampicin, using mechanistic models. In vitro hepatic transport of repaglinide, characterized using sandwich-cultured human hepatocytes, and intrinsic metabolic parameters were used to build a dynamic whole-body physiologically-based pharmacokinetic (PBPK) model. The PBPK model adequately described repaglinide plasma concentration-time profiles; and successfully predicted area under the plasma concentration-time curve ratios of repaglinide (within ±25% error), dosed (staggered 0-24h) after rifampicin treatment, when primarily considering induction of CYP3A4 and reversible inhibition of OATP1B1 by rifampicin. Further, a static mechanistic "extended net-effect" model incorporating transport and metabolic disposition parameters of repaglinide and interaction potency of rifampicin was devised. Predictions based on the static model are similar to that observed in the clinic (average error ~19%), as well as similar to the PBPK model predictions. Both the models suggested that the combined effect of increased gut extraction and decreased hepatic uptake caused minimal repaglinide systemic exposure change when repaglinide is dosed simultaneously or 1h after the rifampicin dose. On the other hand, isolated induction effect as a result of temporal separation of the two drugs translated to ~5-fold reduction in repaglinide systemic exposure. In conclusion, both dynamic and static mechanistic models are instrumental in delineating the quantitative contribution of transport and metabolism in the dosing-time dependent repaglinide-rifampicin interactions.

PMID: 23393219 [PubMed - as supplied by publisher]