RT Journal Article SR Electronic T1 Pharmacokinetic-Pharmacodynamic Modeling of Rifampicin-Mediated Cyp3a11 Induction in SXR Humanized Mice JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.110.176677 DO 10.1124/jpet.110.176677 A1 Joseph J Raybon A1 Devin Pray A1 Daniel G Morgan A1 Mary Zoeckler A1 Ming Zheng A1 Michael W Sinz A1 Sean Kim YR 2010 UL http://jpet.aspetjournals.org/content/early/2010/12/27/jpet.110.176677.abstract AB The purpose of this study was to develop a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to describe the effects of rifampicin on hepatic Cyp3a11 RNA, enzymatic activity and triazolam pharmacokinetics. Rifampicin was administered to SXR humanized mice at 10 mg/kg (P.O.; Q.D. for 3 days) followed by triazolam (4 mg/kg, P.O.) 24 h after the last dose of rifampicin. Rifampicin and triazolam concentrations, Cyp3a11 RNA expression and activity in the liver were measured over the 4-day period. Elevations in Cyp3a11 RNA expression were observed 24 h after the first dose of rifampicin, reaching a maximum (~10-times baseline) after the third dose and were sustained until day 4 and began declining 48 h after the last rifampicin dose. Similar changes in enzymatic activity were also observed. The triazolam serum AUC was 5-fold lower in mice pretreated with rifampicin, consistent with enzyme induction. The final PK-PD model incorporated rifampicin liver concentration as the driving force for the time-delayed Cyp3a11 induction governed by in vitro potency estimates; which in turn regulated the turnover of enzyme activity. The PK-PD model was able to recapitulate the delayed induction of Cyp3a11 mRNA and enzymatic activity by rifampicin. Furthermore, the model was able to accurately anticipate the reduction in the triazolam plasma AUC by integrating a ratio of the predicted induced enzyme activity and basal activity into the equations describing the triazolam pharmacokinetics. In conjunction with the SXR humanized mouse model, this mathematical approach may serve as a tool for predicting clinically relevant drug-drug interactions via PXR-mediated enzyme induction.