title: Pharmacokinetic-pharmacodynamic modeling of rifampicin-mediated Cyp3a11 induction in steroid and xenobiotic X receptor humanized mice.
abstract: 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 steroid and xenobiotic X receptor (SXR) humanized mice at 10 mg/kg p.o. (every day for 3 days) followed by triazolam (4 mg/kg p.o.) 24 h after the last dose of rifampicin. Rifampicin and triazolam concentrations and 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 area under the curve (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 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 pregnane X receptor-mediated enzyme induction and possibly extended to other induction pathways (e.g., constitutive androstane receptor).
authors.affiliation: Metabolism and Pharmacokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, USA. joseph.raybon@bms.com
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Raybon
authors.forename: Devin
authors.initials: D
authors.lastname: Pray
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Morgan
authors.forename: Mary
authors.initials: M
authors.lastname: Zoeckler
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Michael
authors.initials: M
authors.lastname: Sinz
authors.forename: Sean
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism*; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin