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 (ϳ10 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).

A Physiologically Based Pharmacokinetic Model of Rifampin in Mice

“…Figure 5 shows MC simulations of concentration-time profiles for plasma and liver following once-daily 10-mg/kg oral dosing for three consecutive days. The corresponding experimental data points are individual measurements from xenobiotic X receptor (SXR)-humanized mice that were reported by Raybon et al (33). The model tends to overpredict the C max for plasma concentrations but is in good agreement with the liver concentrations, including interindividual variability.…”

“…Empirical and semiphysiologically based pharmacokinetic models for rifampin, which include plasma and a tissue compartment such as liver (33) or lung (65,66), are available. While these models were developed with a focus on a single target organ, they could be incorporated into our rifampin PBPK model as a lung lesion subcompartment (66), pulmonary epithelial lining fluid and alveolar cells (65), and enzyme induction in the liver (33). The basic qualitative pharmacokinetic characteristics of rifampin (26,38,67), described by the PBPK model presented in this study, are (i) rapid and complete oral absorption (on an empty stomach), (ii) good penetration into tissues, (iii) enterohepatic reabsorption, and (iv) elimination in urine and feces.…”

“…Although PBPK modeling has had limited application to anti-TB drugs thus far (58,59), it is well established in other areas of drug development and toxicological risk assessment (60); examples include anticancer (51) and immunosuppresive (61) drugs, monoclonal antibodies (62), nanoparticles (63), and a wide range of environmental toxicants (64). Empirical and semiphysiologically based pharmacokinetic models for rifampin, which include plasma and a tissue compartment such as liver (33) or lung (65,66), are available. While these models were developed with a focus on a single target organ, they could be incorporated into our rifampin PBPK model as a lung lesion subcompartment (66), pulmonary epithelial lining fluid and alveolar cells (65), and enzyme induction in the liver (33).…”

“…Experimental data. Pharmacokinetic data consisting of rifampin concentrations in mouse tissues and fluids, with various doses and routes of administration, were obtained from the literature and separated into those used for model development (26)(27)(28)(29) and those used for additional comparison with model output (9,10,(30)(31)(32)(33)(34)(35). Rifampin was the only rifamycin considered in this study; data for other rifamycins, such as rifapentine or rifabutin, were not used, as drugs in this class differ widely in their pharmacokinetic properties (36).…”

A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

“…However, the indirect response model was not appropriate for our study because significant time delays between DEX exposure and CYP3A1/2 mRNA induction (approximately 16 h for CYP3A1 mRNA and 28 h for CYP3A2 mRNA) were observed. These delayed onsets of induction are likely due to the complex series of events that are required to trigger an induction in transcription [37] . In our study, we applied a series of transit compartments, which explained the time spent by mRNA maturation, to account for this observed temporal delay between the DEX plasma concentration and the increase in mRNA levels.…”