Modeling of Rifampicin-Induced CYP3A4 Activation Dynamics for the Prediction of Clinical Drug-Drug Interactions from In Vitro Data

Abstract

Induction of cytochrome P450 3A4 (CYP3A4) expression is often implicated in clinically relevant drug-drug interactions (DDI), as metabolism catalyzed by this enzyme is the dominant route of elimination for many drugs. Although several DDI models have been proposed, none have comprehensively considered the effects of enzyme transcription/translation dynamics on induction-based DDI. Rifampicin is a well-known CYP3A4 inducer, and is commonly used as a positive control for evaluating the CYP3A4 induction potential of test compounds. Herein, we report the compilation of in vitro induction data for CYP3A4 by rifampicin in human hepatocytes, and the transcription/translation model developed for this enzyme using an extended least squares method that can account for inherent inter-individual variability. We also developed physiologically based pharmacokinetic (PBPK) models for the CYP3A4 inducer and CYP3A4 substrates. Finally, we demonstrated that rifampicin-induced DDI can be predicted with reasonable accuracy, and that a static model can be used to simulate DDI once the blood concentration of the inducer reaches a steady state following repeated dosing. This dynamic PBPK-based DDI model was implemented on a new multi-hierarchical physiology simulation platform named PhysioDesigner.

Determination of a Degradation Constant for CYP3A4 by Direct Suppression of mRNA in a Novel Human Hepatocyte Model, HepatoPac

“…Since the mechanism behind IL6-mediated suppression of CYP3A is by depletion of mRNA levels, it was not surprising that the kinetic data for CYP3A enzyme recovery fit better to the model that considered recovery of both CYP3A mRNA and protein. When the degradation value of 0.0316 hour 21 was used to project the rate of mRNA synthesis (and degradation) after removal of IL6, k deg,RNA was estimated to be 0.0296 hour 21 and 0.0213 hour 21 for removal of 1000 and 10,000 pg/ml, respectively, which are consistent with a previously reported CYP3A mRNA degradation constant of 0.0282 hour 21 (Yamashita et al, 2013). The longevity of HepatoPac cultures should also lend themselves to the conduct of pulse-chase experiments as a fundamental approach to determine protein degradation (Zhou, 2004).…”

“…(B) One-phase exponential decay equation using the mean and standard deviations generated from donors 1, 2, 3, 4, and 5. dmd.aspetjournals.org k deg for the enzyme as a key input parameter. As physiologically based pharmacokinetic modeling is more routinely applied to predict complex drug interactions, many researchers have noted improved prediction accuracy when using a CYP3A k deg of 0.03 hour 21 (Wang, 2010;Friedman et al, 2011;Yamashita et al, 2013), determined from the time course of CYP3A recovery following multiple-dose clarithromycin administration. The current approach, which resulted in an overall CYP3A k deg of 0.0240 hour…”

“…DDI can result in increasing variability of drug exposure in the patient population, the need for dose adjustment to ensure safe and efficacious therapeutic doses (Ogu and Maxa, 2000), and/or can lead to severe adverse events, such as torsades de pointes, as observed with terfenadine (Honig et al, 1993). A central component in providing more predictive models of DDI involving enzyme inactivators and/or inducers (Mayhew et al, 2000;Yamashita et al, 2013) is the degradation rate of P450s. In parallel, regulators are open to applying predictive models of DDI as a viable alternative to conducting clinical studies (Zhao et al, 2011).…”

“…Additionally, improved prediction accuracy has been noted using ) (Quinney et al, 2010;Wang, 2010;Friedman et al, 2011;Yamashita et al, 2013). As discussed in detail by Yang et al (2008), a number of approaches have been applied to estimate half-life of P450 degradation.…”

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

“…Various PBPK models have been developed and have proved useful in predicting the effects of the administration of ARVs in HIV-infected patients with comorbidities (60). Indeed, a recent study described the development of a PBPK model for predicting clinical DDIs from RIF-based in vitro human hepatocyte data (61), and it is therefore hoped that the data presented herein will be of use in the development of PBPK models to predict the effects of coadministering boosted PIs with anti-TB drugs.…”