Cytochrome P450 3A Induction Predicts P-glycoprotein Induction; Part 2: Prediction of Decreased Substrate Exposure After Rifabutin or Carbamazepine

Abstract

Rifampin demonstrated dose-dependent relative induction between cytochrome P (CYP)3A and P-glycoprotein (P-gp), organic anion transporting polypeptides (OATPs), or CYP2C9; P-gp, OATP, and CYP2C9 induction was one drug-drug interaction (DDI) category lower than that observed for CYP3A across a wide range of pregnane X receptor (PXR) agonism. The objective of this study was to determine if these relationships could be utilized to predict transporter induction by other CYP3A inducers (rifabutin and carbamazepine) and of another P-gp substrate, sofosbuvir. Healthy subjects received sofosbuvir and a six-probe drug cassette before and after 300 mg q.d. rifabutin or 300 mg b.i.d. carbamazepine. Induction of P-gp, CYP2C9, and decreased sofosbuvir exposure were successfully predicted by observed CYP3A induction. Carbamazepine induction of OATP was underpredicted, likely due to reported additional non-PXR agonism. The results demonstrate that the effect of a PXR agonist on CYP3A can be leveraged to inform on induction liability for other primarily PXR-regulated P450s/transporters, allowing for prioritization of targeted DDI assessments during new drug development.

Figure 1

Prediction of induction between P‐gp, CYP2C9, and CYP3A. The black points and error bars are observed AUCR mean and 90% CI, respectively, after coadministration with the indicated inducer. The blue lines are the induction relationship between P‐gp and CYP2C9 and CYP3A. Blue areas are predicted P‐gp and CYP2C9 DDI category based on CYP3A or CYP2C9 induction. Weak, moderate, and strong induction classification is denoted as W, M, and S, respectively.

Figure 2

Prediction of OATP induction from CYP3A and CYP2C9 induction. The black points and error bars are observed AUCR mean and 90% CI, respectively, after coadministration with the indicated inducer. The blue lines are the induction relationships between CYP3A, CYP2C9, and OATP. Blue areas are predicted OATP DDI category based on CYP3A or CYP2C9 induction. Weak, moderate, and strong induction classification is denoted as W, M, and S, respectively.

Figure 3

Prediction of P‐gp or OATP (rosuvastatin) induction from OATP induction (pravastatin). The black points and error bars are observed AUCR mean and 90% CI, respectively, after coadministration with the indicated inducer. The blue line is the induction relationship between P‐gp or OATP (ROS) and OATP (PRA). Blue areas are predicted P‐gp DDI category based on OATP induction. Weak, moderate, and strong induction classification is denoted as W, M, and S, respectively.

Figure 4

Prediction of sofosbuvir exposure decrease after inducer coadministration. The black points and error bars are observed AUCR mean and 90% CI, respectively, after coadministration with the indicated inducer. The blue line is the predicted induction relationship between SOF and MDZ AUCR. Blue areas are predicted SOF DDI category based on MDZ induction by the indicated inducer. Weak, moderate, and strong induction classification is denoted as W, M, and S, respectively