Cytochrome P450 3A Induction Predicts P-glycoprotein Induction; Part 1: Establishing Induction Relationships Using Ascending Dose Rifampin

Abstract

Drug transporter and cytochrome P450 expression is regulated by shared nuclear receptors and, hence, an inducer should induce both, although the magnitude may differ. The objective of this study was to establish relative induction relationships between CYP3A and drug transporters (P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP), and breast cancer resistance protein (BCRP)) or other P450s (CYP2C9 and CYP1A2) using ascending doses of the prototypical pregnane xenobiotic receptor (PXR) agonist, rifampin, to elicit weak, moderate, and strong PXR agonism. Healthy subjects received dabigatran etexilate, pravastatin, rosuvastatin, and a midazolam/tolbutamide/caffeine cocktail before and after rifampin 2, 10, 75, or 600 mg q.d. Unlike CYP3A, only moderate induction of P-gp, OATP, and CYP2C9 was observed and dose-dependent induction of P-gp, OATP, and CYP2C9 was always one drug-drug interaction category lower than observed for CYP3A, even when correcting for probe drug sensitivity. Data from this study establish proof-of-concept that P450 induction data can be leveraged to inform on the effect on transporters.

Figure 1

Probe drug mean plasma concentration vs. time curves before and after RIF coadministration. Points and error bars are means and standard deviations, respectively.

Figure 2

Probe drug mean and individual AUCR as a function of RIF dose. Geometric mean (•) and individual (○) AUCR are depicted. Solid and dashed lines represent estimated and intrinsic induction, respectively. The estimated mean (95% CI) ED₅₀, E_max, and E_max,i for each probe is inset. Weak, moderate, and strong induction classification is denoted as W, M, and S, respectively.

Figure 3

Example rifampin dose vs. probe drug mean AUCR curves and resulting probe clearance induction relationship curve with interpretation. Gray areas represent induction magnitude parity between probes, i.e., similar weak/weak, moderate/moderate, and strong/strong induction of probes X and Y.

Figure 4

Rifampin dependent induction relationship between CYP3A and P‐gp, OATP, or CYP2C9. The black points and error bars are observed AUCR mean and 90% CI, respectively, for after RIF coadministration. Solid and dashed lines represent estimated and intrinsic induction, respectively. Gray areas represent induction magnitude parity between probes. Weak, moderate, and strong induction classification is denoted as W, M, and S, respectively.

Figure 5

Rifampin dependent induction relationships between P‐gp, OATP, and CYP2C9. The black points and error bars are observed AUCR mean and 90% CI, respectively, for after RIF coadministration. Solid and dashed lines represent estimated and intrinsic induction, respectively. Gray areas represent induction magnitude parity between probes. Weak, moderate, and strong induction classification is denoted as W, M, and S, respectively.