Rifampin's Acute Inhibitory and Chronic Inductive Drug Interactions: Experimental and Model-Based Approaches to Drug–Drug Interaction Trial Design

Abstract

We studied the time course for the reversal of rifampin's effect on the pharmacokinetics of oral midazolam (a cytochrome P450 (CYP) 3A4 substrate) and digoxin (a P-glycoprotein (P-gp) substrate). Rifampin increased midazolam metabolism, greatly reducing the area under the concentration-time curve (AUC(0-∞)). The midazolam AUC(0-∞) returned to baseline with a half-life of ~8 days. Rifampin's effect on the AUC(0-3 h) of digoxin was biphasic: the AUC(0-3 h) increased with concomitant dosing of the two drugs but decreased when digoxin was administered after rifampin. Digoxin was found to be a weak substrate of organic anion-transporting polypeptide (OATP) 1B3 in transfected cells. Although the drug was transported into isolated hepatocytes, it is not likely that this transport was through OATP1B3 because the transport was not inhibited by rifampin. However, rifampin did inhibit the P-gp-mediated transport of digoxin with a half-maximal inhibitory concentration (IC(50)) below anticipated gut lumen concentrations, suggesting that rifampin inhibits digoxin efflux from the enterocyte to the intestinal lumen. Pharmacokinetic modeling suggested that the effects on digoxin are consistent with a combination of inhibitory and inductive effects on gut P-gp. These results suggest modifications to drug-drug interaction (DDI) trial designs.

Predictive Utility of In Vitro Rifampin Induction Data Generated in Fresh and Cryopreserved Human Hepatocytes, Fa2N-4, and HepaRG Cells

“…The concentration-time profile of rifampin is not directly linked to the time-dependent expression of CYP3A4 because enzyme level is determined by degradation half-life. Hepatic CYP3A4 degradation halflife has been estimated to range from 24 to 72 h, up to 6 to 8 days in some individuals (Galetin et al, 2006;Yang et al, 2008;Reitman et al, 2011), in contrast to intestinal half-life of approximately 24 h Yang et al, 2008). Regardless of reported variability, CYP3A4 half-life is longer than rifampin elimination half-life [ϳ2 h (Furesz et al, 1967)], and functional expression of CYP3A4 should be relatively constant over the period of rifampin exposure.…”

In Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and Transporters

“…[ 3 H]Verapamil (1 mM) and cyclosporine A (CsA, 10 mM) were used as the positive control substrate and inhibitor for Pgp, respectively. The inhibitory effect of BOC on MDR1 Pgp-mediated [ 3 H]digoxin (0.1 mM) transport was evaluated in LLC-PK1 cells stably transfected with a human MDR1 Pgp cDNA, as described previously elsewhere (Reitman et al, 2011).…”

PBPK Models for CYP3A4 and P‐gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin

“…De‐induction depends on the half‐lives of the perpetrator and the induced protein; we implemented CYP3A4 with protein half‐lives of 36 and 23 hours in the liver and intestine, respectively10, 11 (see Table S7 in Appendix S1). De‐induction kinetics were evaluated by prediction of midazolam PK when administered 1, 2, or 4 weeks after the last dose of rifampicin, as studied by Reitman et al 12. The rifampicin‐midazolam model successfully predicts the time course of CYP3A4 activity return to baseline after the last dose of rifampicin, shown by the correct simulation of the midazolam plasma concentration‐time profiles of this study ( Figure 4 b ).…”

“…AUC, area under the plasma concentration‐time curve; bol, bolus; cap, capsule; C max , peak plasma concentration; DDI, drug‐drug interaction; fast, oral administration in fasted conditions; fed, oral administration with a meal; GMFE, geometric mean fold error; obs, observed; pred, predicted; sol, solution; syr, syrup; tab, tablet. a Cerebrotendinous xanthomatosis (CTX) patients, b coccidioidomycosis patients, c see Reitman et al 12. …”

“…rifampicin treatment. Observed data are from Reitman et al 12. Predicted and observed DDI area under the plasma concentration‐time curve ratios and DDI peak plasma concentration ratios are given in Table 1.…”