Characterizing complex and competing drug–drug interactions between the antiviral regimen of glecaprevir and pibrentasvir with rifampin or carbamazepine

Abstract

The fixed-dose combination of the direct acting antivirals glecaprevir (GLE) and pibrentasvir (PIB) is an oral, once-daily treatment for all six major genotypes of chronic hepatitis C virus infection. A single and multiple-dose rifampin study (N = 12) and a carbamazepine study (N = 12) were conducted in healthy subjects to evaluate the effects of CYP3A/P-gp induction and OATP inhibition on the pharmacokinetics of GLE and PIB. In study 1, GLE 300 mg + PIB 120 mg was administered as a single dose either alone, after single and multiple daily doses of rifampin 600 mg, or 24 h after the last rifampin dose. In study 2, GLE 300 mg + PIB 120 mg was administered as a single dose either alone or after multiple doses of carbamazepine 200 mg. Relative to GLE + PIB alone, exposure of GLE was significantly increased by the first co-administered rifampin dose due to OATP inhibition, significantly decreased 24 h after the last rifampin dose due to CYP3A/P-gp induction, and slightly increased when co-administered with steady-state rifampin due to a combination of inhibition and induction forces. Exposure of PIB was not affected when co-administered with the first rifampin dose but was significantly decreased with steady-state rifampin co-administration, or 24 h after the last rifampin dose due to P-gp induction. Carbamazepine significantly decreased GLE and PIB exposure, mainly attributed to P-gp induction. The regimens tested were generally well-tolerated by the subjects and no new safety issues were identified. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Rifampin single-dose inhibits OATP1B1/3 transport and when given over multiple days induces P-gp transport and CYP3A metabolism. Carbamazepine also induces P-gp and CYP3A with multiple dosing. Advanced clinical study designs allow identification of rifampin mediated drug-drug interactions (DDIs) due to inhibition versus induction. The direct acting antivirals glecaprevir (GLE) and F I G U R E 1 Study design schematics for drug-drug interaction studies of GLE and pibrentasvir with rifampin (study 1) or with carbamazepine (study 2

Pharmacokinetics of asundexian with combined CYP3A and P‐gp inhibitors and an inducer: Target in vitro and in vivo studies

“…The effect of carbamazepine on the apparent volume of distribution V z /F and C max is likely a result of a decrease in oral bioavailability, related to intestinal P‐gp induction. These results are in line with several published studies suggesting that P‐gp induction by carbamazepine is more pronounced in the intestine, as in most cases, the main effect was observed on victim drug bioavailability 15,16 . However, most of the investigated objects exhibit limited bioavailability due to P‐gp‐mediated intestinal efflux, with less relevant biliary P‐gp excretion only able to qualify intestinal P‐gp induction.…”

“…These results are in line with several published studies suggesting that P-gp induction by carbamazepine is more pronounced in the intestine, as in most cases, the main effect was observed on victim drug bioavailability. 15,16 However, most of the investigated objects exhibit limited bioavailability due to P-gpmediated intestinal efflux, with less relevant biliary P-gp excretion only able to qualify intestinal P-gp induction. Thus, the observed effect on CL/F could be the sum of decreased bioavailability (due to intestinal P-gp induction) and an increase in the intrinsic asundexian hepatic clearance (CYP3A4 induction) as well as an increase in P-gpmediated biliary, extrabiliary and kidney excretion.…”