Physiology-based pharmacokinetic modelling and experimental data suggest that rifabutin alters dolutegravir kinetics by both P-glycoprotein induction and concurrent inhibition

Abstract

A recent population pharmacokinetic model describes how the pharmacokinetic profile of dolutegravir is changed upon (simultaneous) adminstration of rifabutin (after a two-week induction phase). While this model fits the observed data well, the population pharmacokinetic approach cannot provide direct mechanistic explanations for the interaction per se. We aimed to illuminate potential mechanisms and to evaluate them via a physiology-based pharmacokinetic (PBPK) model and experimental in vitro data. Within a PBPK modeling platform, we implemented a gastrointestinal efflux process for clearance by P-glycoprotein (Pgp). Mimicking the expected effect of rifabutin, we pragmatically introduced correction factors for both gastrointestinal efflux and enhanced hepatic metabolism. This exploratory approach yielded dolutegravir profiles that could be verified against original data on the interaction between rifabutin and dolutegravir. To pursue the assumption of Pgp inhibition further, we assessed the human Pgp-inhibitory effect of rifabutin and rifampicin via an established in vitro system. Our assay data showed that rifabutin can strongly (estimated EC50 18.7 micromol) inhibit cellular efflux. We conclude that rifabutin can enhance absorption (indicated by higher Cmax) of Pgp substrate victim drugs by inhibiting intestinal Pgp. This might be most important during the initial phase of combination therapy. Beyond, rifabutin in fact is an inducer of drug-metabolizing enzymes and drug transporters after repetitive administration, potentially leading to lowered victim drug exposure. However, Pgp inhibition – albeit only temporary with simultaneous exposure – can still overlap (or even exceed) with induction effects.

Andreas D. Meid

Post-doctoral researcher in Clinical Pharmacology & Pharmacoepidemiology

My research interests include the study of appropriate drug therapy using methods of pharmacoepidemiology, quantitative pharmacology, and pharmacometrics.