Physiologically based pharmacokinetic modelling to support the clinical management of drug-drug interactions with bictegravir.

Bictegravir is equally metabolized by cytochrome P-450 (CYP)3A and uridine diphosphate-glucuronosyltransferase (UGT)1A1. Drug-drug interaction (DDI) studies were only conducted for strong inhibitors and inducers, leading to some uncertainty whether moderate perpetrators or multiple drug associations, can be safely co-administered with bictegravir. We used physiologically based pharmacokinetic (PBPK) modelling to simulate DDI magnitudes of various scenarios to guide the clinical DDI management of bictegravir. Clinically observed DDI data for bictegravir co-administered with voriconazole, darunavir/cobicistat, atazanavir/cobicistat, and rifampicin were predicted within the 95% confidence interval of the PBPK model simulations. The area under the curve (AUC) ratio of the DDI divided by the control scenario was always predicted within 1.25-fold of the clinically observed data, demonstrating the predictive capability of the used modelling approach. After the successful verification, various DDI scenarios with drug pairs and multiple concomitant drugs were simulated to analyze their effect on bictegravir exposure. Generally, our simulation results suggest that bictegravir should not be co-administered with strong CYP3A and UGT1A1 inhibitors and inducers (e.g. atazanavir, nilotinib, and rifampicin), but based on the present modelling results, bictegravir could be administered with moderate dual perpetrators (e.g. efavirenz). Importantly, the inducing effect of rifampicin on bictegravir was predicted to be reversed with the concomitant administration of a strong inhibitor such as ritonavir, resulting in a DDI magnitude within the efficacy and safety margin for bictegravir (0.5-2.4-fold). In conclusion, the PBPK modelling strategy can effectively be used to guide the clinical management of DDIs for novel drugs with limited clinical experience, such as bictegravir. This article is protected by copyright. All rights reserved.