Predicting Drug-Drug Interactions between Rifampicin and Ritonavir-Boosted Atazanavir Using PBPK Modelling.

Objectives The aim of this study was to simulate the drug-drug interaction (DDI) between ritonavir-boosted atazanavir (ATV/r) and rifampicin (RIF) using physiologically based pharmacokinetic (PBPK) modelling, and to predict suitable dose adjustments for ATV/r for the treatment of people living with HIV (PLWH) co-infected with tuberculosis. Methods A whole-body DDI PBPK model was designed using Simbiology 9.6.0 (MATLAB R2019a) and verified against reported clinical data for all drugs administered alone and concomitantly. The model contained the induction mechanisms of RIF and ritonavir (RTV), the inhibition effect of RTV for the enzymes involved in the DDI, and the induction and inhibition mechanisms of RIF and RTV on the uptake and efflux hepatic transporters. The model was considered verified if the observed versus predicted pharmacokinetic values were within twofold. Alternative ATV/r dosing regimens were simulated to achieve the trough concentration (Ctrough) clinical cut-off of 150 ng/mL. Results The PBPK model was successfully verified according to the criteria. Simulation of different dose adjustments predicted that a change in regimen to twice-daily ATV/r (300/100 or 300/200 mg) may alleviate the induction effect of RIF on ATV Ctrough, with > 95% of individuals predicted to achieve Ctrough above the clinical cut-off. Conclusions The developed PBPK model characterized the induction-mediated DDI between RIF and ATV/r, accurately predicting the reduction of ATV plasma concentrations in line with observed clinical data. A change in the ATV/r dosing regimen from once-daily to twice-daily was predicted to mitigate the effect of the DDI on the Ctrough of ATV, maintaining plasma concentration levels above the therapeutic threshold for most patients.