Cabotegravir (CAB) and rilpivirine (RPV) are two investigational long-acting (LA) agents and their interaction with rifampin (RIF) has not been fully elucidated. The aim of this study was to simulate and predict the influence of RIF on the pharmacokinetics (PK) of CAB and RPV four-weekly intramuscular (IM) administration using a physiologically-based pharmacokinetic (PBPK) model.
The PBPK model was designed in Simbiology v. 4.3.1 (MATLAB 2013b) and 100 healthy adult individuals were used for simulations. PBPK models were qualified for the three drugs against available oral clinical data. Standard oral doses of 30 mg, 25 mg and 600 mg were used for CAB, RPV and RIF, respectively. Loading doses of 800 mg and 900 mg were used for CAB and RPV, respectively. 400/800 mg and 600/900 mg were used as q4/8-weekly IM maintenance doses for CAB and RPV. Models were also qualified against PK data in the LATTE-2 IM CAB and RPV study. Oral CAB-RIF, midazolam (CYP3A4 probe)-RIF and RPV-RIF drug-drug interaction (DDI) models were also qualified against PK data from clinical studies. The PBPK models were assumed to be qualified if the simulated values were ± 100 % from the mean reported clinical values. We evaluated the effect of 600 mg oral once-daily RIF on the PK of LA IM 4-weekly CAB and RPV loading and maintenance doses. Variation in PK parameters AUC, C[sub]max[/sub] and C[sub]trough[/sub] values are reported.
For the IM loading dose of CAB with 600 mg OD RIF, the PK parameters Cmax, AUC and Ctrough decreased by 57.6%, 43.8% and 44.0%, respectively, compared to CAB alone. For the maintenance doses there was an overall reduction between 39% and 46% in the PK parameters. A more marked reduction was observed for rilpivirine PK, with a decrease in Cmax, AUC and Ctrough of 90.9%, 83.9% and 83.6% for the loading dose, and a reduction in these parameters between 80.5% and 83% for maintenance doses.
Models were qualified and PK data successfully predicted for CAB and RPV with RIF. This computational approach supports the prediction of potential DDIs for LA regimens, which cannot be readily investigated in vivo due to ethical and logistical barriers. This approach could rationally guide the design of alternative dosing strategies. The co-administration of RIF with CAB and RPV is predicted to substantially decrease ARV concentrations.