Evaluation of drug-drug interaction between rilpivirine and rifapentine using PBPK modelling

Tuberculosis remains the leading cause of death among people living with HIV. Rifapentine is increasingly used to treat active disease or prevent reactivation, in both cases given either as weekly or daily therapy. However, rifapentine is an inducer of CYP3A4, potentially interacting with antiretrovirals like rilpivirine. This in silico study investigates the drug-drug interaction (DDI) magnitude between daily oral rilpivirine 25 mg with either daily 600 mg or weekly 900 mg rifapentine. A physiologically based pharmacokinetic (PBPK) model was built in Simbiology (Matlab R2018a) to simulate the drug-drug interaction. The simulated PK parameters from the PBPK model were verified against reported clinical data for rilpivirine and rifapentine separately, daily rifapentine with midazolam, and weekly rifapentine with doravirine. The simulations of concomitant administration of rifapentine with rilpivirine at steady-state lead to a maximum decrease on AUC_0-24 and C_trough by 83% and 92% on day 5 for the daily rifapentine regimen and 68% and 92% for the weekly regimen on day 3. In the weekly regimen, prior to the following dose, AUC_0-24 and C_trough were still reduced by 47% and 53%. In both simulations, the induction effect ceased 2 weeks after the interruption of rifapentine's treatment. A daily double dose of rilpivirine after initiating rifapentine 900 mg weekly was simulated but failed to compensate the drug-drug interaction. The drug-drug interaction model suggested a significant decrease on rilpivirine exposure which is unlikely to be corrected by dose increment, thus coadministration should be avoided.