Verification of a physiologically based pharmacokinetic model of ritonavir to estimate drug-drug interaction potential of CYP3A4 substrates

Ritonavir is one of several ketoconazole alternatives used to evaluate strong CYP3A4 inhibition potential in clinical drug-drug interaction (DDI) studies. In this study, four physiologically based pharmacokinetic (PBPK) models of ritonavir as an in vivo time-dependent inhibitor of CYP3A4 were created and verified for oral doses of 20, 50, 100 and 200mg using the fraction absorbed (F-a) and oral clearance (CLoral) values reported in the literature, because transporter and CYP enzyme reaction phenotyping data were not available. The models were used subsequently to predict and compare the magnitude of the AUC increase in nine reference DDI studies evaluating the effect of ritonavir at steady-state on midazolam (CYP3A4 substrate) exposure. Midazolam AUC and C-max ratios were predicted within 2-fold of the respective observations in seven studies. Simulations of the hepatic and gut CYP3A4 abundance after multiple oral dosing of ritonavir indicated that a 3-day treatment with ritonavir 100mg twice daily is sufficient to reach maximal CYP3A4 inhibition and subsequent systemic exposure increase of a CYP3A4 substrate, resulting in the reliable estimation of f(m,CYP3A4). The ritonavir model was submitted as part of the new drug application for Kisqali (R) (ribociclib) and accepted by health authorities.