Development of a physiologically-based pharmacokinetic model for Ritonavir characterizing exposure and drug interaction potential at both acute and steady-state conditions

Abstract

Ritonavir (RTV) is a potent CYP3A inhibitor that is widely used as a pharmacokinetic (PK) enhancer to increase exposure to select protease inhibitors. However, as a strong and complex perpetrator of CYP3A interactions, RTV can also enhance the exposure of other co-administered CYP3A substrates, potentially causing toxicity. Therefore, the prediction of drug-drug interactions (DDIs) and estimation of dosing requirements for concomitantly administered drugs is imperative. In this study, we aimed to develop a physiologically-based PK (PBPK) model for RTV using the PK-sim® software platform. A total of 13 clinical PK studies of RTV covering a wide dose range (100 to 600 mg including both single and multiple dosing), and eight clinical DDI studies with RTV on CYP3A and P-gp substrates, including alprazolam, midazolam, rivaroxaban, clarithromycin, fluconazole, sildenafil, and digoxin were used for the model development and evaluation. Chronopharmacokinetic differences (between morning vs. evening doses) and limitations in parameter estimation for biochemical processes of RTV from in vitro studies were incorporated in the PBPK model. The final developed PBPK model predicted 100% of RTV AUC_last and C_max within a twofold dimension error. The geometric mean fold error (GMFE) from all PK datasets was 1.275 and 1.194, respectively. In addition, 97% of the DDI profiles were predicted with the DDI ratios within a twofold dimension error. The GMFE values from all DDI datasets were 1.297 and 1.212, respectively. Accordingly, this model could be applied to the prediction of DDI profiles of RTV and CYP3A substrates and used to estimate dosing requirements for concomitantly administered drugs.

FIGURE 1

Predicted and observed plasma concentration‐time curves of RTV after oral administration of (a) single dose and (b) multiple doses of RTV in humans. Solid gray lines are predicted values. Circles are clinical observations. In multiple dosing studies, observations and predictions in the evening are noted as blue color. Details on dosing regimens, characteristics, subject demographics, and references are listed in Table 1.

FIGURE 2

Predicted and observed plasma concentration‐time curves of RTV and substrates in Alprazolam, Midazolam, Clarithromycin, Rivaroxaban, and Fluconazole DDI clinical studies. Solid lines are predicted values. Circles are clinical observations. Details on dosing regimens, characteristics, subject demographics, and references are listed in Table 1.

FIGURE 3

Goodness‐of‐fit plots for the developed PBPK for the prediction of AUC_last, C _max, and plasma concentration for RTV PK profiles (upper row) and RTV DDI profiles (lower row). The unity line is presented as a solid line; 1.5‐fold error and 2.0‐fold error are shown using dashed and dotted lines, respectively. In the upper row plots, the doses (100–600 mg) are represented by colors ranging from dark purple to yellow. In the first two plots in the lower row, a drug with the RTV combination is marked as a blue triangle and the drug alone is marked in red triangle. In the last plot in the lower row, substrate points are colored in blue, while ritonavir is colored in red. DV, drug concentration.