Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy

Abstract

Pregnant women are usually excluded from clinical trials. Physiologically based pharmacokinetic (PBPK) modelling may provide a method to predict pharmacokinetics in pregnant women, without the need to perform extensive in vivo clinical trials. Here, we used mechanistic modelling to delineate the potential impact of drug transporters on darunavir pharmacokinetics and to identify current knowledge gaps that limit accurate PBPK modelling of darunavir/ritonavir (darunavir/r) exposure in pregnancy. Simcyp (version 13.2) was used for PBPK modelling, using physicochemical and in vitro pharmacokinetic parameters of darunavir and ritonavir from the literature. The Michaelis–Menten constant (Km) and the maximum rate of metabolite formation (Vmax) for cytochrome P450 3A4-mediated darunavir biotransformation and inhibition by ritonavir were determined experimentally, while the contributions of hepatocyte influx and efflux transporters were assessed by sensitivity analysis. The simulations were compared with previously published clinical pharmacokinetic data. We found that use of a well-stirred liver model overestimated darunavir exposure substantially. A permeability-limited liver model, including hepatic uptake and efflux transporters and an efficient enterohepatic circulation step, resulted in an acceptable description of darunavir/r exposure. For the 600/100 mg darunavir/r twice-daily dose and the 800/100 mg once-daily dose, the estimated pharmacokinetic parameters were within a 2-fold range of the reported data. The predicted decreases in the area under the concentration–time curve (AUC) values during pregnancy for the twice- and once-daily doses were 27 and 41 %, respectively, which were in line with the observed decreases of 17–22 and 33 %. In conclusion, our data support a clinically relevant role of hepatic transporters in darunavir pharmacokinetics. By including them in our model, we successfully approximated the increase in darunavir exposure mediated by ritonavir co-administration and the decrease in darunavir exposure observed during pregnancy.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0325-8) contains supplementary material, which is available to authorized users.

Application of physiologically based pharmacokinetic modeling to predict drug disposition in pregnant populations

“…The present investigation builds upon the results of previous studies using PBPK modeling to predict drug disposition during pregnancy. This includes studies evaluating drugs cleared by specific CYP pathways such as CYP1A, CYP2D, CYP2C and CYP3A (Gaohua et al, ; Ke et al, , ), as well as medications used to treat diseases such as HIV (Colbers et al, ). Collectively, these investigations support the application of an in silico systems pharmacology approach using PBPK modeling to anticipate changes in drug exposure as pregnancy progresses.…”

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

“…Utilizing a pop-PK model, it has been suggested that OATP3A1 polymorphisms are associated with DRV PK (39). In addition, a recent physiologically based PK (PBPK) modeling-based study that investigated the PK of DRV/r during pregnancy has also suggested a role for hepatic transporters in DRV disposition (40).…”

Physiologically Based Pharmacokinetic Modeling in Pregnancy: A Systematic Review of Published Models

“…At that time, different PBPK models for pregnant women were developed in MatLab or as part of Simcyp, GastroPlus, and also in the Open Systems Pharmacology (OSP) software suite which includes the software programs PK‐Sim and MoBi (https://github.com/Open-Systems-Pharmacology/Pregnancy-Models). Some of these models were subsequently used as a basis for further model refinement and/or incorporation of information on system‐specific parameters that were not part of the original model, such as changes in the activity of specific CYP enzymes . Furthermore, a variety of semimechanistic or minimal PBPK models for pregnant women can also be found in the literature .…”