Placental Transfer of Darunavir and Simulation of Fetal Exposure
Stein SCHALKWIJK1,2, Aaron O. BUABEN1, Angela P. COLBERS1, David M. BURGER1, Rick GREUPINK2, Frans G.M. RUSSEL2
1Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, The Netherlands; 22. Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud university medical center, The Netherlands
Objectives: Fetal antiretroviral exposure is usually derived from the cord-to-maternal (ctm) concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship. Pregnancy physiologically-based pharmacokinetic (p-PBPK) modeling could provide a solution, although incorporation of placental antiretroviral transfer remains challenging. Here, we aimed to incorporate placental transfer into a p-PBPK model to simulate fetal darunavir exposure at term.
Methods: An existing and validated p-PBPK model of maternal darunavir/ritonavir [1] exposure was coded in Berkeley Madonna to allow expansion with a feto-placental unit and include bidirectional placental transport of darunavir, at term. In order to parameterize the model, we determined maternal-to-fetal (mtf) and fetal-to-maternal (ftm) darunavir/ritonavir placental clearance with an ex vivo human cotyledon perfusion model. Simulated maternal PK profiles were compared with observed clinical data to verify the validity of the maternal model aspect. Next, population fetal PK profiles were simulated for different darunavir/ritonavir dosing regimens. These profiles were compared with available cord blood concentrations in vivo.
Results: An average (±SD) mtf cotyledon clearance of 0.91±0.11 mL/min and ftm of 1.6±0.3 mL/min was determined (n=6 perfusions). Scaled placental transfer was included into a feto-placental unit and integrated in the p-PBPK model. For darunavir 600/100mg twice a day, the simulated fetal plasma Cmax, Ctrough, Tmax and T1/2 were; 1.1 mg/L, 0.57 mg/L, 3 hours, and 21 hours, respectively. This indicates that the fetal population Ctrough is higher than the protein-adjusted EC90 for wild type virus (0.20 mg/L) and around the EC90 for resistant virus (0.55 mg/L). The simulated ftm plasma concentration ratio (range) over a dosing interval was 0.30 (0.16 - 0.37), compared to a median (range) ratio for observed darunavir ctm plasma ratio of 0.18 (0 - 0.82).
Conclusions: A p-PBPK model for maternal darunavir exposure was extended with a feto-placental unit. The results indicate that fetal exposure after oral maternal darunavir dosing is therapuetic and this may provide benefits to the prevention of mother-to-child transmission of HIV. Moreover, this model provides a valuable tool to assess fetal exposure with new maternal darunavir dosing regimens and, hence, to optimize therapeutic benefit for the unborn.
References:
[1] Colbers A et al. Physiologically Based Modelling of Darunavir/ritonavir pharmacokinetics during pregnancy. Clinical Pharmacokinetics 55(3), 381-396, March 2016