The online version of this article (doi:10.1007/s40262-017-0583-8) contains supplementary material, which is available to authorized users.
Stein Schalkwijk and Aaron O. Buaben contributed equally to the article.
Fetal antiretroviral exposure is usually derived from the cord-to-maternal concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure–effect relationship.
The aim of this study was to incorporate placental transfer into a pregnancy physiologically based pharmacokinetic model to simulate and evaluate fetal darunavir exposure at term.
An existing and validated pregnancy physiologically based pharmacokinetic model of maternal darunavir/ritonavir exposure was extended with a feto-placental unit. To parameterize the model, we determined maternal-to-fetal and fetal-to-maternal darunavir/ritonavir placental clearance with an ex-vivo human cotyledon perfusion model. Simulated maternal and fetal pharmacokinetic profiles were compared with observed clinical data to qualify the model for simulation. Next, population fetal pharmacokinetic profiles were simulated for different maternal darunavir/ritonavir dosing regimens.
An average (±standard deviation) maternal-to-fetal cotyledon clearance of 0.91 ± 0.11 mL/min and fetal-to-maternal clearance of 1.6 ± 0.3 mL/min was determined (n = 6 perfusions). Scaled placental transfer was integrated into the pregnancy physiologically based pharmacokinetic model. For darunavir 600/100 mg twice a day, the predicted fetal maximum plasma concentration, trough concentration, time to maximum plasma concentration, and half-life were 1.1, 0.57 mg/L, 3, and 21 h, respectively. This indicates that the fetal population trough concentration is higher or around the half-maximal effective darunavir concentration for a resistant virus (0.55 mg/L).
The results indicate that the population fetal exposure after oral maternal darunavir dosing is therapeutic and this may provide benefits to the prevention of mother-to-child transmission of human immunodeficiency virus. Moreover, this integrated approach provides a tool to prevent fetal toxicity or enhance the development of more selectively targeted fetal drug treatments.
Supplementary material 1 (DOCX 71 kb)40262_2017_583_MOESM1_ESM.docx
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- Prediction of Fetal Darunavir Exposure by Integrating Human Ex-Vivo Placental Transfer and Physiologically Based Pharmacokinetic Modeling
Aaron O. Buaben
Jolien J. M. Freriksen
Angela P. Colbers
David M. Burger
Frans G. M. Russel
- Springer International Publishing