Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically-Based Pharmacokinetic Modeling.

Autor: Freriksen JJM; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Schalkwijk S; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Colbers AP; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Abduljalil K; Simcyp Division, Certara UK Limited, Sheffield, UK., Russel FGM; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Burger DM; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands., Greupink R; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2020 Jun; Vol. 107 (6), pp. 1352-1361. Date of Electronic Publication: 2020 Jan 24.
DOI: 10.1002/cpt.1748
Abstrakt: Antiretroviral therapy during pregnancy reduces the risk of vertical HIV-1 transmission. However, drug dosing is challenging as pharmacokinetics (PK) may be altered during pregnancy. We combined a pregnancy physiologically-based pharmacokinetic (PBPK) modeling approach with data on placental drug transfer to simulate maternal and fetal exposure to dolutegravir (DTG). First, a PBPK model for DTG exposure in healthy volunteers was established based on physiological and DTG PK data. Next, the model was extended with a fetoplacental unit using transplacental kinetics obtained by performing ex vivo dual-side human cotyledon perfusion experiments. Simulations of fetal exposure after maternal dosing in the third trimester were in accordance with clinically observed DTG cord blood data. Furthermore, the predicted fetal trough plasma concentration (C trough ) following 50 mg q.d. dosing remained above the concentration that results in 90% of viral inhibition. Our integrated approach enables simulation of maternal and fetal DTG exposure, illustrating this to be a promising way to assess DTG PK during pregnancy.
(© 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
Externí odkaz: