Successful Prediction of Fetal Exposure to Dual BCRP/P-gp Drug Substrates Using the Efflux Ratio-Relative Expression Factor Approach and PBPK M&S.

Autor: Balhara A; Department of Pharmaceutics, University of Washington, Seattle, Washington, USA., Yin M; Department of Pharmaceutics, University of Washington, Seattle, Washington, USA., Unadkat JD; Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2024 May; Vol. 115 (5), pp. 1044-1053. Date of Electronic Publication: 2024 Jan 08.
DOI: 10.1002/cpt.3157
Abstrakt: To inform fetal drug safety, it is important to determine or predict fetal drug exposure throughout pregnancy. The former is not possible in the first or second trimester. In contrast, at the time of birth, fetal drug exposure, relative to maternal exposure, can be estimated as K p,uu (unbound fetal umbilical venous (UV) plasma area under the curve (AUC)/unbound maternal plasma (MP) AUC), provided the observed UV/MP values, spanning the dosing interval, are available from multiple maternal-fetal dyads. However, this fetal K p,uu cannot be extrapolated to other drugs. To overcome the above limitations, we have used an efflux ratio-relative expression factor (ER-REF) approach to successfully predict the fetal K p,uu of P-gp substrates. Because many drugs taken by pregnant people are also BCRP substrates, here, we extend this approach to drugs that are effluxed by both placental BCRP and P-gp or P-gp alone. To verify our predictions, we chose drugs for which UV/MP data were available at term: glyburide and imatinib (both BCRP and P-gp substrates) and nelfinavir (only P-gp substrate). First, the ER of the drugs was determined using Transwells and MDCKII cells expressing either BCRP or P-gp. Then, the ER was scaled using the proteomics-informed REF value to predict the fetal K p,uu of the drug at term. The ER-REF predicted fetal K p,uu of glyburide (0.43), imatinib (0.42), and nelfinavir (0.40) fell within two-fold of the corresponding in vivo fetal K p,uu (0.44, 0.37, and 0.46, respectively). These data confirm that the ER-REF approach can successfully predict fetal drug exposure to BCRP/P-gp and P-gp substrates, at term.
(© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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