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

Clin Pharmacol Ther. 2023 Dec 20. doi: 10.1002/cpt.3157. Online ahead of print.ABSTRACTTo inform fetal drug safety, it is important to determine or predict fetal drug exposure throughout pregnancy. The former is not possible in the 1st or 2nd trimester. In contrast, at the time of birth, fetal drug exposure, relative to maternal exposure, can be estimated as Kp,uu (unbound fetal umbilical venous [UV] plasma 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 Kp,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 Kp,uu of P-gp substrates. Since 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 Kp,uu of the drug at term. The ER-REF predicted fetal Kp,uu of glyburide (0.43), imatinib (0.42) and nelfinavir (0.40) fell within 2-fold of the correspondi...
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research