Affiliation:
1. Center for Drug Evaluation and Research US Food and Drug Administration Silver Spring Maryland USA
2. Oak Ridge Institute for Science and Education Oak Ridge Tennessee USA
3. National Center for Toxicological Research US Food and Drug Administration Silver Spring Maryland USA
Abstract
AimsSelective serotonin reuptake inhibitors (SSRIs) are indicated for a variety of psychiatric conditions which may require treatment during pregnancy. Knowledge of appropriate SSRI dosages that maintain maternal therapeutic benefit and minimize fetal risk are needed. Assessment of fetal exposure to drugs is challenging since sampling is often limited to a single concentration from the umbilical cord at delivery. Physiologically based pharmacokinetic (PBPK) modelling provides a non‐invasive approach to quantify exposure in pregnancy.MethodsWe incorporated sertraline clearances mediated by passive diffusion, placental efflux transporters P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) into our previously published pregnancy PBPK model for sertraline. Simulations were performed for various sertraline doses (25–200 mg) at 40 weeks gestational age to predict the minimum (Cmin), maximum (Cmax) and average (Cavg) sertraline maternal and fetal plasma concentrations and evaluated them against observed maternal and cord concentrations obtained at delivery from five clinical studies.ResultsThe accuracy of the PBPK predictions as indicated by the average fold error (AFE) value for Cmax, Cmin and Cavg for maternal plasma sertraline concentrations at delivery was 1.7, 1.2 and 1.4, respectively. The AFE for the Cmax, Cmin and Cavg for cord blood sertraline concentration at delivery was 1.2, 1 and 1.1, respectively. The AFE for cord‐maternal sertraline concentration ratio at delivery for Cmax, Cmin and Cavg was 0.7, 0.9 and 0.8, respectively.ConclusionsThe PBPK model we developed may serve as a guide for maternal sertraline dose adjustment during pregnancy considering changes in exposures for both mother and fetus.
Funder
U.S. Food and Drug Administration
Subject
Pharmacology (medical),Pharmacology