Application of Physiologically ‐Based Pharmacokinetic Modeling to Predict Drug Disposition in Pregnant Populations

ABSTRACT Pregnancy is associated with numerous physiologic changes that influence absorption, distribution, metabolism and excretion. Moreover, the magnitude of these effects changes as pregnancy matures. For most medications, there is limited information available about changes in drug disposition that can occur in pregnant patients, yet most women are prescribed one or more medications during pregnancy. In this investigation, PBPK modeling was used to assess the impact of pregnancy on the pharmacokinetic profiles of three medications (metformin, tacrolimus, oseltamivir) using the Simcyp® Simulator. The Simcyp pregnancy‐PBPK model accounts for the known physiologic changes that occur during pregnancy. For each medication, plasma concentration‐time profiles were simulated using Simcyp® virtual populations of healthy volunteers and pregnant patients. Predicted systemic exposure metrics (Cmax, AUC) were compared to published clinical data, and the fold error (FE, ratio of predicted and observed data) was calculated. The PBPK model was able to capture observed changes in Cmax and AUC across each trimester of pregnancy compared to post‐partum for metformin (FE range 0.86 – 1.19), tacrolimus (FE range 1.03 – 1.64) and oseltamivir (FE range 0.54 – 1.02). Simcyp model outputs were used to correlate these findings with pregnancy‐induced alterations in renal blood flow (metformin, oseltamivir), hepatic CYP3A4 activity (tacrolimus) and reduced plasma protein levels and ...
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL PAPER Source Type: research