Application of physiologically based pharmacokinetic modeling to predict drug disposition in pregnant populations

Abstract

Pregnancy is associated with numerous physiological 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 physiological changes that occur during pregnancy. For each medication, plasma concentration-time profiles were simulated using Simcyp® virtual populations of healthy volunteers and pregnant patients. The predicted systemic exposure metrics (C , AUC) were compared with published clinical data, and the fold error (FE, ratio of predicted and observed data) was calculated. The PBPK model was able to capture the observed changes in C and AUC across each trimester of pregnancy compared with 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 hemodilution (tacrolimus). The results illustrate how PBPK modeling can help to establish appropriate dosing guidelines for pregnant patients and to predict potential changes in systemic exposure during pregnancy for compounds undergoing clinical development.

Quetiapine dose optimisation during gestation: a pharmacokinetic modelling study

“…Given the lack of more detailed clinical studies examining these phenomena, this study applied the principle of pharmacokinetic modelling to prospectively assess the use of quetiapine in pregnancy population groups and attempted to relate changes in plasma concentrations during gestation to a potential therapeutic window region. The Simcyp Pregnancy PBPK model has been utilised by our group and others for prediction of the impact of changes in plasma concentrations associated with gestation; however, this is the first time it has been utilised in the context of quetiapine.…”

“…The ‘Healthy Volunteer’ population group was used for ‘non‐pregnant’ women, and the ‘Pregnancy’ population group utilised for all ‘pregnancy’ studies. The latter population group included necessary gestational dependant changes in physiology, such as blood volume and organ/tissue perfusion and enzyme/protein expression, which are thought to play a role in altering the pharmacokinetics of drugs . A 4‐stage modelling approach was implemented.…”

Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

“…31,32 Since then, a number of publications have provided independent verification and application of a pregnancy module to study drugs in the pregnant population. The tested drugs covered a wide spectrum of clearance mechanisms, including several major isoforms of CYP enzymes (CYP3A4, 2D6, 1A2, 2B6, 2C9, and 2C19), 9,33,34 and renal clearance. 34,35 These examples followed the best practice approach in PBPK modeling of drug PKs in special populations, demonstrating the performance of drug models for the nonpregnant subjects, verifying the key model components using independent clinical PK and drug-drug interaction data, before predicting the drug PKs in the pregnant subjects ( Figure 1).…”

Translational Systems Pharmacology Studies in Pregnant Women

“…These models typically used static parameter models, describing the gestational age of interest. In more recent years, pregnancy PBPK models have incorporated dynamic changes in maternal and fetal physiology to estimate exposure across gestation . Although the majority of published pregnancy PBPK models have been user‐built, the commercial PBPK modeling software Simcyp (Certera) has released a pregnancy population model that utilizes a combined placental‐fetal compartment and allows for longitudinal changes in number of key physiologic parameters across gestation …”

“…In more recent years, pregnancy PBPK models have incorporated dynamic changes in maternal and fetal physiology to estimate exposure across gestation. 11,15 Although the majority of published pregnancy PBPK models have been user-built, the commercial PBPK modeling software Simcyp (Certera) has released a pregnancy population model that utilizes a combined placental-fetal compartment and allows for longitudinal changes in number of key physiologic parameters across gestation. 11,15 One limitation in the development of pregnancy PBPK models is the availability of data regarding changes in physiological parameters affecting drug disposition and clinical pharmacokinetic data for model verification.…”