Physiologically Based Pharmacokinetic Modelling of UGT Substrate Drugs Lamotrigine and Raltegravir during Pregnancy

Abstract

Pregnancy is associated with various physiological changes that can significantly impact the disposition of drugs. To further the insight into how pregnancy affects the pharmacokinetics of drugs at different stages, clinical studies can be simulated using Physiologically Based Pharmacokinetic modelling. PBPK modelling of drugs metabolised by Phase I enzymes (CYPs) in pregnant population models had been reported in the past, while its use in Phase II (UGTs) is not known. In this study, based on the results of a recent meta-analysis, lamotrigine (UGT1A4) and raltegravir (UGT1A1) were selected as candidate drugs, and pregnancy-specific models were developed for both using the Simcyp v.21 simulator. A middle-out strategy was used where previously published drug parameters were adapted from a minimal to a full PBPK model to allow their application for the pregnancy population models using Simcyp PBPK software. Adapted models were successfully validated against observed clinical data both qualitatively (visual overlay of plasma concentrations on graphs) and quantitatively (calculating the predicted/observed ratios for AUC, Cmax and CL as well as statistical analysis using model prediction power metrics). They were then applied to predict the PKs of both drugs in pregnancy population models. The temporal changes in maternal enzymatic activities during gestation were modelled based on in vitro data reported in literature and default relationships encoded in the Simcyp platform for UGT1A1 and UGT1A4, respectively. Our study demonstrates the successful development and validation of a PBPK model for LTG and RTG in pregnancy population models. Future work with additional UGT1A4 substrate drugs using the proposed changes in UGT1A4 activity may enable validating the pregnancy population model and its subsequent use for the prospective prediction of PK.