Use of Physiologically Based Pharmacokinetic Modeling for Hepatically Cleared Drugs in Pregnancy: Regulatory Perspective

Abstract

Physiologically based pharmacokinetic modeling could be used to predict changes in exposure during pregnancy and possibly inform medicine use in pregnancy in situations in which there is currently limited or no available clinical PK data. The Medicines and Healthcare Product Regulatory Agency has been evaluating the available models for a number of medicines cleared by hepatic clearance mechanisms. Models were evaluated for metoprolol, tacrolimus, clindamycin, ondansetron, phenytoin, caffeine, fluoxetine, clozapine, carbamazepine, metronidazole, and paracetamol. The hepatic metabolism through cytochrome P450 (CYP) contributes significantly to the elimination of these drugs, and available knowledge of CYP changes during pregnancy has been implemented in the existing pregnancy physiology models. In general, models were able to capture trends in exposure changes in pregnancy to some extent, but the magnitude of pharmacokinetic change for these hepatically cleared drugs was not captured in each case, nor were models always able to capture overall exposure in the populations. A thorough evaluation was hampered by the lack of clinical data for drugs cleared by a specific clearance pathway. The limited clinical data, as well as complex elimination pathways involving CYPs, uridine 5′‐diphospho‐glucuronosyltransferase and active transporter for many drugs, currently limit the confidence in the prospective use of the models. Pregnancy‐related changes in uridine 5′‐diphospho‐glucuronosyltransferase and transport functions are emerging, and incorporation of such changes in current physiologically based pharmacokinetic modeling software is in progress. Filling this gap is expected to further enhance predictive performance of models and increase the confidence in predicting PK changes in pregnant women for hepatically cleared drugs.

Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy

“…A PBPK model was previously developed and used to simulate the total and unbound systemic plasma and blood exposure of tacrolimus in nonpregnant and pregnant populations during the first, second, and third trimester [19]. The observed and simulated clinical PK data for tacrolimus are presented in Table 2.…”

“…The binding of the drug of interest to the blood cells and the predominant plasma proteins is described in the drug model either as a ratio, fraction unbound or, mechanistically, as dissociation constants, Kds. Consequently, these PBPK models could be used to predict changes in exposure, as plasma protein concentrations change, in the pregnant population of both free and total drug and, possibly, to support dosing strategies [18,19].…”