Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: assessing the impact of the
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ORIGINAL PAPER
Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: assessing the impact of the longitudinal changes in the activity of CYP1A2, CYP2D6 and CYP3A4 enzymes during pregnancy Khaled Abduljalil1
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Amita Pansari1 • Masoud Jamei1
Received: 28 July 2020 / Accepted: 11 August 2020 Ó Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Concerns over gestational effects on the disposition of drugs has highlighted the need for a better understanding of drug distribution and elimination during pregnancy. This study aimed at predicting maternal drug kinetics using a physiologically based pharmacokinetic (PBPK) modelling approach focusing on the observed gestational changes in three important Cytochrome P450 metabolizing enzymes, namely, CYP1A2, CYP2D6 and CYP3A4 at different gestational weeks (GWs). The Pregnancy PBPK model within the Simcyp Simulator V19 was used to predict the pharmacokinetics of sensitive probes to these enzymes; namely caffeine, theophylline, metoprolol, propranolol, paroxetine, midazolam, nifedipine and rilpivirine. PBPK model predictions were compared against clinical data collated from multiple studies for each compound to cover a wide spectrum of gestational ages. Pregnancy PBPK model predictions were within 2-fold error and indicated that CYP1A2 activity is approximately 0.70, 0.44 and 0.30 fold of the non-pregnant level at the end of the first, second and third trimesters, respectively. On the other hand, CYP2D6 activity increases by 1.36, 2.16 and 3.10 fold of the nonpregnant level at the end of the first, second and third trimesters, respectively. Likewise, CYP3A4 activity increases by 1.25, 1.75 and 2.32 fold of the non-pregnant level at the end of the first, second and third trimesters, respectively. The enzymes activity have been qualified throughout pregnancy. Quantified changes in drug dosing are most relevant during the third trimester, especially for drugs that are mainly eliminated by CYP1A2, CYP2D6 and CYP3A4 enzymes. The provided functions describing the continuous changes to the activity of these enzymes during pregnancy are important when modelling long term pharmacokinetic studies where longitudinal modelling or time-varying covariates are used. Keywords Pregnancy PBPK Pharmacokinetics Inter-individual variability CYP1A2 CYP2D6 CYP3A4 Abbreviations PBPK Physiologically-based pharmacokinetics GWs Gestational weeks
& Khaled Abduljalil [email protected] 1
Simcyp Division, Certara UK Limited, Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, UK
Introduction Pharmacokinetics during pregnancy has gained considerable interest over the last few years. Multifactorial changes develop ‘‘physiologically’’ with pregnancy progression [1] and can alter drugs kinetics [2]. Drug-metabolizing enzyme activity is one of many factors affecting patient exposure and hence response to medications. Among these enzymes, the cytochrome P450 (CYP) enzymes are involved in the metabolism of more than 70% of d
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