Paola Mian (1), John van den Anker (1,2,3), Kristel van Calsteren (4,5), Pieter Annaert (5), Dick Tibboel (1), Marc Pfister (2,6), Karel Allegaert (1,5), André Dallmann (2)
(1) Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, Netherlands; (2) Pediatric Pharmacology and Pharmacometrics Research Center, University Children’s Hospital Basel (UKBB), Switzerland; (3) Children’s National Health System, Washington, DC, USA; (4) UZ Leuven, Belgium; (5) KU Leuven, Belgium; (6) Certara LP, Princeton, NJ, USA
Introduction: Paracetamol (acetaminophen) is one of the most commonly prescribed drugs for acute pain during pregnancy [1]. Despite its frequent use during pregnancy, little is known about the risk of hepatotoxicity in both pregnant women and their fetuses. The aim of this study was to develop and evaluate a physiologically-based pharmacokinetic (PBPK) model that predicts the disposition of intravenously administered paracetamol and its metabolites in term pregnant women. The model was then scaled to the late first trimester and maternal disposition of paracetamol and its metabolites was predicted with the aim to characterize the hepatotoxicity risk.
Methods: PBPK models for paracetamol and its metabolites generated by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1, sulfotransferase (SULT) 1A1, and cytochrome P450 (CYP) 2E1 were built using the Open Systems Pharmacology software suite together with the therein implemented compound templates (www.open-systems-pharmacology.org) [2]. Owing to missing information, detoxification of the CYP2E1-metabolite (NAPQI) by glutathione conjugation could not be modeled. It was therefore assumed that the concentration of paracetamol cysteine conjugates (APAP-cys) is equivalent to NAPQI concentration. Once qualified for a reference population of adult women, the model was scaled to pregnancy according to a previously described workflow [3] using a system-specific model parameterization for pregnancy [4-6]. Since quantitative information on pregnancy-induced changes in UGT1A1 tissue concentrations was lacking, the model was informed by a herein presented in vitro-in vivo intersystem extrapolation approach. Based on reported animal or human data, SULT1A1 tissue concentrations were assumed to be unaffected by pregnancy [7,8] and CYP2E1 tissue concentrations were assumed to be constantly increased by 80% in pregnancy [9,10]. The disposition of paracetamol was predicted in a population of term pregnant women and evaluated using in vivo data [10]. After successful model qualification, it was scaled to the late first trimester and maternal disposition of paracetamol and its metabolites was predicted. The risk for hepatotoxicity was then assessed through the predicted exposure to APAP-cys in the late first trimester and at term pregnancy.
Results: The simulated disposition of paracetamol in populations of non-pregnant women was in good agreement with observed in vivo data. All simulated paracetamol plasma concentrations were within a 2-fold error range. As judged from observed metabolite urine concentrations, the disposition of paracetamol metabolites was also well described by the model. The pregnancy PBPK model predicted paracetamol disposition in term pregnant women reasonably well. All predicted paracetamol plasma concentrations were within a 2-fold error range. Based on the extrapolation approach for UGT1A1 expression, the activity at term pregnancy was estimated to be on average 6-fold higher compared to non-pregnant women. Urine concentrations of paracetamol metabolites were adequately predicted, although those of paracetamol glucuronide were slightly overestimated. Scaling of the model to the late first trimester of pregnancy showed that the exposure to APAP-cys was approximately 30% higher compared to term pregnancy.
Conclusions: The developed pregnancy PBPK model accounts for physiological changes during pregnancy, such as altered organ weights, blood flows and enzyme activity. UGT1A1 activity at term pregnancy was adequately estimated by the presented extrapolation approach. This approach should be further evaluated using in vivo data of additional UGT-substrates at different stages of pregnancy. Importantly, the model can be scaled to earlier gestational weeks allowing an investigation of paracetamol hepatotoxicity throughout pregnancy in silico. While the underlying assumptions of the model, such as pregnancy-induced changes in CYP2E1 activity or concentration equivalence of NAPQI and APAP-cys, should be tested by further research, the presented results show that maternal exposure to APAP-cys was higher in the first vs. third trimester. This suggests that the risk of hepatotoxicity is higher in early pregnant women stressing the importance of careful dose selection. Ultimately, the clinical usefulness of this model could be further enhanced by investigating and predicting placental transfer of paracetamol and fetal exposure to paracetamol and its metabolites.
References:
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Reference: PAGE 27 (2018) Abstr 8540 [www.page-meeting.org/?abstract=8540]
Poster: Drug/Disease Modelling - Absorption & PBPK