Aymara Sancho-Araiz 1, Michael Gertz 2, Bianca D.van Groen 2, Yumi Cleary 2, Saskia N. de Wildt 3,4, Janneke M/ BRussee 5, Johannes N. van den Anker 6, Jeffrey S. Barret 7, Elke H.J. Krekels 1,8, Anthony R. Gebhart 1, Catherijne A.J.Knibbe 1,9
1 Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University (Leiden, The Netherlands), 2 Roche Pharma Research and Early Development, Roche Innovation Center Basel (Basel, Switzerland), 3 Neonatal and Pediatric Intensive Care; Erasmus MC - Sophia Children’s Hospital (Rotterdam, The Netherlands), 4 Department of Pharmacy, Pharmacology and Toxicology , Radboud University Medical Centre (Nijmegen, The Netherlands), 5 qPharmetra (Leiden, The Netherlands), 6 Division of Clinical Pharmacology, Children’s National Hospital (Washington, US), 7 Critical Path Institute (Tucson, US), 8 Certara Inc (Princeton, US), 9 Department of Clinical Pharmacy, St. Antonius Hospital (Nieuwegein, The Netherlands)
Objectives:
While the ontogeny of CYP3A enzymes and the difference between gut wall and hepatic maturation have been extensively studied, important knowledge gaps remain across the paediatric age range [1-3]. To address paediatric pharmacological questions and fill this gap, physiologically-based pharmacokinetic (PBPK) models have become a very important tool. However, their complexity and computational demands can restrict their practical application. PopPBPK model reductions have been proposed describing first-pass metabolism and their ability to estimate intestinal (FG) and hepatic availability (FH).
Our aim was to describe CYP3A ontogeny in the gut wall and liver and quantify their respective contribution to intrinsic clearance (CLint,G and CLint,H) and total oral bioavailability (Ftotal) across the pediatric age range (0-18 years), and adults using a generalized reduced PBPK model [4].
Methods:
Midazolam, a CYP3A probe drug, and 1-OH-midazolam, plasma concentrations, were available from three studies:
(a) 43 ICU neonates and infants (2 days to 5.3 years) receiving intravenous midazolam and an oral microdose of [¹⁴C]-midazolam [5];
(b) 264 children (1-18 years) receiving oral midazolam postoperatively [1];
(c) 12 healthy adults receiving intravenous and oral midazolam [6].
Data were analyzed using a minimal PBPK model implemented in NONMEM 7.5. To use this model is important to note two assumptions: (i) drug absorption is the rate limiting step, and (ii) steady-state is reached immediately after drug administration. The minimal model resembles an empirical compartment model (one-, two-, and three-compartment models). Despite the empirical structure, the model accounted for physiological blood flows, tissue volumes, unbound fractions in plasma and tissue/blood concentration ratios, surface areas and permeability clearances, fixed from literature and scaled according to each patient’s characteristics (Figure 1) [1-6]. Estimated parameters include absorption rate constant, volume of distribution of central and peripheral compartments, and inter-compartmental clearance, and CLint,G and CLint,H, allowing for the characterization of gut wall (FG) and hepatic (FH) bioavailability, respectively. Additionally, to describe the age-related differences in CLint several ontogeny models for CYP3A maturation [10-14] including the Upreti function [13] and body-weight-dependent exponent (BDE) function [14], were evaluated.
Results
The minimal popPBPK model allowed the accurately description of midazolam and 1-OH-midazolam pharmacokinetics across the entire pediatric age range. Moreover, despite its simple structure, it retained interpretability of physiological parameters. Individual CLint,G and CLint,H estimates showed a rapid CYP3A activity increase in the gut wall and liver during the first year of life, with near-adult levels per gram of organ being reached by approximately six years. The BDE function best captured this ontogeny pattern, with low intrinsic clearance at low body weights and a sharp increase until adult values. Median oral bioavailability (Ftotal) decreased from ~80% in neonates to ~30% in adults, reflecting maturation of first-pass metabolism.
Conclusions:
The minimal PBPK model provides a generalized mechanistic yet computationally efficient approach to investigate complex pharmacological questions. It allowed efficient and accurate characterization of CYP3A-mediated clearance in the gut wall and liver across a wide age range. Additionally, the BDE function adequately captured the maturation of CYP3A from neonates to adults.
References:
1. Brussee JM, et. al. Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach. Pharm Res. 2018 Jul 30;35(9):182.
2. Brussee JM, et. al. First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates. CPT Pharmacometrics Syst Pharmacol. 2018 Jun;7(6):374-383.
3. PAGE 29 (2021) Abstr 9824 [www.page-meeting.org/?abstract=9824]
4. van Groen BD, et. al. The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study. Clin Pharmacol Ther. 2021 Jan;109(1):140-149.
5. PAGE 30 (2022) Abstr 9979 [www.page-meeting.org/?abstract=9979]
6. Gertz M, et. al. Physiologically based pharmacokinetic modeling of intestinal first-pass metabolism of CYP3A substrates with high intestinal extraction. Drug Metab Dispos. 2011 Sep;39(9):1633-42.
7. Pang KS, et. al. Hepatic clearance concepts and misconceptions: Why the well-stirred model is still used even though it is not physiologic reality? Biochem Pharmacol. 2019 Nov;169:113596.
8. Yang J, et. al. Prediction of intestinal first-pass drug metabolism. Curr Drug Metab. 2007 Oct;8(7):676-84.
9. PAGE 33 (2025) Abstr 11661 [www.page-meeting.org/?abstract=11661]
10. Edginton A.N., et. al.. Development and Evaluation of a Generic Physiologically Based Pharmacokinetic Model for Children. Clin Pharmacokinet 45, 1013–1034 (2006).
11. Salem, F., et al. A Re-evaluation and Validation of Ontogeny Functions for Cytochrome P450 1A2 and 3A4 Based on In Vivo Data. Clin Pharmacokinet 54, 671 (2015).
12. Björkman, S. Prediction of Cytochrome P450-Mediated Hepatic Drug Clearance in Neonates, Infants and Children. Clin Pharmacokinet 45, 1–11 (2006).
13. Upreti VV, Wahlstrom JL. Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling. J Clin Pharmacol. 2016 Mar;56(3):266-83.
14. Wang, C., et al. A Bodyweight-Dependent Allometric Exponent for Scaling Clearance Across the Human Life-Span. Pharm Res 29, 1570–1581 (2012).
Reference: PAGE 34 (2026) Abstr 11931 [www.page-meeting.org/?abstract=11931]
Poster: Drug/Disease Modelling - Paediatrics