(M-100) Development of a Quantitative Systems Toxicology Model to Predict Drug-Induced Liver Injury in Pediatrics

An Dela – Simulations Plus; Kyunghee Yang – Quantitative Systems Pharmacology Solutions, Simulations Plus; James Beaudoin – Simulations Plus; Jeffrey Woodhead – Simulations Plus

Objectives: Drug-induced liver injury (DILI) is an underrecognized cause of pediatric liver disease which accounts for almost 20% of pediatric acute liver failure cases, and is a major reason for liver transplantation in the USA [1]. However, challenges such as inadequate numbers of available subjects, the need for special infrastructure and expertise, and ethical considerations often preclude extensive clinical studies in pediatric populations. In this study, our primary objective was to develop a pediatric representation in a quantitative systems toxicity (QST) modeling platform, DILIsym®, to explore children's relative susceptibility to DILI.

Methods: DILIsym is a multi-scale, mathematical model of DILI, which includes key liver cell populations, intracellular biochemical systems (e.g., mitochondrial function, bile acid synthesis and transport), drug exposure, and drug-mediated toxicological mechanisms [2]. Healthy and diseased adult populations were previously represented within DILIsym. In the current study, we developed a novel representation of pediatrics that includes pediatric-specific physiology. Four age groups of pediatrics were represented: toddler, preschool, school age, and adolescent (1-, 4-, 10-, and 14-year-old, respectively). First, “small adults” were created by implementing age-specific body weights, organ weights, organ volumes, and organ blood flow rates using the PEAR-PhysiologyTM in GastroPlus®. Next, physiology representing age-specific expression/activity of transporters and enzymes involved in bile acid homeostasis, mitochondrial bioenergetics, and oxidative stress pathways were developed based on available data [3-6]. As a proof-of-concept, acetaminophen (APAP)-mediated hepatoxicity was simulated in pediatrics and adults by integrating age-specific APAP exposure, which was predicted based on enzyme ontogeny, age-specific physiology representation in DILIsym, and a toxicity parameter representing N-acetyl-p-benzoquinone imine (NAPQI, a reactive metabolite of APAP)-mediated oxidative stress.

Results: Simulated bile acid levels, circulating and hepatic nutrients in our representative pediatric individuals aligned reasonably well with the observed data ranges [7]. Simulated APAP exposure levels were consistent with clinical PK data [8]. Proof-of-concept simulations of APAP (a single oral dose ranging 15 – 400 mg/kg) in baseline adults and pediatrics predicted dose-dependent liver injury and ALT elevations. Consistent with clinical reports [9]-[11], simulations predicted lower susceptibility to APAP-induced hepatotoxicity in pediatrics compared to adults, which was attributed to lower expression of CYP2E1 and NAPQI formation; simulations suggested that higher glutathione S-transferase activity in pediatrics had minimal impact on NAPQI detoxification and thus DILI.

Conclusions: Our work demonstrates that existing pediatric data can be applied in a QST model to reproduce the differential susceptibility of pediatric populations (relative to adults) and paves the way for prospective application to improve our mechanistic understanding of pediatric liver safety signals observed in clinical studies.

Citations: [1] M. D. Amin, S. Harpavat, and D. H. Leung, “Drug-induced liver injury in children,” Curr Opin Pediatr, vol. 27, no. 5, pp. 625–633, Oct. 2015, doi: 10.1097/MOP.0000000000000264.
[2] P. B. Watkins, “Quantitative Systems Toxicology Approaches to Understand and Predict Drug-Induced Liver Injury,” Clin Liver Dis, vol. 24, no. 1, pp. 49–60, Feb. 2020, doi: 10.1016/j.cld.2019.09.003.
[3] S. Sharma et al., “Hepatobiliary Disposition of 17-OHPC and Taurocholate in Fetal Human Hepatocytes: A Comparison with Adult Human Hepatocytes,” Drug Metab Dispos, vol. 41, no. 2, pp. 296–304, Feb. 2013, doi: 10.1124/dmd.112.044891.
[4] B. Prasad et al., “Ontogeny of Hepatic Drug Transporters as Quantified by LC-MS/MS Proteomics,” Clin Pharmacol Ther, vol. 100, no. 4, pp. 362–370, Oct. 2016, doi: 10.1002/cpt.409.
[5] F. Freudenberg, F. Gothe, F. Beigel, C. Rust, and S. Koletzko, “Serum 7-alpha-hydroxy-4-cholesten-3-one as a marker for bile acid loss in children,” J Pediatr, vol. 163, no. 5, pp. 1367-1371.e1, Nov. 2013, doi: 10.1016/j.jpeds.2013.06.083.
[6] B. D. van Groen et al., “Proteomics of human liver membrane transporters: a focus on fetuses and newborn infants,” Eur J Pharm Sci, vol. 124, pp. 217–227, Nov. 2018, doi: 10.1016/j.ejps.2018.08.042.
[7] J. Jahnel, E. Zöhrer, H. Scharnagl, W. Erwa, G. Fauler, and T. Stojakovic, “Reference ranges of serum bile acids in children and adolescents,” Clin Chem Lab Med, vol. 53, no. 11, pp. 1807–1813, Oct. 2015, doi: 10.1515/cclm-2014-1273.
[8] Jiang, X‐L., et al. "Application of physiologically based pharmacokinetic modeling to predict acetaminophen metabolism and pharmacokinetics in children." CPT: pharmacometrics & systems pharmacology 2.10 (2013): 1-9.
[9] Ferrajolo, Carmen, et al. "Drug‐induced hepatic injury in children: a case/non‐case study of suspected adverse drug reactions in VigiBase." British journal of clinical pharmacology 70.5 (2010): 721-728.
[10] Mahadevan SBK, McKiernan PJ, Davies P, et al Paracetamol induced hepatotoxicity. Archives of Disease in Childhood 2006;91:598-603.
[11] Zhou L, Maviglia SM, Mahoney LM, et al. Supratherapeutic Dosing of Acetaminophen Among Hospitalized Patients. Arch Intern Med. 2012;172(22):1721–1728. doi:10.1001/2013.jamainternmed.438

Keywords: QST, Pediatrics, DILI