Physiologically based pharmacokinetic modelling of acetaminophen in preterm neonates—The impact of metabolising enzyme ontogeny and reduced cardiac output

Abstract

In preterm neonates, physiologically based pharmacokinetic (PBPK) models are suited for studying the effects of maturational and non-maturational factors on the pharmacokinetics of drugs with complex age-dependent metabolic pathways like acetaminophen (APAP). The aim of this study was to determine the impact of drug metabolising enzymes ontogeny on the pharmacokinetics of APAP in preterm neonates and to study the effect of reduced cardiac output (CO) on its PK using PBPK modelling. A PBPK model for APAP was first developed and validated in adults and then scaled to paediatric age groups to account for the effect of enzyme ontogeny. In preterm neonates, CO was reduced by 10%, 20%, and 30% to determine how this might affect APAP PK in preterm neonates. In all age groups, the predicted concentration-time profiles of APAP were within 5th and 95th percentile of the clinically observed concentration-time profiles and the predicted Cmax and AUC were within 2-folds of the reported parameters in clinical studies. Sulfation accounted for most of APAP metabolism in children, with the highest contribution of 68% in preterm neonates. A reduction in CO by up to 30% did not significantly alter the clearance of APAP in preterm neonates. The model successfully incorporated the ontogeny of drug metabolising enzymes involved in APAP metabolism and adequately predicted the PK of APAP in preterm neonates. A reduction in hepatic perfusion as a result of up to 30% reduction in CO has no effect on the PK of APAP in preterm neonates.

Desorption Electrospray Ionization Mass Spectrometry Imaging Allows Spatial Localization of Changes in Acetaminophen Metabolism in the Liver after Intervention with 4-Methylpyrazole

“…Despite the numerous clinical pharmacokinetic studies of APAP − and the emergence of MSI, only a few recent studies have investigated the liver zonation and whole-body distribution of APAP and its metabolites. These were carried out with MALDI-MSI, which is the most widely used MSI technique.…”

The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups - an Investigation using Physiologically based Pharmacokinetic Modelling

“…PBPK models have been successfully used for similar analyses where for example, the non-maturational impact of CYP2B6 genetic polymorphism and drug-drug interaction between efavirenz and lumefantrine alongside maturational changes in children was quantified [18]. More recently, Olusola et al demonstrated that the reduction in CO, as non-maturational parameter, did not significantly alter the acetaminophen pharmacokinetics in preterm neonates owing to immaturity of acetaminophen clearance pathways in preterms and the inherent low hepatic clearing capacity of acetaminophen [19].…”

The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling

“…PBPK models have been successfully used for similar analyses where, for example, the non-maturational impact of CYP2B6 genetic polymorphism and drug-drug interaction between efavirenz and lumefantrine alongside maturational changes in children was quantified [18]. More recently, Olusola et al demonstrated that the reduction in CO, as a non-maturational parameter, did not significantly alter the acetaminophen pharmacokinetics in preterm neonates owing to immaturity of acetaminophen clearance pathways in preterms and the inherent low hepatic clearance capacity of acetaminophen [19].…”