Population pharmacokinetics of intravenous acetaminophen (Paracetamol) and Its metabolites in Neonates

Pain management is a critical component of neonatal intensive care, not only for ethical reasons, but also because the failure to provide adequate analgesia during early life has been associated with poor outcomes. Intravenous acetaminophen is an attractive option for treatment of neonatal pain; however, there is a lack of consensus regarding optimal dosing guidelines, and safety data are limited. A principal safety concern is acetaminophen-induced hepatotoxicity, which depends highly on drug metabolism. Unfortunately, neonatal pharmacokinetic data for acetaminophen metabolites are scarce. The objective of this dissertation was to explore maturational changes in the pharmacokinetics of intravenous acetaminophen and its metabolites in neonates. This goal was achieved by completion of three major aims that centered on a prospective clinical trial. Neonates with a clinical indication for intravenous analgesia received multiple doses of intravenous acetaminophen, and pharmacokinetic samples were collected throughout a 72-h study period. Aim 1 focused on development and validation of a novel high-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification of acetaminophen and the metabolites derived from acetaminophen glucuronidation, sulfation, and oxidation. Suitability of the assay was demonstrated by analysis of plasma and urine samples from the neonatal pharmacokinetic study. In Aim 2, a population pharmacokinetic model was developed from the parent drug concentration-time data. In extremely preterm to full-term neonates, body weight iv was the principal predictor of intravenous acetaminophen pharmacokinetics. External evaluation with a dataset from an independent study suggested that these findings should be generalizable to other similar patient populations. Aim 3 focused on development of a parent-metabolite population pharmacokinetic model using the data obtained from the neonatal pharmacokinetic study. As part of model development, an extensive covariate analysis was performed to identify patient characteristics that influenced metabolite pharmacokinetic parameters, with a particular focus on formation clearance of metabolites derived from acetaminophen oxidation. Maturational changes in the fraction of acetaminophen undergoing oxidation were small relative to between-subject variability. Collectively, these results improve understanding of the factors influencing acetaminophen disposition during the neonatal period, and these findings inform appropriate dosing strategies for intravenous acetaminophen in this vulnerable patient population.