Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model

Abstract

Objectives: This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CLformation) of oxidative pathway metabolites.

Methods: Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (<28 weeks' gestation) or seven 15-mg/kg doses at 8-h intervals (≥28 weeks' gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration-time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2.

Results: The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CLformation for all metabolites increased with weight; CLformation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CLformation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038-0.062; 62 %) for glucuronidation, 0.21 L/h (0.17-0.24; 33 %) for sulfation, and 0.058 L/h (0.044-0.078; 72 %) for oxidation. Expression of individual oxidation CLformation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CLformation increased <15 % when plotted against weight or postnatal age.

Conclusions: The parent-metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.

Conflict of interest statement

Conflicts of interest Sarah Cook, Chris Stockmann, Samira Samiee-Zafarghandy, Amber King, Nina Deutsch, Elaine Williams, Diana Wilkins, Catherine Sherwin, and John van den Anker have no potential conflicts of interest to declare.

Figures

Fig. 1

Schematic of the structural pharmacokinetic model for paracetamol and its metabolites in plasma (circles) and urine (squares). All formation and renal clearances were modeled as first-order processes. CP, CG, CS, and CO represent, respectively, plasma concentrations of paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine); AP, AG, AS, and AO represent, respectively, urinary amounts of unchanged paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the oxidative pathway metabolites; VP, VG, VS, and VO represent, respectively, volumes of distribution for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the oxidative pathway metabolites; CLfG, CLfS, and CLfO represent, respectively, formation (hepatic) clearances for paracetamol-glucuronide, paracetamol-sulfate, and the oxidative pathway metabolites; CLRP, CLRG, CLRS, and CLRO represent, respectively, renal clearances for unchanged paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the oxidative pathway metabolites

Fig. 2

Observed plasma concentrations vs. time for neonates who received five doses at 12-h intervals (a, c 15-mg/kg per dose) and for neonates who received seven doses at 8-h intervals (b, d 15-mg/kg per dose). a, b Show paracetamol concentrations (gray x marks); c, d show concentrations of paracetamol-glucuronide (blue plus signs), paracetamol-sulfate (green circles), and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine, orange triangles)

Fig. 3

Diagnostic plots for the final model. Observed vs. population-predicted (upper row) and individual-predicted (lower row) plasma concentrations (a), and observed vs. population-predicted (upper row) and individual-predicted (lower row) urinary amounts (b). The solid black lines depict the lines of identity (y = x) and the solid red lines depict the LOESS fits of the data

Fig. 4

Visual predictive checks of the final model for plasma concentrations of a paracetamol, b paracetamol-glucuronide, c paracetamol-sulfate, and d the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine). Individual observations are depicted as open black circles. The solid red lines depict the observed 50th percentiles, and the solid black lines depict the observed 5th and 95th percentiles. The shaded red regions depict the 95 % confidence intervals surrounding the predicted 50th percentiles, and the shaded gray regions depict the 95 % confidence intervals surrounding the predicted 5th and 95th percentiles. Note that all plotted values reflect prediction-corrected concentrations

Fig. 5

Typical values of total paracetamol clearance from the final model for a patient with a procedural analgesia indication and assuming the median urine flow rate (6.5 mL/h) for a a range of body weights at the median postnatal age of 6 days and b a range of postnatal ages at the median body weight of 2.8 kg. Within each bar, typical clearance values for each pathway are shown (from bottom to top)ingray for renal clearance of unchanged parent drug, blue for glucuronidation, green for sulfation, and orange for oxidation

Fig. 6

Fraction of total paracetamol clearance accounted for by glucuronidation, sulfation, oxidation, and renal clearance of unchanged parent drug. Fractional clearances for each subject (open black circles) are shown vs. the significant covariates current body weight (a) and postnatal age (b). The dashed red lines depict quasibinomial fits of the data, and the shaded gray regions depict 95 % confidence intervals surrounding the regression curves. Fractional clearances were calculated from individual formation (hepatic) clearance estimates for paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) and from the median individual estimates for renal clearance of unchanged paracetamol