Studying paracetamol disposition in children using a minimally invasive microsampling technique : a preliminary PK analysis

Introduction: Paracetamol, the most used analgesic, undergoes hepatic metabolism, with toxic NAPQI potentially causing liver damage. Data on infants remains scarce. This study explores target concentration attainment in paediatric patients, aiming to minimize toxicity. We describe paracetamol pharmacokinetics, metabolites, and factors influencing inter-individual variability and metabolic pathways in children. Methods: Children included in this observational study received preoperative acetaminophen (15-20 mg/kg) intravenously. Blood was collected at predefined time points with a volumetric absorptive collection device (VAMs) of 10 µL and analyzed via LC-MS/MS. Blood concentrations of acetaminophen and its metabolites (glucuronide, sulfate, cysteine, mercapturate, and glutathione) were determined. Area under the plasma concentration-time curves (AUC) was determined with non-compartmental analysis performed with PKanalix (MonolixSuite). Results: Sixteen patients (median age 11 years, weight 32.5 kg) had a median AUC of 78.70 mgh/L, clearance of 5.46 L/h, and volume of distribution of 21.2 L. The median time above the 6.6 mg/L target concentration was 4 h 5 min, but 50% did not maintain it for 4 h. Sulfation was the primary metabolic pathway, though glucuronide levels exceeded sulfate in blood after 3 h. CYP2E1 metabolite concentrations reached a median of 0.37 mg/L after 2 h. Preliminary data suggest age-related differences in metabolic pathway contributions. Conclusion: Target attainment analysis showed suboptimal paracetamol exposure, suggesting inadequate analgesia. Glucuronidation increased with age, but sulfate was the major pathway. CYP2E1 metabolites (cysteine, mercapturate) were higher than in adults, with unclear relevance. Larger Population Pharmacokinetic studies are needed to further investigate pediatric paracetamol metabolism.