Previous reports have questioned the safety of multiple doses of acetaminophen administered to ill children. Acetaminophen protein adducts (adducts) are a biomarker of acetaminophen-induced liver injury and reflect the oxidative metabolism of acetaminophen, a known mechanism in acetaminophen toxicity. In this prospective observational study, we analyzed adduct concentrations in 1034 blood samples obtained from 181 hospitalized children (1 to 18 years inclusive) who received 2 or more doses of acetaminophen. Linear regression analysis showed that serum adduct concentrations increased as a function of the cumulative acetaminophen dose, which could be attributed, in part, to a long half-life of adducts (2.17 ± 1.04 days [mean ± standard deviation]) in children. However, few patients (2%) were found to have adduct concentrations higher than 1.0 nmol/mL, a previously identified toxicity cut point for the diagnosis of acetaminophen-induced liver injury in patients with alanine aminotransferase values exceeding 1000 IU/L. A small cohort of patients with suspected infection was noted to show higher adduct concentrations. In addition, adduct concentrations showed a stronger correlation with cumulative acetaminophen doses in adolescents compared with children (R2 = 0.41 vs 0.26). No other covariates (body weight, body mass index z score, sex, race, or surgery) remarkably correlated with adduct elevation. In summary, low levels of adducts can be detected in hospitalized children receiving multiple doses of acetaminophen, and adduct levels correlate with cumulative acetaminophen dose.
Keywords: acetaminophen protein adducts; biomarkers; cumulative doses; hepatotoxicity; pediatrics.
© 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.