Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study

Purpose: The prodrug metamizole is prescribed intravenously for postoperative pain in children, including off-label use in infants < 1 year. We aimed to assess the pharmacokinetics of the main metabolites of metamizole in children aged 3–72 months. Methods: A single dose of 10 mg/kg metamizole was administered intravenously for postoperative analgesia. Pharmacokinetic samples were drawn at predefined time points. Pharmacokinetics of the main active metabolite 4-methylaminoantipyrine and three other metabolites was characterized by both non-compartmental and population pharmacokinetic analysis. AUC_0–inf of 4-methylaminoantipyrine was calculated by non-compartmental analysis for two age cohorts (3–23 months, 2–6 years) and compared with the 80–125% range of adult dose–adjusted reference exposure (AUC_ref). Population pharmacokinetic analysis investigated age and weight dependency of the pharmacokinetics and optimal dosing strategies to achieve equivalent adult exposure. Results: A total of 25 children aged 5 months–5.8 years (7.8–24.8 kg) with at least one concentration sample were included; 19 children had ≥ 5 predefined samples up to 10 h after metamizole dose administration. AUC_0–inf of 4-methylaminoantipyrine in children 2–6 years was 29.9 mg/L/h (95% CI 23.4–38.2), significantly lower than AUC_ref (80–125% range 39.2–61.2 mg/L/h). AUC_0–inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8–119.0), comparable with AUC_ref, while infants < 12 months showed increased exposure. Observed variability could be partially explained by covariates weight and age. Conclusions: Age-related changes in pharmacokinetics of 4-methylaminoantipyrine requires reduced weight–based IV dosing in infants < 1 year compared with infants and children up to 6 years (5 versus 10–20 mg/kg) to achieve equivalent adult exposure. Trial registration: ClinicalTrials.gov identifier: NCT02660177.