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

Ziesenitz, Victoria C; Rodieux, Frédérique; Atkinson, Andrew; Borter, Carole; Bielicki, Julia A; Haschke, Manuel; Duthaler, Urs; Bachmann, Fabio; Erb, Thomas O; Gürtler, Nicolas; Holland-Cunz, Stefan; van den Anker, Johannes N; Gotta, Verena; Pfister, Marc (2019). Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study. European journal of clinical pharmacology, 75(11), pp. 1491-1502. Springer 10.1007/s00228-019-02720-2

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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 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). 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 of 4-methylaminoantipyrine in children 2-6 years was 29.9 mg/L/h (95% CI 23.4-38.2), significantly lower than AUC (80-125% range 39.2-61.2 mg/L/h). AUC of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8-119.0), comparable with AUC, 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 .

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