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

Abstract

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. AUC0-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 (AUCref). 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. AUC0-inf of 4-methylaminoantipyrine in children 2-6 years was 29.9 mg/L/h (95% CI 23.4-38.2), significantly lower than AUCref (80-125% range 39.2-61.2 mg/L/h). AUC0-inf of 4-methylaminoantipyrine in infants < 2 years was 43.6 mg/L/h (95% CI 15.8-119.0), comparable with AUCref, 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 .

• Authors: Victoria C Ziesenitz, Frédérique Rodieux, Andrew Atkinson, Carole Borter, Julia A Bielicki, Manuel Haschke, Urs Duthaler, Fabio Bachmann, Thomas O Erb, Nicolas Gürtler, Stefan Holland-Cunz, Johannes N van den Anker, Verena Gotta, Marc Pfister
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 75 Issue 11 Pg. 1491-1502 (Nov 2019) ISSN: 1432-1041 [Electronic] Germany
• PMID: 31388703 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Analgesics
• Anti-Inflammatory Agents, Non-Steroidal
• Dipyrone

Topics

• Administration, Intravenous
• Analgesics (administration & dosage, blood, pharmacokinetics)
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, blood, pharmacokinetics)
• Child
• Child, Preschool
• Dipyrone (administration & dosage, blood, pharmacokinetics)
• Female
• Humans
• Infant
• Male
• Models, Biological
• Pain, Postoperative (blood, drug therapy, metabolism)