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

Ziesenitz, VC; Rodieux, F; Atkinson, A; Borter, C; Bielicki, JA; Haschke, M; Duthaler, U; Bachmann, F; Erb, TO; Gürtler, N; et al. Ziesenitz, VC; Rodieux, F; Atkinson, A; Borter, C; Bielicki, JA; Haschke, M; Duthaler, U; Bachmann, F; Erb, TO; Gürtler, N; Holland-Cunz, S; van den Anker, JN; Gotta, V; Pfister, M (2019) Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study. Eur J Clin Pharmacol, 75 (11). pp. 1491-1502. ISSN 1432-1041 https://doi.org/10.1007/s00228-019-02720-2
SGUL Authors: Bielicki, Julia Anna

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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 .

Item Type: Article
Additional Information: This is a post-peer-review, pre-copyedit version of an article published in European Journal of Clinical Pharmacology. The final authenticated version is available online at: http://dx.doi.org/10.1007/s00228-019-02720-2
Keywords: Children, Dipyrone, Infants, Metamizole, Pharmacokinetics, 1115 Pharmacology And Pharmaceutical Sciences, Pharmacology & Pharmacy
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Eur J Clin Pharmacol
ISSN: 1432-1041
Language: eng
Dates:
DateEvent
November 2019Published
7 August 2019Published Online
11 July 2019Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
SNF 31003A_160216Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschundUNSPECIFIED
PubMed ID: 31388703
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111108
Publisher's version: https://doi.org/10.1007/s00228-019-02720-2

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