Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study
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.
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.
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.
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.
KeywordsMetamizole Dipyrone Pharmacokinetics Children Infants
Adverse drug reaction
Akaike information criterion
Area under the curve
Maximal plasma concentration
Hydrolysis rate of metamizole, MAA formation rate
Lower limit of quantification
Objective function value
Post-anesthesia care unit
Time of Cmax
Visual predictive check
World Health Organization
The authors would like to thank the study nurses at the University of Basel Children’s Hospital Outpatient Study Centre (ASZ): Claudia Werner, Michelle Kress, Sabrina Trinkl, and Aurora Frei, study physician Dr. Marie-Luise Decker, and the attending Anesthesiologists Drs. Jens Moll†, Sandra Jeker, Eva Jordi, and Andreas Zutter. We also thank Prof. Christiane Pauli-Magnus, Head of the Department of Clinical Research at the University Hospital Basel, and Prof. Urs Frey, Chief Medical officer at UKBB, for their valuable input regarding the study design. We also would like to thank the patients and their parents for their participation in this study.
F.R., M.P., A.A., T.O.E., M.H., N.G., and J.N.v.d.A. designed the research; V.C.Z., F.R., and J.A.B. performed the research; A.A., V.G., C.B., U.D., F.B., and V.C.Z. analyzed the data; M.H., U.D., and F.B. performed the bioanalysis; V.C.Z., F.R., V.G., and M.P. wrote the manuscript, J.N.v.d.A, T.O.E., M.H., N.G., and S.H.-C. critically revised the manuscript. All authors reviewed and approved the final version of the manuscript before submission.
This study was funded by internal funds of the Division of Pediatric Pharmacology & Pharmacometrics of the University Children’s Hospital Basel (UKBB) and the Swiss National Science Foundation (M.H., SNF 31003A_160216).
Compliance with ethical standards
Conflict of interest
J.A.B.: Her husband is a senior corporate counsel at Novartis International AG, Basel, Switzerland, and holds Novartis stock and stock options.
M.P. is a part-time consultant for Certara, L.P.
The Division of Pediatric Pharmacology & Pharmacometrics of the University Children’s Hospital Basel (M.P.) has received an unrestricted educational grant from Sanofi-Aventis Suisse SA.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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