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European Journal of Clinical Pharmacology

, Volume 75, Issue 11, pp 1491–1502 | Cite as

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

  • 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 GottaEmail author
  • Marc Pfister
Clinical Trial

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.

Keywords

Metamizole Dipyrone Pharmacokinetics Children Infants 

Abbreviations

AA

4-Aminoantipyrine

AAA

4-Acetyl aminoantipyrine

ADR

Adverse drug reaction

AEs

Adverse events

AIC

Akaike information criterion

AUC

Area under the curve

BSV

Between-subject variability

CL

Clearance

Cmax

Maximal plasma concentration

COX

Cyclooxygenase

CYP

Cytochrome P450

FAA

4-Formylaminoantipyrine

IV

Intravenously/intravenous

kh,

Hydrolysis rate of metamizole, MAA formation rate

LLOQ

Lower limit of quantification

MAA

4-Methylaminoantipyrine

NAT2

N-Acetyltransferase 2

OFV

Objective function value

PACU

Post-anesthesia care unit

PK

Pharmacokinetics(s)

PPK

Population PK

t1/2

Elimination half-life

Tmax

Time of Cmax

TV

Typical value

VPC

Visual predictive check

WHO

World Health Organization

Notes

Acknowledgements

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.

Author contributions

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.

Funding

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

V.C.Z.: none

F.R.: none

A.A.: none

V.G.: none

C.B.: none

J.A.B.: Her husband is a senior corporate counsel at Novartis International AG, Basel, Switzerland, and holds Novartis stock and stock options.

M.H.: none

T.O.E.: none

U.D.: none

F.B.: none

N.G.: none

S.H.-C.: none

J.N.v.d.A.: none

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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.

Supplementary material

228_2019_2720_MOESM1_ESM.pdf (709 kb)
ESM 1 (PDF 709 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Victoria C. Ziesenitz
    • 1
    • 2
  • Frédérique Rodieux
    • 1
    • 3
  • Andrew Atkinson
    • 1
    • 4
  • Carole Borter
    • 1
  • Julia A. Bielicki
    • 1
    • 5
  • Manuel Haschke
    • 6
    • 7
  • Urs Duthaler
    • 8
  • Fabio Bachmann
    • 8
  • Thomas O. Erb
    • 9
  • Nicolas Gürtler
    • 10
  • Stefan Holland-Cunz
    • 11
  • Johannes N. van den Anker
    • 1
    • 12
  • Verena Gotta
    • 1
    • 13
    Email author
  • Marc Pfister
    • 1
  1. 1.Pediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel (UKBB)University of BaselBaselSwitzerland
  2. 2.Pediatric and Congenital CardiologyUniversity Children’s Hospital HeidelbergHeidelbergGermany
  3. 3.Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency MedicineGeneva University HospitalsGenevaSwitzerland
  4. 4.Department of Infectious DiseasesUniversity Hospital BernBernSwitzerland
  5. 5.Pediatric Infectious Diseases, University Children’s Hospital Basel (UKBB)University of BaselBaselSwitzerland
  6. 6.Clinical Pharmacology and Toxicology, Department of General Internal MedicineInselspital, University HospitalBernSwitzerland
  7. 7.Institute of PharmacologyUniversity of BernBernSwitzerland
  8. 8.Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Clinical ResearchUniversity and University Hospital of BaselBaselSwitzerland
  9. 9.Pediatric Anesthesiology, University Children’s Hospital Basel (UKBB)University of BaselBaselSwitzerland
  10. 10.Department of Otolaryngology, Head and Neck Surgery, University Hospital BaselUniversity of BaselBaselSwitzerland
  11. 11.Pediatric Surgery, University Children’s Hospital Basel (UKBB)University of BaselBaselSwitzerland
  12. 12.Division of Clinical PharmacologyChildren’s National Health SystemWashingtonUSA
  13. 13.Hospital PharmacyUniversity Hospital BaselBaselSwitzerland

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