Pharmacokinetics of Intravenous Metamizole in Children Less Than 6 Years Old (PPMS)

Single Center, Open-label, Prospective Study to Characterize the Pharmacokinetics of Metamizole and Its Metabolites Following Intravenous Administration in Children Less Than 6 Years Old

This study aims to assess the PK parameters of metamizole following a single IV administration of metamizole in children less than 6 years of age.

Study Overview

• Status: Completed
• Conditions: Pain; Children; Surgery
• Intervention / Treatment: Drug: Metamizole

Detailed Description

This is an open-label pharmacokinetics (PK) study. It aims to assess the PK parameters of metamizole and its metabolites following a single IV administration of metamizole (10mg/kg) in children less than 6 years of age.

Thirty-nine children, 3-72 months of age, undergoing elective surgery at the University of Basel Children's Hospital, will receive, on the day of surgical procedure, a single dose of metamizole 10 mg/kg. After this dose, blood and saliva samples will be obtained at predetermined post-dose time points to measure concentrations of metamizole and its metabolites. The maximal duration of subject participation will be 24 hours. Plasma PK parameters (AUC, Cmax, Tmax, t1/2) of each analyte will be derived using noncompartmental methods. A population PK approach will be applied to characterize inter-subject variability and quantify the potential influence of age, sex and body weight on the PK parameters.

There are no published pharmacokinetic studies of metamizole in pediatrics. Furthermore, although Swissmedic provides no dose information for IV administration in infants with a body weight of less than 9 kg, IV is the most frequently used route of administration for direct postoperative analgesia in pediatrics, including infants with body weights of less than 9 kg. Due to the absence of data and the lack of any dosing recommendation for infants with a body weight less than 9 kg, the IV administration of metamizole in infants is "off-label" and inconsistent across hospitals and prescribing paediatricians.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4056
    • UKBB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 6 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Infants and children 3-72 months of age at time of inclusion
• Body weight more than 5 kg at time of inclusion
• Children undergoing elective surgery at University of Basel Children's Hospital (UKBB) with planned administration of intravenous analgesia
• Patients who require surgical procedures that necessitate at least 24 hours in the hospital
• Parent/Legal guardian has been informed about the study and has signed Informed Consent Form

Exclusion Criteria:

• Infants and children who were born prematurely (before 37 weeks gestation), regardless of corrected gestational age
• Known kidney or liver disease
• Known neutropenia, anemia or other hematological disorders
• Known diagnosis of asthma
• Ongoing immunosuppression, except corticosteroid treatment, or primary immunodeficiency
• Treatment with strong inhibitors or inducers of CYP2C19 within 3 months prior to study
• Treatment with drugs known to induce agranulocytosis within 3 months prior to study
• Documented previous adverse reaction to metamizole
• Treatment with metamizole within 30 days prior to screening
• Any concomitant condition, which in the opinion of the investigator would preclude a subject's participation in the study
• Family members of investigators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: metamizole; single IV metamizole (10mg/kg) administration	Drug: Metamizole; metamizole IV administration; Other Names: Novalgin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration-time curves (AUC0-inf, AUC0-24, AUC0-last) for metamizole and its metabolites in plasma and saliva	Time points of evaluation of these PK parameters: sampling at 1, 2, 4, 6, 10 and 24 hours after single IV metamizole dose.	0- 24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax) for metamizole and its metabolites in plasma and saliva	Time points of evaluation of these PK parameters: sampling at 1, 2, 4, 6, 10	0- 24 hours
Time to reach Cmax (tmax) for metamizole and its metabolites in plasma and saliva	Time points of evaluation of these PK parameters: sampling at 1, 2, 4, 6, 10	0- 24 hours
Terminal elimination rate constant with respective half-life time (t½) for metamizole and its metabolites in plasma and saliva	Time points of evaluation of these PK parameters: sampling at 1, 2, 4, 6, 10	0- 24 hours
Incidence of adverse events (AEs)		0- 24 hours
Correlation between metamizole and its metabolites in saliva and plasma		0- 24 hours

Collaborators and Investigators

• Sponsor: University Children's Hospital Basel
• Investigators: Principal Investigator: Marc Pfister, Professor, University Children's Hospital Basel; Principal Investigator: Rodieux Frederique, Dr. med, University Hospital, Geneva

Publications and helpful links

General Publications

• Ziesenitz VC, Rodieux F, Atkinson A, Borter C, Bielicki JA, Haschke M, Duthaler U, Bachmann F, Erb TO, Gurtler N, Holland-Cunz S, van den Anker JN, Gotta V, Pfister M. Dose evaluation of intravenous metamizole (dipyrone) in infants and children: a prospective population pharmacokinetic study. Eur J Clin Pharmacol. 2019 Nov;75(11):1491-1502. doi: 10.1007/s00228-019-02720-2. Epub 2019 Aug 7.

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: January 14, 2016
• First Submitted That Met QC Criteria: January 18, 2016
• First Posted (Estimate): January 21, 2016

Study Record Updates

• Last Update Posted (Actual): May 30, 2018
• Last Update Submitted That Met QC Criteria: May 28, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antipyretics; Dipyrone
• Other Study ID Numbers: 2015-00020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No