Clinical trial NCT02660177: Pharmacokinetics of Intravenous Metamizole in Children Less Than 6 Years Old
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Children
Pain
Surgery
Lead sponsor: University Children's Hospital Basel
Sponsor class: OTHER
First posted: 2016-01-21
Enrollment: 33
Sex: ALL
Minimum age (years): 3
Maximum age (years): 72
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Area under the plasma concentration-time curves (AUC0-inf, AUC0-24, AUC0-last) for metamizole and its metabolites in plasma and saliva
timeFrame: 0- 24 hours
Secondary outcomes:
measure: Maximum plasma concentration (Cmax) for metamizole and its metabolites in plasma and saliva
timeFrame: 0- 24 hours
measure: Time to reach Cmax (tmax) for metamizole and its metabolites in plasma and saliva
timeFrame: 0- 24 hours
measure: Terminal elimination rate constant with respective half-life time (t½) for metamizole and its metabolites in plasma and saliva
timeFrame: 0- 24 hours
measure: Incidence of adverse events (AEs)
timeFrame: 0- 24 hours
measure: Correlation between metamizole and its metabolites in saliva and plasma
timeFrame: 0- 24 hours
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: UKBB
Study officials:
affiliation: University Children's Hospital Basel
name: Marc Pfister, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Geneva
name: Rodieux Frederique, Dr. med
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.