Victoria C Ziesenitz1,2, Frédérique Rodieux1,3, Andrew Atkinson1,4, Carole Borter1, Julia A Bielicki1,5, Manuel Haschke6,7, Urs Duthaler8, Fabio Bachmann8, Thomas O Erb9, Nicolas Gürtler10, Stefan Holland-Cunz11, Johannes N van den Anker1,12, Verena Gotta13,14, Marc Pfister1. 1. Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. 2. Pediatric and Congenital Cardiology, University Children's Hospital Heidelberg, Heidelberg, Germany. 3. Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals, Geneva, Switzerland. 4. Department of Infectious Diseases, University Hospital Bern, Bern, Switzerland. 5. Pediatric Infectious Diseases, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. 6. Clinical Pharmacology and Toxicology, Department of General Internal Medicine, Inselspital, University Hospital, Bern, Switzerland. 7. Institute of Pharmacology, University of Bern, Bern, Switzerland. 8. Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Clinical Research, University and University Hospital of Basel, Basel, Switzerland. 9. Pediatric Anesthesiology, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. 10. Department of Otolaryngology, Head and Neck Surgery, University Hospital Basel, University of Basel, Basel, Switzerland. 11. Pediatric Surgery, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. 12. Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA. 13. Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland. verena.gotta@ukbb.ch. 14. Hospital Pharmacy, University Hospital Basel, Basel, Switzerland. verena.gotta@ukbb.ch.
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 .
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 .
Authors: Carmen Martínez; Inmaculada Andreu; Gemma Amo; Miguel A Miranda; Gara Esguevillas; María José Torres; Natalia Blanca-López; Miguel Blanca; Elena García-Martín; José A G Agúndez Journal: Biochem Pharmacol Date: 2014-09-21 Impact factor: 5.858