Evelyne Jacqz-Aigrain1,2,3, Stéphanie Leroux1,2,4, Alison H Thomson5,6, Karel Allegaert7,8, Edmund V Capparelli9, Valérie Biran10, Nicolas Simon11,12,13, Bernd Meibohm14, Yoke-Lin Lo15,16, Remedios Marques17, José-Esteban Peris18, Irja Lutsar19, Jumpei Saito20, Hidefumi Nakamura21, Johannes N van den Anker6,22,23,24, Mike Sharland25, Wei Zhao1,26,27. 1. Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France. 2. Clinical Investigation Center CIC1426, Hôpital Robert Debré, Paris, France. 3. University Paris Diderot, Sorbonne Paris Cité, Paris, France. 4. Division of Neonatology, Department of Child and Adolescent Medicine, CHU de Rennes, Rennes, France. 5. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. 6. Pharmacy Department, Glasgow Royal Infirmary, Glasgow, UK. 7. Department of Development and Regeneration, KU Leuven, Leuven, Belgium. 8. Intensive Care, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. 9. Pediatric Pharmacology and Drug Discovery, University of California, San Diego, CA, USA. 10. Neonatal Intensive Care Unit, Hôpital Robert Debré, Paris, France. 11. Department of Pharmacology, Hôpital de la Timone, APHM, Université de la Méditerranée, Marseille, France. 12. Service de Pharmacologie Clinique, Hôpital Sainte marguerite, CAP-TV, 13274 Marseille, France. 13. Aix Marseille University, INSERM, IRD, SESSTIM, Marseille, France. 14. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA. 15. Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. 16. School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia. 17. Department of Pharmacy Services, La Fe Hospital, Valencia, Spain. 18. Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Valencia, Spain. 19. Institute of Medical Microbiology, University of Tartu, Tartu, Estonia. 20. Department of Pharmacy, National Children's Hospital National Center for Child Health and Development, Tokyo, Japan. 21. Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan. 22. Division of Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA. 23. Departments of Pediatrics, Pharmacology & Physiology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA. 24. Department of Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel, Basel, Switzerland. 25. Paediatric Infectious Disease Unit, St George's Hospital, London, UK. 26. Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China. 27. Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Abstract
OBJECTIVES: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. METHODS: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates. RESULTS: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients. CONCLUSIONS: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.
OBJECTIVES: In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. METHODS: A 'meta-model' with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0-24 of 400 mg·h/L at steady-state in at least 80% of neonates. RESULTS: A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0-24 target earlier than a standard 'Blue Book' dosage regimen in >89% of the treated patients. CONCLUSIONS: The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.
Authors: Louise F Hill; Mark A Turner; Irja Lutsar; Paul T Heath; Pollyanna Hardy; Louise Linsell; Evelyne Jacqz-Aigrain; Emmanuel Roilides; Mike Sharland Journal: Trials Date: 2020-04-15 Impact factor: 2.279