Stéphanie Leroux1,2,3,4, Mark A Turner5,6, Chantal Barin-Le Guellec7, Helen Hill5,6, Johannes N van den Anker8,9,10,11, Gregory L Kearns12,13, Evelyne Jacqz-Aigrain1,2,3,14, Wei Zhao15,16,17,18,19. 1. Sino-French Pediatric Research Center, Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012, Jinan, China. 2. Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France. 3. EA7323, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 4. Department of Neonatology, CHU de Rennes, Rennes, France. 5. Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 6. Neonatal Unit, Liverpool Women's Hospital, Liverpool, UK. 7. EA4245, Faculté de Médecine, Université François Rabelais, Tours, France. 8. Intensive Care, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. 9. Division of Pediatric Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA. 10. Departments of Pediatrics, Pharmacology and Physiology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA. 11. Department of Paediatric Pharmacology, University Children's Hospital Basel, Basel, Switzerland. 12. Division of Clinical Pharmacology and Therapeutic Innovation, the Children's Mercy Hospital, Kansas City, MO, USA. 13. Department of Pediatrics, University of Missouri-Kansas City, Kansas City, MO, USA. 14. Clinical Investigation Center CIC1426, INSERM, Paris, France. 15. Sino-French Pediatric Research Center, Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012, Jinan, China. wei.zhao@rdb.aphp.fr. 16. Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France. wei.zhao@rdb.aphp.fr. 17. EA7323, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. wei.zhao@rdb.aphp.fr. 18. Clinical Investigation Center CIC1426, INSERM, Paris, France. wei.zhao@rdb.aphp.fr. 19. Department of Pharmacy, Qianfoshan Hospital Affiliated to Shandong University, Jian, China. wei.zhao@rdb.aphp.fr.
Abstract
BACKGROUND AND OBJECTIVE: The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach. METHODS: Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients. RESULTS: Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin. CONCLUSION: Blood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements.
BACKGROUND AND OBJECTIVE: The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach. METHODS: Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients. RESULTS: Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin. CONCLUSION: Blood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements.
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