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PHARMACOKINETIC STUDIES IN NEONATES: IS AN OPPORTUNISTIC SAMPLING STRATEGY SUFFICIENT FOR POPULATION PHARMACOKINETIC MODELLING AND DOSE PREDICTION?
  1. Stéphanie Leroux1,
  2. Mark A. Turner2,
  3. Chantal Barin-Le Guellec3,
  4. Helen Hill2,
  5. Johannes N. van den Anker4,
  6. Gregory L. Kearns5,
  7. Evelyne Jacqz-Aigrain6,
  8. Wei Zhao6
  1. 1Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Université Paris Diderot, Paris, France
  2. 2Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Neonatal Unit, Liverpool Women's Hospital, Liverpool, UK
  3. 3EA4245, Faculté de Médecine, Université François Rabelais, Tours, France
  4. 4Intensive Care, Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands; Division of Pediatric Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA; Departments of Pediatrics, Pharmacology & Physiology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA; Department of Paediatric Pharmacology, University Children's Hospital Basel, Basel, Switzerland
  5. 5Division of Clinical Pharmacology and Therapeutic Innovation, the Children's Mercy Hospital, Kansas City, MO USA; Department of Pediatrics, University of Missouri–Kansas City, Kansas City, MO USA
  6. 6Department of Pediatric Pharmacology and Pharmacogenetics, Clinical Investigation Center CIC1426, Hôpital Robert Debré, Université Paris Diderot, Paris, France

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 to a pre-determined pharmacokinetic sampling approach.

Methods Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), pre-determined (i.e., scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), respectively, 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 pre-determined times and 165 that were scavenged from those obtained as part of clinical care. All data sets 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) as compared to 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 AUC0–24/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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