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Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design

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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.

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Acknowledgments

We thank the UK National Institute for Health Research for supporting the delivery of the ciprofloxacin trial, and the clinical teams at Liverpool Women’s National Health Service Foundation Trust (NHS FT) (Tim Neal, Christine Chesters) and Alder Hey Children’s NHS FT (Sarah Mahoney, Stephane Paulus), Liverpool, UK.

Funding

This work was supported by the TINN (Treat Infections in NeoNates, European Commission FP7 project, Grant Agreement Number 223614), the GRIP (Global Research in Paediatrics, European Commission FP7 project, Grant Agreement Number 261060), and The Fundamental Research Funds of Shandong University.

Conflicts of interest

Stéphanie Leroux, Mark A. Turner, Chantal Barin-Le Guellec, Helen Hill, Johannes N. van den Anker, Gregory L. Kearns, Evelyne Jacqz-Aigrain, and Wei Zhao declare no conflicts of interest relating to this work.

Ethical approval

All procedures in this study were in accordance with the 1964 Helsinki declaration (and its amendments). The study was approved by the institutional ethics board and independent ethics board of the TINN project (EudraCT 2010-019955-23), and was also monitored by an independent safety monitoring board.

Informed consent

Parental written consent to participate was obtained.

Author information

Authors and Affiliations

  1. Sino-French Pediatric Research Center, Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012, Jinan, China

    Stéphanie Leroux, Evelyne Jacqz-Aigrain & Wei Zhao

  2. Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France

    Stéphanie Leroux, Evelyne Jacqz-Aigrain & Wei Zhao

  3. EA7323, Université Paris Diderot, Sorbonne Paris Cité, Paris, France

    Stéphanie Leroux, Evelyne Jacqz-Aigrain & Wei Zhao

  4. Department of Neonatology, CHU de Rennes, Rennes, France

    Stéphanie Leroux

  5. Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    Mark A. Turner & Helen Hill

  6. Neonatal Unit, Liverpool Women’s Hospital, Liverpool, UK

    Mark A. Turner & Helen Hill

  7. EA4245, Faculté de Médecine, Université François Rabelais, Tours, France

    Chantal Barin-Le Guellec

  8. Intensive Care, Erasmus MC - Sophia Children’s Hospital, Rotterdam, The Netherlands

    Johannes N. van den Anker

  9. Division of Pediatric Clinical Pharmacology, Children’s National Medical Center, Washington, DC, USA

    Johannes N. van den Anker

  10. Departments of Pediatrics, Pharmacology and Physiology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA

    Johannes N. van den Anker

  11. Department of Paediatric Pharmacology, University Children’s Hospital Basel, Basel, Switzerland

    Johannes N. van den Anker

  12. Division of Clinical Pharmacology and Therapeutic Innovation, the Children’s Mercy Hospital, Kansas City, MO, USA

    Gregory L. Kearns

  13. Department of Pediatrics, University of Missouri–Kansas City, Kansas City, MO, USA

    Gregory L. Kearns

  14. Clinical Investigation Center CIC1426, INSERM, Paris, France

    Evelyne Jacqz-Aigrain & Wei Zhao

  15. Department of Pharmacy, Qianfoshan Hospital Affiliated to Shandong University, Jian, China

    Wei Zhao

Authors
  1. Stéphanie Leroux
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  2. Mark A. Turner
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  3. Chantal Barin-Le Guellec
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  4. Helen Hill
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  5. Johannes N. van den Anker
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  6. Gregory L. Kearns
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  7. Evelyne Jacqz-Aigrain
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  8. Wei Zhao
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Consortia

On behalf of the TINN (Treat Infections in NeoNates) and GRiP (Global Research in Paediatrics) Consortiums

Corresponding author

Correspondence to Wei Zhao.

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Leroux, S., Turner, M.A., Guellec, C.BL. et al. Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design. Clin Pharmacokinet 54, 1273–1285 (2015). https://doi.org/10.1007/s40262-015-0291-1

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  • DOI: https://doi.org/10.1007/s40262-015-0291-1

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