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Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation

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Abstract

Objectives

The aims of this study were to develop a population pharmacokinetic model for intravenous paracetamol in preterm and term neonates and to assess the generalizability of the model by testing its predictive performance in an external dataset.

Methods

Nonlinear mixed-effects models were constructed from paracetamol concentration–time data in NONMEM 7.2. Potential covariates included body weight, gestational age, postnatal age, postmenstrual age, sex, race, total bilirubin, and estimated glomerular filtration rate. An external dataset was used to test the predictive performance of the model through calculation of bias, precision, and normalized prediction distribution errors.

Results

The model-building dataset included 260 observations from 35 neonates with a mean gestational age of 33.6 weeks [standard deviation (SD) 6.6]. Data were well-described by a one-compartment model with first-order elimination. Weight predicted paracetamol clearance and volume of distribution, which were estimated as 0.348 L/h (5.5 % relative standard error; 30.8 % coefficient of variation) and 2.46 L (3.5 % relative standard error; 14.3 % coefficient of variation), respectively, at the mean subject weight of 2.30 kg. An external evaluation was performed on an independent dataset that included 436 observations from 60 neonates with a mean gestational age of 35.6 weeks (SD 4.3). The median prediction error was 10.1 % [95 % confidence interval (CI) 6.1–14.3] and the median absolute prediction error was 25.3 % (95 % CI 23.1–28.1).

Conclusions

Weight predicted intravenous paracetamol pharmacokinetics in neonates ranging from extreme preterm to full-term gestational status. External evaluation suggested that these findings should be generalizable to other similar patient populations.

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Acknowledgments

The authors would like to thank Syamala Mankala of the Division of Clinical Pharmacology at the Children’s National Health System (Washington, DC, USA) for administrative support.

Author information

Authors and Affiliations

  1. Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA

    Sarah F. Cook, Amber D. King & Diana G. Wilkins

  2. Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT, 84108, USA

    Jessica K. Roberts, Chris Stockmann & Catherine M. T. Sherwin

  3. Division of Clinical Pharmacology, Children’s National Health System, Washington, DC, USA

    Samira Samiee-Zafarghandy, Elaine F. Williams & John N. van den Anker

  4. Division of Neonatology, Department of Pediatrics, McMaster University, Hamilton, ON, Canada

    Samira Samiee-Zafarghandy

  5. Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA

    Chris Stockmann

  6. Division of Anesthesiology, Sedation, and Perioperative Medicine, Children’s National Health System, Washington, DC, USA

    Nina Deutsch

  7. Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium

    Karel Allegaert

  8. Department of Development and Regeneration, KU Leuven, Leuven, Belgium

    Karel Allegaert

  9. Division of Medical Laboratory Sciences, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA

    Diana G. Wilkins

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

    John N. van den Anker

  11. Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, The Netherlands

    John N. van den Anker

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

    John N. van den Anker

Authors
  1. Sarah F. Cook
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Corresponding author

Correspondence to Catherine M. T. Sherwin.

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Funding

This work was supported by National Institutes of Health grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD060543, to John N. van den Anker) and the National Center for Advancing Translational Sciences (UL1TR000075, to the Children’s National Health System), and by a contract for analytical laboratory services from McNeil Consumer Healthcare (Division of McNEIL-PPC, Inc., Fort Washington, PA, USA, to Diana G. Wilkins). Karel Allegaert was supported by a Fundamental Clinical Investigatorship (1800214N) from the Fund for Scientific Research—Flanders (FWO-Vlaanderen, Belgium). Sarah F. Cook received stipend support from the Howard Hughes Medical Institute (Med into Grad Initiative); Sarah F. Cook and Chris Stockmann were supported by pre-doctoral fellowships from the American Foundation for Pharmaceutical Education; and Jessica K. Roberts was supported by a Pharmacotherapy Subspecialty Award from the Primary Children’s Hospital Foundation (Salt Lake City, UT, USA).

Conflicts of interest

Sarah Cook, Jessica Roberts, Samira Samiee-Zafarghandy, Chris Stockmann, Amber King, Nina Deutsch, Elaine Williams, Karel Allegaert, Diana Wilkins, Catherine Sherwin, and John van den Anker have no potential conflicts of interest to declare.

Ethical approval

All human studies were approved by the appropriate Ethics Committees and were carried out in concordance with ICH Guidelines for Good Clinical Practice [19]. Informed consent was obtained prior to study inclusion.

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Cook, S.F., Roberts, J.K., Samiee-Zafarghandy, S. et al. Population Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) in Preterm and Term Neonates: Model Development and External Evaluation. Clin Pharmacokinet 55, 107–119 (2016). https://doi.org/10.1007/s40262-015-0301-3

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