Skip to main content
SpringerLink
Log in

Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Objectives

This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CLformation) of oxidative pathway metabolites.

Methods

Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (<28 weeks’ gestation) or seven 15-mg/kg doses at 8-h intervals (≥28 weeks’ gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration–time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2.

Results

The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CLformation for all metabolites increased with weight; CLformation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CLformation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038–0.062; 62 %) for glucuronidation, 0.21 L/h (0.17–0.24; 33 %) for sulfation, and 0.058 L/h (0.044–0.078; 72 %) for oxidation. Expression of individual oxidation CLformation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CLformation increased <15 % when plotted against weight or postnatal age.

Conclusions

The parent–metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Allegaert K, Tibboel D, van den Anker J. Pharmacological treatment of neonatal pain: in search of a new equipoise. Semin Fetal Neonatal Med. 2013;18(1):42–7.

    Article  PubMed  Google Scholar 

  2. Pacifici GM, Allegaert K. Clinical pharmacology of paracetamol in neonates: a review. Curr Ther Res Clin Exp. 2015;77:24–30.

    Article  CAS  PubMed  Google Scholar 

  3. Duggan ST, Scott LJ. Intravenous paracetamol (acetaminophen). Drugs. 2009;69(1):101–13.

    Article  CAS  PubMed  Google Scholar 

  4. Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child. 2011;96(6):575–80.

    Article  PubMed  Google Scholar 

  5. Zuppa AF, Hammer GB, Barrett JS, Kenney BF, Kassir N, Mouksassi S, et al. Safety and population pharmacokinetic analysis of intravenous acetaminophen in neonates, infants, children, and adolescents with pain or fever. J Pediatr Pharmacol Ther. 2011;16(4):246–61.

    PubMed  PubMed Central  Google Scholar 

  6. van Ganzewinkel C, Derijks L, Anand KJ, van Lingen RA, Neef C, Kramer BW, et al. Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants. Acta Paediatr. 2014;103(6):612–7.

    Article  PubMed  Google Scholar 

  7. Cook SF, Roberts JK, Samiee-Zafarghandy S, Stockmann C, King AD, Deutsch N, et al. Population pharmacokinetics of intravenous paracetamol (acetaminophen) in preterm and term neonates: model development and external evaluation. Clin Pharmacokinet. 2016;55(1):107–19.

    Article  CAS  PubMed  Google Scholar 

  8. Anderson BJ, van Lingen RA, Hansen TG, Lin YC, Holford NH. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology. 2002;96(6):1336–45.

    Article  CAS  PubMed  Google Scholar 

  9. Allegaert K, Vanhaesebrouck S, Verbesselt R, van den Anker JN. In vivo glucuronidation activity of drugs in neonates: extensive interindividual variability despite their young age. Ther Drug Monit. 2009;31(4):411–5.

    Article  CAS  PubMed  Google Scholar 

  10. McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm Res. 2013;30(9):2174–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. James LP, Mayeux PR, Hinson JA. Acetaminophen-induced hepatotoxicity. Drug Metab Dispos. 2003;31(12):1499–506.

    Article  CAS  PubMed  Google Scholar 

  12. Jaeschke H, McGill MR, Ramachandran A. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev. 2012;44(1):88–106.

    Article  CAS  PubMed  Google Scholar 

  13. Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol. 2010;196:369–405.

    Article  CAS  PubMed  Google Scholar 

  14. Levy G, Khanna NN, Soda DM, Tsuzuki O, Stern L. Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and d-glucaric acid excretion. Pediatrics. 1975;55(6):818–25.

    CAS  PubMed  Google Scholar 

  15. Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther. 1976;19(3):284–94.

    Article  CAS  PubMed  Google Scholar 

  16. van Lingen RA, Deinum JT, Quak JM, Kuizenga AJ, van Dam JG, Anand KJ, et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonatal Ed. 1999;80(1):F59–63.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Allegaert K, de Hoon J, Verbesselt R, Vanhole C, Devlieger H, Tibboel D. Intra- and interindividual variability of glucuronidation of paracetamol during repeated administration of propacetamol in neonates. Acta Paediatr. 2005;94(9):1273–9.

    Article  PubMed  Google Scholar 

  18. Krekels EH, van Ham S, Allegaert K, de Hoon J, Tibboel D, Danhof M, et al. Developmental changes rather than repeated administration drive paracetamol glucuronidation in neonates and infants. Eur J Clin Pharmacol. 2015;71(9):1075–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cook SF, King AD, van den Anker JN, Wilkins DG. Simultaneous quantification of acetaminophen and five acetaminophen metabolites in human plasma and urine by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: method validation and application to a neonatal pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2015;1007:30–42.

    Article  CAS  PubMed  Google Scholar 

  20. Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28(5):481–504.

    Article  CAS  PubMed  Google Scholar 

  21. Boeckmann AJ, Sheiner LB, Beal SL. NONMEM users guide, part v: introductory guide. San Francisco: NONMEM Project Group, University of California at San Francisco; 2011.

    Google Scholar 

  22. Bauer RJ. NONMEM users guide: introduction to NONMEM 7.2.0. Ellicott City: ICON Development Solutions; 2011.

    Google Scholar 

  23. Ludden TM, Beal SL, Sheiner LB. Comparison of the Akaike information criterion, the Schwarz criterion and the F test as guides to model selection. J Pharmacokinet Biopharm. 1994;22(5):431–45.

    Article  CAS  PubMed  Google Scholar 

  24. Owens KH, Murphy PG, Medlicott NJ, Kennedy J, Zacharias M, Curran N, et al. Population pharmacokinetics of intravenous acetaminophen and its metabolites in major surgical patients. J Pharmacokinet Pharmacodyn. 2014;41(3):211–21.

    Article  CAS  PubMed  Google Scholar 

  25. Kulo A, Peeters MY, Allegaert K, Smits A, de Hoon J, Verbesselt R, et al. Pharmacokinetics of paracetamol and its metabolites in women at delivery and post-partum. Br J Clin Pharmacol. 2013;75(3):850–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development, part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacometrics Syst Pharmacol. 2013;2(4):e38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629–37.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhao L, Pickering G. Paracetamol metabolism and related genetic differences. Drug Metab Rev. 2011;43(1):41–52.

    Article  CAS  PubMed  Google Scholar 

  29. Krasniak AE, Knipp GT, Svensson CK, Liu W. Pharmacogenomics of acetaminophen in pediatric populations: a moving target. Front Genet. 2014;5:314.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults. Clin Pharmacol Ther. 2007;81(6):840–8.

    Article  CAS  PubMed  Google Scholar 

  31. Owens KH, Medlicott NJ, Zacharias M, Curran N, Chary S, Thompson-Fawcett M, et al. The pharmacokinetic profile of intravenous paracetamol in adult patients undergoing major abdominal surgery. Ther Drug Monit. 2012;34(6):713–21.

    Article  CAS  PubMed  Google Scholar 

  32. Allegaert K, Verbesselt R, Rayyan M, Debeer A, de Hoon J. Urinary metabolites to assess in vivo ontogeny of hepatic drug metabolism in early neonatal life. Methods Find Exp Clin Pharmacol. 2007;29(4):251–6.

    Article  CAS  PubMed  Google Scholar 

  33. van der Marel CD, Anderson BJ, van Lingen RA, Holford NH, Pluim MA, Jansman FG, et al. Paracetamol and metabolite pharmacokinetics in infants. Eur J Clin Pharmacol. 2003;59(3):243–51.

    Article  PubMed  Google Scholar 

  34. Owen JS, Fiedler-Kelly J. Introduction to population pharmacokinetic/pharmacodynamic analysis with nonlinear mixed effects models. London: Wiley; 2014.

    Book  Google Scholar 

  35. Ette EI. Stability and performance of a population pharmacokinetic model. J Clin Pharmacol. 1997;37(6):486–95.

    Article  CAS  PubMed  Google Scholar 

  36. Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol Ther. 2007;82(1):17–20.

    Article  CAS  PubMed  Google Scholar 

  37. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143–51.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Keizer RJ, Karlsson MO, Hooker A. Modeling and simulation workbench for NONMEM: tutorial on Pirana, PsN, and Xpose. CPT Pharmacometrics Syst Pharmacol. 2013;2:e50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brendel K, Comets E, Laffont C, Mentre F. Evaluation of different tests based on observations for external model evaluation of population analyses. J Pharmacokinet Pharmacodyn. 2010;37(1):49–65.

    Article  PubMed  Google Scholar 

  40. Holford NHG, Gobburu JVS, Mould DR, editors. Implications of including and excluding correlation of random effects in hierarchical mixed effects pharmacokinetic models. Verona: Population Approach Group in Europe; 2003.

    Google Scholar 

  41. Salinger DH, Blough DK, Vicini P, Anasetti C, O’Donnell PV, Sandmaier BM, et al. A limited sampling schedule to estimate individual pharmacokinetic parameters of fludarabine in hematopoietic cell transplant patients. Clin Cancer Res. 2009;15(16):5280–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lowenthal DT, Oie S, Van Stone JC, Briggs WA, Levy G. Pharmacokinetics of acetaminophen elimination by anephric patients. J Pharmacol Exp Ther. 1976;196(3):570–8.

    CAS  PubMed  Google Scholar 

  43. Johnsrud EK, Koukouritaki SB, Divakaran K, Brunengraber LL, Hines RN, McCarver DG. Human hepatic CYP2E1 expression during development. J Pharmacol Exp Ther. 2003;307(1):402–7.

    Article  CAS  PubMed  Google Scholar 

  44. Vieira I, Sonnier M, Cresteil T. Developmental expression of CYP2E1 in the human liver: hypermethylation control of gene expression during the neonatal period. Eur J Biochem. 1996;238(2):476–83.

    Article  CAS  PubMed  Google Scholar 

  45. Krekels EH, Danhof M, Tibboel D, Knibbe CA. Ontogeny of hepatic glucuronidation; methods and results. Curr Drug Metab. 2012;13(6):728–43.

    Article  CAS  PubMed  Google Scholar 

  46. Xie Y, McGill MR, Cook SF, Sharpe MR, Winefield RD, Wilkins DG, et al. Time course of acetaminophen-protein adducts and acetaminophen metabolites in circulation of overdose patients and in HepaRG cells. Xenobiotica. 2015;45(10):921–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Allegaert K, Anderson BJ, Naulaers G, de Hoon J, Verbesselt R, Debeer A, et al. Intravenous paracetamol (propacetamol) pharmacokinetics in term and preterm neonates. Eur J Clin Pharmacol. 2004;60(3):191–7.

    Article  CAS  PubMed  Google Scholar 

  48. Palmer GM, Atkins M, Anderson BJ, Smith KR, Culnane TJ, McNally CM, et al. I.V. acetaminophen pharmacokinetics in neonates after multiple doses. Br J Anaesth. 2008;101(4):523–30.

    Article  CAS  PubMed  Google Scholar 

  49. Siegers CP, Loeser W, Gieselmann J, Oltmanns D. Biliary and renal excretion of paracetamol in man. Pharmacology. 1984;29(5):301–3.

    Article  CAS  PubMed  Google Scholar 

  50. Jayasinghe KS, Roberts CJ, Read AE. Is biliary excretion of paracetamol significant in man? Br J Clin Pharmacol. 1986;22(3):363–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Allegaert K, Naulaers G, Vanhaesebrouck S, Anderson BJ. The paracetamol concentration-effect relation in neonates. Paediatr Anaesth. 2013;23(1):45–50.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Syamala Mankala of the Division of Clinical Pharmacology at Children’s National Health System (Washington, DC, USA) for administrative support, Dr. David M. Reith of the Dunedin School of Medicine at the University of Otago (Dunedin, New Zealand) and Dr. Katie H. Owens of the Department of Pharmaceutics at the University of Washington (Seattle, WA, USA) for helpful advice during model development, and Dr. Jessica K. Roberts of the Department of Pharmaceutical Sciences at St. Jude Children’s Research Hospital (Memphis, TN, USA) for constructive feedback during manuscript preparation.

Author contributions

JNA designed the clinical study; JNA, SSZ, ND, and EFW performed the trial and acquired the clinical data; SFC, ADK, and DGW developed and validated the analytical methods and analyzed the study samples; SFC and CS developed the pharmacokinetic model; CMTS supervised the pharmacokinetic model development; SFC drafted the manuscript. All authors critically revised the manuscript and approved the final version.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Center for Human 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

    Chris Stockmann & Catherine M. T. Sherwin

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

    Chris Stockmann & Catherine M. T. Sherwin

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

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

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

    Samira Samiee-Zafarghandy

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

    Nina Deutsch

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

    Diana G. Wilkins

  8. Clinical Trials Office, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA

    Catherine M. T. Sherwin

  9. 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

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

    John N. van den Anker

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

    John N. van den Anker

Authors
  1. Sarah F. Cook
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chris Stockmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samira Samiee-Zafarghandy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amber D. King
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nina Deutsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elaine F. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Diana G. Wilkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Catherine M. T. Sherwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. John N. van den Anker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catherine M. T. Sherwin.

Ethics declarations

Funding

This work was supported by the National Institutes of Health grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD060543; to John van den Anker) and the National Center for Advancing Translational Sciences (UL1TR000075; to 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 Wilkins). Sarah Cook received stipend support from the Howard Hughes Medical Institute (Med into Grad Initiative). Sarah Cook and Chris Stockmann were supported by pre-doctoral fellowships from the American Foundation for Pharmaceutical Education.

Conflicts of interest

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

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from a parent or legal guardian of all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2284 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cook, S.F., Stockmann, C., Samiee-Zafarghandy, S. et al. Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model. Clin Pharmacokinet 55, 1395–1411 (2016). https://doi.org/10.1007/s40262-016-0408-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-016-0408-1

Keywords

Search

Navigation