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21.05.2016 | Original Research Article

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

verfasst von: Sarah F. Cook, Chris Stockmann, Samira Samiee-Zafarghandy, Amber D. King, Nina Deutsch, Elaine F. Williams, Diana G. Wilkins, Catherine M. T. Sherwin, John N. van den Anker

Erschienen in: Clinical Pharmacokinetics | Ausgabe 11/2016

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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 (CL_formation) 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). CL_formation for all metabolites increased with weight; CL_formation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CL_formation 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 CL_formation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CL_formation 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.

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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.PubMedCrossRef

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

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

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

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.PubMedPubMedCentral

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

11.

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

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.PubMedCrossRef

13.

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

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.PubMed

15.

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

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

20.

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

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.

22.

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentral

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

28.

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

29.

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

34.

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

35.

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

36.

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

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.

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.PubMedPubMedCentralCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCrossRef

45.

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

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

49.

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

50.

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

51.

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

Titel: Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model
verfasst von: Sarah F. Cook
Chris Stockmann
Samira Samiee-Zafarghandy
Amber D. King
Nina Deutsch
Elaine F. Williams
Diana G. Wilkins
Catherine M. T. Sherwin
John N. van den Anker
Publikationsdatum: 21.05.2016
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 11/2016
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-016-0408-1

Springer Medizin

Abstract

Objectives

Methods

Results

Conclusions

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