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Clinical Pharmacokinetics

, Volume 54, Issue 2, pp 167–178 | Cite as

Tramadol and O-Desmethyl Tramadol Clearance Maturation and Disposition in Humans: A Pooled Pharmacokinetic Study

  • Karel Allegaert
  • Nick Holford
  • Brian J. Anderson
  • Sam Holford
  • Frank Stuber
  • Alain Rochette
  • Iñaki F. Trocóniz
  • Horst Beier
  • Jan N. de Hoon
  • Rasmus S. Pedersen
  • Ulrike Stamer
Original Research Article

Abstract

Background and Objectives

We aimed to study the impact of size, maturation and cytochrome P450 2D6 (CYP2D6) genotype activity score as predictors of intravenous tramadol disposition.

Methods

Tramadol and O-desmethyl tramadol (M1) observations in 295 human subjects (postmenstrual age 25 weeks to 84.8 years, weight 0.5–186 kg) were pooled. A population pharmacokinetic analysis was performed using a two-compartment model for tramadol and two additional M1 compartments. Covariate analysis included weight, age, sex, disease characteristics (healthy subject or patient) and CYP2D6 genotype activity. A sigmoid maturation model was used to describe age-related changes in tramadol clearance (CLPO), M1 formation clearance (CLPM) and M1 elimination clearance (CLMO). A phenotype-based mixture model was used to identify CLPM polymorphism.

Results

Differences in clearances were largely accounted for by maturation and size. The time to reach 50 % of adult clearance (TM50) values was used to describe maturation. CLPM (TM50 39.8 weeks) and CLPO (TM50 39.1 weeks) displayed fast maturation, while CLMO matured slower, similar to glomerular filtration rate (TM50 47 weeks). The phenotype-based mixture model identified a slow and a faster metabolizer group. Slow metabolizers comprised 9.8 % of subjects with 19.4 % of faster metabolizer CLPM. Low CYP2D6 genotype activity was associated with lower (25 %) than faster metabolizer CLPM, but only 32 % of those with low genotype activity were in the slow metabolizer group.

Conclusions

Maturation and size are key predictors of variability. A two-group polymorphism was identified based on phenotypic M1 formation clearance. Maturation of tramadol elimination occurs early (50 % of adult value at term gestation).

Keywords

Tramadol Relative Standard Error CYP2D6 Genotype CYP2D6 Activity Slow Metabolizers 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The clinical research of Karel Allegaert is supported by the Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen, 1800,214N). The clinical research of U. Stamer was supported in part by a grant of the R. Sackler Research Foundation (Germany). We are grateful to Dr. B. Kukanich and Dr. M. Giorgi for access to the data from their studies in dogs, which was essential for us to distinguish the different elimination pathways of tramadol. Horst Beier, co-author of this paper is an employee of Grünenthal, Aachen, Germany, one the manufacturers of tramadol. All other authors have no conflicts of interest to disclose.

Supplementary material

40262_2014_191_MOESM1_ESM.pdf (843 kb)
Supplementary material 1 (PDF 842 kb)

References

  1. 1.
    Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879–923.PubMedCrossRefGoogle Scholar
  2. 2.
    Reeves RR, Burke RS. Tramadol: basic pharmacology and emerging concepts. Drugs Today. 2008;44(11):827–36.PubMedCrossRefGoogle Scholar
  3. 3.
    Ardakani YH, Rouini MR. Pharmacokinetics of tramadol and its three main metabolites in healthy male and female volunteers. Biopharm Drug Dispos. 2007;28(9):527–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Gong L, Stamer UM, Tzvetkov MV, et al. PharmGKB summary: tramadol pathway. Pharmacogenet Genomics. 2014;24(7):374–80.PubMedCrossRefGoogle Scholar
  5. 5.
    Allegaert K, Anderson BJ, Verbesselt R, et al. Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity. Br J Anaesth. 2005;95(2):231–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Allegaert K, van den Anker JN, de Hoon JN, et al. Covariates of tramadol disposition in the first months of life. Br J Anaesth. 2008;100(4):525–32.PubMedCrossRefGoogle Scholar
  7. 7.
    Pedersen RS, Damkier P, Brosen K. Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers. Eur J Clin Pharmacol. 2006;62(7):513–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Stamer UM, Lehnen K, Höthker F, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain. 2003;105(1–2):231–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Murthy BV, Pandya KS, Booker PD, et al. Pharmacokinetics of tramadol in children after i.v. or caudal epidural administration. Br J Anaesth. 2000;84(3):346–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Garrido MJ, Habre W, Rombout F, et al. Population pharmacokinetic/pharmacodynamic modelling of the analgesic effects of tramadol in pediatrics. Pharm Res. 2006;23(9):2014–23.PubMedCrossRefGoogle Scholar
  11. 11.
    Bressolle F, Rochette A, Khier S, et al. Population pharmacokinetics of the two enantiomers of tramadol and O-demethyl tramadol after surgery in children. Br J Anaesth. 2009;102(3):390–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Lintz W, Barth H, Osterloh G, et al. Bioavailability of enteral tramadol formulations. 1st communication: capsules. Arzneimittelforschung. 1986;36(8):1278–83.PubMedGoogle Scholar
  13. 13.
    Lintz W, Barth H, Becker R, et al. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol. Arzneimittelforschung. 1998;48(5):436–45.PubMedGoogle Scholar
  14. 14.
    Lintz W, Barth H, Osterloh G, et al. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd communication: suppositories. Arzneimittelforschung. 1998;48(9):889–99.PubMedGoogle Scholar
  15. 15.
    Lintz W, Beier H, Gerloff J. Bioavailability of tramadol after i.m. injection in comparison to i.v. infusion. Int J Clin Pharmacol Ther. 1999;37(4):175–83.PubMedGoogle Scholar
  16. 16.
    Lintz W, Becker R, Gerloff J, et al. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 4th communication: drops (without ethanol). Arzneimittelforschung. 2000;50(2):99–108.PubMedGoogle Scholar
  17. 17.
    Stamer UM, Musshoff F, Kobilay M, et al. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther. 2007;82(1):41–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Abdel-Rahman SM, Leeder JS, Wilson JT, et al. Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation. J Clin Pharmacol. 2002;42(1):24–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Blake MJ, Gaedigk A, Pearce RE, et al. Ontogeny of dextromethorphan O- and i-demethylation in the first year of life. Clin Pharmacol Ther. 2007;81(4):510–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Becker R, Lintz W. Determination of tramadol in human serum by capillary gas chromatography with nitrogen-selective detection. J Chromatogr. 1986;377:213–20.PubMedCrossRefGoogle Scholar
  21. 21.
    Gan SH, Ismail R. Validation of a high-performance liquid chromatography method for tramadol and O-desmethyltramadol in human plasma using solid-phase extraction. J Chromatogr B. 2001;759(2):325–35.CrossRefGoogle Scholar
  22. 22.
    Nobilis M, Kopecky J, Kvetina J, et al. High-performance liquid chromatographic determination of tramadol and its O-desmethylated metabolite in blood plasma: application to a bioequivalence study in humans. J Chromatogr A. 2002;949(1–2):11–22.PubMedCrossRefGoogle Scholar
  23. 23.
    KuKanich B, Papich MG. Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs. J Vet Pharmacol Ther. 2004;27(4):239–46.PubMedCrossRefGoogle Scholar
  24. 24.
    Giorgi M, Del Carlo S, Saccomanni G, et al. Pharmacokinetics of tramadol and its major metabolites following rectal and intravenous administration in dogs. N Z Vet J. 2009;57(3):146–52.PubMedCrossRefGoogle Scholar
  25. 25.
    Giorgi M, Soldani G, Manera C, et al. Pharmacokinetics of tramadol and its metabolites M1, M2 and M4 in horses following intravenous, immediate release (fasted/fed) and sustained release single dose administration. J Equine Vet Sci. 2007;27(11):481–8.CrossRefGoogle Scholar
  26. 26.
    Holford S, Allegaert K, Anderson BJ, et al. Parent-metabolite pharmacokinetic models for tramadol: tests of assumptions and predictions. J Pharmacol Clin Toxicol. 2014;2(1):1023.Google Scholar
  27. 27.
    Parke J, Holford NH, Charles BG. A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Programs Biomed. 1999;59(1):19–29.PubMedCrossRefGoogle Scholar
  28. 28.
    Holford NH. The visual predictive check: superiority to standard diagnostic (Rorschach) plots (http://www.page-meeting.org/?abstract=972). PAGE 2005;14:972.
  29. 29.
    Bergstrand M, Hooker AC, Wallin JE, et al. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143–51.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.PubMedCrossRefGoogle Scholar
  31. 31.
    West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science. 1997;276(5309):122.PubMedCrossRefGoogle Scholar
  32. 32.
    Tod M, Lokiec F, Bidault R, et al. Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis. Antimicrob Agents Chemother. 2001;45(1):150–7.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Anderson BJ, Allegaert K, Holford NH. Population clinical pharmacology of children: general principles. Eur J Pediatr. 2006;165(11):741–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Tod M, Jullien V, Pons G. Facilitation of drug evaluation in children by population methods and modelling. Clin Pharmacokinet. 2008;47(4):231–43.PubMedCrossRefGoogle Scholar
  35. 35.
    Karlsson MO, Jonsson NE, Wiltse CG, et al. Assumption testing in population pharmacokinetic models: illustrated with an analysis of moxonidine data from congestive heart failure patients. J Pharmacokinet Biopharm. 1998;26(2):207–46.PubMedCrossRefGoogle Scholar
  36. 36.
    Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009;24(1):67–76.PubMedCrossRefGoogle Scholar
  37. 37.
    Allegaert K, Rochette A, Veyckemans F. Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance. Paediatr Anaesth. 2011;21(3):266–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25–36.PubMedCrossRefGoogle Scholar
  39. 39.
    Alvan G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol. 1990;39(6):533–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Sachse C, Brockmoller J, Bauer S, et al. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet. 1997;60(2):284–95.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Caraco Y. Genes and the response to drugs. N Engl J Med. 2004;351(27):2867–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Stamer UM, Stüber F, Muders T, et al. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg. 2008;107(3):926–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Karel Allegaert
    • 1
  • Nick Holford
    • 2
  • Brian J. Anderson
    • 3
  • Sam Holford
    • 2
  • Frank Stuber
    • 4
    • 5
  • Alain Rochette
    • 6
  • Iñaki F. Trocóniz
    • 7
  • Horst Beier
    • 8
  • Jan N. de Hoon
    • 1
  • Rasmus S. Pedersen
    • 9
  • Ulrike Stamer
    • 4
    • 5
  1. 1.Neonatal Intensive Care Unit and Center for Clinical PharmacologyUniversity Hospitals LeuvenLeuvenBelgium
  2. 2.Department of Pharmacology and Clinical PharmacologyUniversity of AucklandAucklandNew Zealand
  3. 3.Department of AnaesthesiologyUniversity of AucklandAucklandNew Zealand
  4. 4.Department of Anaesthesiology and Pain MedicineUniversity of BernBernSwitzerland
  5. 5.Department of Clinical ResearchUniversity of BernBernSwitzerland
  6. 6.Department of Anaesthesia and Intensive Care AHôpital LapeyronieMontpellierFrance
  7. 7.Department of Pharmacy and Pharmaceutical Technology, School of PharmacyUniversity of NavarraPamplonaSpain
  8. 8.Grünenthal GmbHAachenGermany
  9. 9.Institute of Public Health, Research Unit of Clinical PharmacologyUniversity of Southern DenmarkOdenseDenmark

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