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Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects

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Abstract

Background

Tramadol is frequently used in geriatric patients; however, pharmacokinetic (PK) publications on tramadol and O-desmethyltramadol (ODM) in elderly patients are rare.

Objective

Our objective was to characterize the PK of tramadol and ODM, including absorption processes and covariates for tramadol, in elderly and young subjects after single-dose administration of 200-mg extended-release tablets.

Methods

We conducted a PK study in 15 elderly (aged ≥75 years) subjects with mild renal insufficiency and 20 young (18–40 years) subjects; blood and urine samples were collected for 48 h post-dose. Non-compartmental analysis (NCA) of each tramadol and ODM enantiomer included area under the concentration–time curve (AUC), terminal elimination rate (k el), total body clearance, volume of distribution (V area/ F), and renal clearance (Clr0–48). A one-compartment population model of total tramadol concentration was parameterized with clearance (CL/F), volume of distribution (V/F), and mixed order absorption (first-order and zero-order absorption rate constants with lag times).

Results

NCA demonstrated comparable maximum plasma concentration (C max) and AUC between age groups for tramadol enantiomers, but significant differences in V area/ F (mean 34 % higher) and k el (mean 28 % lower) in the elderly. PK of ODM were significantly different in the elderly for AUC0–inf (mean 35 % higher), Clr0–48 (mean 29 % lower), and k el (mean 33 % lower). The population analysis identified age as a covariate of V/F (young 305 L; elderly 426 L), with a 50 % longer mean elimination half-life in the elderly. No differences in absorption processes were observed.

Conclusions

Tramadol exposure was similar between the age groups; exposure to ODM was higher in elderly subjects.

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Acknowledgments

The study was contracted by Labopharm Inc. MDS Pharma conducted the clinical portions of the study. Dr. Kenneth Swart of Farmovs-Parexel, Bloemfontein, Orange Free State, South Africa, led the quantitative bioanalysis. The authors performed the population PK analysis independently. Dr. Jun Li is acknowledged for his early contribution to model development and preliminary data analysis.

Author contributions

Sybil Skinner-Robertson made substantial contribution to study conception and design, acquisition of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content; and final approval of the version to be published.

Caroline Fradette contributed to study conception and design, acquisition of data, manuscript revision, and final approval of the version to be published.

Sylvie Bouchard contributed to study conception and design, manuscript revision, and final approval of the version to be published.

Mohamed Samer Mouksassi contributed to population pharmacokinetic model development, critical review of the manuscript, and final approval of the version to be published.

France Varin made substantial contribution to study conception and design, acquisition of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content; and final approval of the version to be published.

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Authors and Affiliations

  1. Faculté de pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC, H3C 3J7, Canada

    Sybil Skinner-Robertson, Mohamad-Samer Mouksassi & France Varin

  2. Labopharm Inc, Laval, QC, Canada

    Sybil Skinner-Robertson, Caroline Fradette & Sylvie Bouchard

  3. Lakeshore General Hospital, Montréal, QC, Canada

    Sylvie Bouchard

  4. Certara Consulting Services, Montréal, QC, Canada

    Mohamad-Samer Mouksassi

Authors
  1. Sybil Skinner-Robertson
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Corresponding author

Correspondence to France Varin.

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Conflict of interest

Sybil Skinner-Robertson and Caroline Fradette were employees of Labopharm Inc. prior to Nov 2011. Sylvie Bouchard, France Varin and Mohamad-Samer Mouksassi have no conflicts of interest.

Funding

Labopharm sponsored the conduct of the study. The analyses presented herein were conducted independently as part of the doctoral research of Sybil Skinner-Robertson.

Ethical approval and informed consent

Before initiation of the study, the protocol and informed consent for this study were reviewed and approved by two independent ethics committees (Comité d’Ethique de la Recherche des Sciences de la Santé, Université de Montréal; and Investigational Review Board, MDS Pharma Services, Montreal, QC, Canada). All subjects provided their written informed consent prior to the initiation of any study-related procedures. The study was conducted in accordance with the Declaration of Helsinki as well as the Enoncé de politique des trois Conseils. The study is registered at clinicaltrials.gov (NCT02329561).

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Skinner-Robertson, S., Fradette, C., Bouchard, S. et al. Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects. Drugs Aging 32, 1029–1043 (2015). https://doi.org/10.1007/s40266-015-0315-4

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  • DOI: https://doi.org/10.1007/s40266-015-0315-4

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