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Population Pharmacokinetic/Pharmacodynamic Modeling of O-Desmethyltramadol in Young and Elderly Healthy Volunteers

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Abstract

Background

Age-related changes in the concentration–effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol’s active metabolite, are not documented in the elderly.

Objective

The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets.

Methods

A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18–40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/fm), volume of distribution (V/fm) and a sigmoid maximum effect (Emax) model incorporating baseline (E0) and placebo effect was used.

Results

Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V/fm was 76% larger and CL/fm 16% slower. Baseline (E0) and sensitivity (C50) for pain tolerance were similar between young and elderly subjects. However, the Emax parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135–221) in the young and 194 (149–252) in the elderly; that is, 15% higher in the elderly.

Conclusions

This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects.

Clinicaltrials.gov identifier: NCT02329561.

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Acknowledgements

MDS Pharma conducted the clinical portions of the pharmacokinetics study. Dr Chunlin Chen is thanked for his participation in the collection of the pharmacodynamic data.

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Authors and Affiliations

  1. Faculté de Pharmacie, Université de Montréal, Succursale Centre-Ville, C.P. 6128, Montréal, Québec, H3C 3J7, Canada

    Sybil Skinner Robertson, Mohamad Samer Mouksassi & France Varin

  2. Certara Consulting Services, Montréal, Québec, Canada

    Mohamad Samer Mouksassi

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  1. Sybil Skinner Robertson
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  2. Mohamad Samer Mouksassi
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  3. France Varin
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Contributions

The pharmacodynamic measures and analyses presented herein were conducted entirely independently as part of the doctoral research of SSR, PhD, who also managed the literature searches and summaries of previous related work and wrote the first draft of the manuscript. FV, PhD and M-SM, PhD provided revisions for intellectual content and final approval of the manuscript.

Corresponding author

Correspondence to France Varin.

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Conflict of Interest

The study was contracted by Labopharm Inc. Sybil Skinner-Robertson was an employee of Labopharm Inc. prior to Nov 2011. France Varin and Mohamad-Samer Mouksassi have no conflicts of interest.

Funding

Labopharm sponsored the conduct of the study but not the analyses presented herein.

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). 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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Robertson, S.S., Mouksassi, M.S. & Varin, F. Population Pharmacokinetic/Pharmacodynamic Modeling of O-Desmethyltramadol in Young and Elderly Healthy Volunteers. Drugs Aging 36, 747–758 (2019). https://doi.org/10.1007/s40266-019-00681-w

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  • DOI: https://doi.org/10.1007/s40266-019-00681-w

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