Tramadol and o-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study.

Allegaert, Karel; Holford, Nick; Anderson, Brian J; Holford, Sam; Stüber, Frank; Rochette, Alain; Trocóniz, Iñaki F; Beier, Horst; de Hoon, Jan N; Pedersen, Rasmus S; Stamer, Ulrike (2015). Tramadol and o-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study. Clinical pharmacokinetics, 54(2), pp. 167-178. Springer 10.1007/s40262-014-0191-9

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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).

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Intensive Care, Emergency Medicine and Anaesthesiology (DINA) > Clinic and Policlinic for Anaesthesiology and Pain Therapy

UniBE Contributor:

Stüber, Frank and Stamer, Ulrike

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0312-5963

Publisher:

Springer

Language:

English

Submitter:

Jeannie Wurz

Date Deposited:

22 May 2015 16:15

Last Modified:

28 Feb 2018 09:36

Publisher DOI:

10.1007/s40262-014-0191-9

PubMed ID:

25258277

URI:

https://boris.unibe.ch/id/eprint/69120

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