Tramadol and O-Desmethyl Tramadol Clearance Maturation and Disposition in Humans: A Pooled Pharmacokinetic Study
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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.
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.
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.
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).
KeywordsTramadol Relative Standard Error CYP2D6 Genotype CYP2D6 Activity Slow Metabolizers
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.
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