Pronounced differences in the dispositon of clomipramine between Japanese and Swedish patients.

The aim of this study was to compare the disposition of the tricyclic antidepressant clomipramine (C) in Japanese and Swedish patients receiving continuous treatment. Therapeutic drug monitoring data for C and the active metabolite N-desmethylclomipramine (DC) in Japanese patients receiving monotherapy (N = 12) and in those receiving C plus benzodiazepines (BZDs) (N = 96) as well as in Swedes receiving C monotherapy (N = 131) and in those receiving C plus BZDs (N = 43) were used. A population kinetic approach with Bayesian feedback was used to estimate the individual clearance values for C. The relationships between kinetic variables and covariates were evaluated by linear multiple regression. The median (25% and 75% quartiles, respectively) oral clearance of C was 12.7 L/hr (11.6, 30.6) in Japanese patients receiving C monotherapy, 18.1 L/hr (5.6, 31.8) in Japanese patients receiving C plus BZDs, 62.7 L/hr (40.0, 90.6) in Swedish patients receiving C monotherapy, and 56.5 L/hr (34.3, 74.1) in Swedish patients receiving C plus BZDs. When combining all populations in a linear multiple regression, clearance was correlated with ethnic group (p < 0.00001) and age (p < 0.0005), but it was uncorrelated with gender, body weight, and administration of BZDs. The C/DC plasma concentration ratios were 1.08 in Japanese patients receiving C monotherapy, 0.90 in Japanese patients receiving C plus BZDs, 0.51 in Swedish patients receiving C monotherapy, and 0.49 in Swedish patients receiving C plus BZDs. Thus, the lower oral clearance of C in Japanese patients compared with that in Swedish patients is not accounted for by the lower body weight in Japanese patients or by concomitant treatment with BZDs and is therefore likely to be a true ethnic difference. The higher C/DC ratio implicates a more pronounced serotonergic than noradrenergic effect in Japanese patients than in Swedish patients.