Pronounced differences in the disposition of clomipramine between Japaneseand Swedish patients

The aim of this study was to compare the disposition of the tricyclic antid epressant clomipramine (C) in Japanese and Swedish patients receiving conti nuous treatment. Therapeutic drug monitoring data for C and the active meta bolite N-desmethylclomipramine (DC) in Japanese patients receiving monother apy (N = 12) and in those receiving C plus benzodiazepines (BZDs) (N = 96) as well as int Swedes receiving C monotherapy (N = 131) and, in those recei ving C plus BZDs (N = 43) were used. A population kinetic approach with Bay esian feedback was used to estimate the individual clearance values for C. The relationships between kinetic variables and covariates were evaluated b y linear multiple regression. The median (25% and 75% quartiles, respective ly) oral clearance of C was 12.7 L/hr (11.6, 30.6) in Japanese patients rec eiving 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 monothe rapy, 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 Swe dish patients receiving C monotherapy, and 0.49 in Swedish patients receivi ng C plus BZDs. Thus, the lower oral clearance of C in Japanese patients co mpared with that in Swedish patients is not accounted fbr by the lower body weight in Japanese patients or by concomitant treatment with BZDs and is t herefore likely to be a true ethnic difference. The higher C/DC ratio impli cates a more pronounced serotonergic than noradrenergic effect in Japanese patients than in Swedish patients.