Effects of gender and age on plasma levels of clozapine and its metabolites: Analyzed by critical statistics

Background: Previous reports concerning the effects of gender and age on st eady-state plasma concentrations of clozapine and its major metabolites, no rclozapine and clozapine-N-oxide, have been controversial. Since the freque ncy distribution of the plasma levels is asymmetrical and skewed to the rig ht, the statistical methods (such as analysis of variance and regression an alysis) used earlier are actually inappropriate for analyzing the effects o f the variables on the concentrations and might contribute to the inconsist ent results. The goal of the present study, with befitting statistics, is t o measure the potential effect of dose, gender, age, and body weight on pla sma levels of clozapine and its 2 major metabolites. Method: We retrospectively analyzed data from a therapeutic drug monitoring study for steady-state plasma clozapine, norclozapine, and clozapine-N-oxi de levels that was conducted in a large group of Chinese schizophrenic inpa tients (male:female ratio = 83:79; age range, 33.8 +/- 9.3 years). The dail y doses of clozapine had ranged from 100 to 900 mg, with a mean +/- SD valu e of 379.5 +/- 142.2 mg, Plasma concentrations had been measured using high performance liquid chromatography with ultraviolet detection. Multiple line ar regression was adopted to quantify the effects of various factors on the plasma levels. The natural logarithm of the plasma level was used as the d ependent variable to overcome the skewness problem. Results: After adjusting the effects of gender, age, and body weight by mul tiple linear regression, each l-mg increment in the daily dose could raise the clozapine level by 0.31%, norclozapine by 0.27%, and clozapine-N-oxide by 0.16%. Female patients had 34.9% higher clozapine levels and 36.3% highe r norclozapine, with other variables being controlled. No sex differences w ere demonstrated for clozapine-N-oxide levels. Each 1-year increment in age would elevate the clozapine level by 1.1%, norclozapine by 1.0%, and cloza pine-N-oxide by 1.0%. Body weight could not influence the levels of these c ompounds. Conclusion: The present results suggest that women possess higher plasma le vels (about one third higher) of clozapine and norclozapine, but not the N- oxide metabolite. Each addition of 1 year in age elevated clozapine and eit her metabolite's levels by about 1%. Furthermore, every l-mg increase in th e daily dose raised clozapine and norclozapine concentrations by approximat ely 0.3%. These findings could assist clinicians in optimizing clozapine do sing strategies.