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Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients.

Abstract：

:The measurement of plasma clozapine concentrations is useful in assessing compliance, optimizing therapy, and minimizing toxicity. We measured plasma clozapine and norclozapine (N-desmethylclozapine) concentrations in samples from 3782 patients (2648 male, 1127 female). No clozapine was detected in 291 samples (227 patients, median prescribed dose 300 mg/d). In 4963 (50.2 %) samples (2222 patients); plasma clozapine concentration ranged from 10 to 350 ng/mL.Step-wise backward multiple regression analysis (37 % of the total samples) of log10 plasma clozapine concentration against log10 clozapine dose (mg/d), age (year), sex (male = 0, female = 1), cigarette smoking habit (nonsmokers = 0; smokers = 1), body weight (kg), and plasma clozapine/norclozapine ratio (clozapine metabolic ratio, MR) showed that these covariates explained 48% of the observed variation in plasma clozapine concentration (C = ng/mL x 10-3) (P < 0.001) according to the following equation: log 10 (C) = 0.811 log 10 (dose) + 0.332 (MR) + 69.42 X 10 (-3) (sex) + 2.263 x 10 (-3) (age) + 1.976 x 10(-3) (weight) - 0.171 (smoking habit) - 3.180. This model and its associated confidence intervals were used to develop nomograms of plasma clozapine concentration versus dose for male and female smokers and nonsmokers. Predicted plasma clozapine changes by +48% in nonsmokers, +17% in females, +/-8 % for every 0.1 change in MR (reference 1.32), +/-4% for every 5 years (reference 40 years), and +/-5 % for every 10 kg body weight (reference 80 kg). The nomograms can be used (i) to individualize dosage to achieve a given target plasma clozapine concentration, and (ii) for quantitative evaluation of adherence by estimating the likelihood of an observed concentration being achieved by a given dosage regimen. The model has been validated against published data.

journal_name

J Clin Psychopharmacol

journal_title

Journal of clinical psychopharmacology

authors

Rostami-Hodjegan A,Amin AM,Spencer EP,Lennard MS,Tucker GT,Flanagan RJ

doi

10.1097/01.jcp.0000106221.36344.4d

subject

Has Abstract

pub_date

2004-02-01 00:00:00

pages

70-8

issue

eissn

0271-0749

issn

1533-712X

journal_volume

pub_type

杂志文章

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Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients.