title: 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.
authors.affiliation: Molecular Pharmacology and Pharmacogenetics, The University of Sheffield, Sheffield, UK. a.rostami@sheffield.ac.uk
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.forename: Ajmal M
authors.initials: AM
authors.lastname: Amin
authors.forename: Edgar P
authors.initials: EP
authors.lastname: Spencer
authors.forename: Martin S
authors.initials: MS
authors.lastname: Lennard
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Tucker
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Flanagan
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism* / Q000502:physiology; D000465:Algorithms; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003024:Clozapine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005544:Forecasting; D006801:Humans; D008297:Male; D008954:Models, Biological; D010349:Patient Compliance; D012189:Retrospective Studies; D012737:Sex Factors; D012907:Smoking / Q000378:metabolism* / Q000503:physiopathology; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: C058272:norclozapine; D003024:Clozapine