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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

Rostami-Hodjegan, Amin PhD*; Amin, Ajmal M. MSc†‡; Spencer, Edgar P. PhD; Lennard, Martin S. PhD*; Tucker, Geoffrey T. PhD*; Flanagan, Robert J. PhD

Journal of Clinical Psychopharmacology: February 2004 - Volume 24 - Issue 1 - p 70-78
doi: 10.1097/01.jcp.0000106221.36344.4d
Original Contributions
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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 × 10−3) (P < 0.001) according to the following equation:

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.

*Molecular Pharmacology and Pharmacogenetics, The University of Sheffield, Sheffield, UK; †Medical Toxicology Unit, Guy's & St Thomas' Hospital Trust, London, UK; ‡Pathology Laboratory, South London and Maudsley NHS Trust, London, UK.

Received March 10, 2003; accepted after revision May 9, 2003.

Address correspondence and reprint requests to Dr. Amin Rostami-Hodjegan, Molecular Pharmacology and Pharmacogenetics, Floor L, The Royal Hallamshire Hospital, Sheffield S10 2JF, UK. E-mail: a.rostami@sheffield.ac.uk.

© 2004 Lippincott Williams & Wilkins, Inc.