Plasma Clozapine, Norclozapine, and the Clozapine:Norclozapine Ratio in Relation to Prescribed Dose and Other Factors: Data From a Therapeutic Drug Monitoring Service, 1993-2007

Lewis Couchman, Phillip Edgar Morgan, Edgar Pathrose Spencer, Bob Flanagan

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    148 Citations (Scopus)

    Abstract

    Therapeutic drug monitoring of plasma clozapine and of its principal plasma metabolite N-desmethylclozapine (norclozapine) (predose or "trough" sample) can help in monitoring adherence, in dose adjustment, and in minimizing the risk of toxicity. To obtain data to assist in the interpretation of analytical results, the results from a clozapine therapeutic drug monitoring service, 1993-2007, have been audited. There were 104,127 samples from 26,796 patients [18,750 (70%) men aged at time of first sample (median, range) 34 (10-89) years, and 7763 (30%) female aged 38 (12-90) years]. Clozapine was not detected (plasma concentration 1.0 mg/L at prescribed clozapine doses up to 150 mg/d (76.2% <0.35 mg/L), whereas 23.3% of samples had plasma clozapine <0.35 mg/L at doses of 850 mg/d and over (18.0% > 1.0 mg/L). The highest plasma clozapine and norclozapine concentrations encountered were 4.95 and 2.45 mg/L, respectively. Although the median plasma clozapine: norclozapine ratio was 1.25 at plasma clozapine concentrations <0.35 mg/L, the median ratio was 2.08 at plasma clozapine concentrations > 1.0 mg/L. Data (median, 10th-90th percentile) for both clozapine and norclozapine by prescribed clozapine dose band are useful in assessing partial adherence. Analysis of the plasma clozapine: norclozapine ratio by clozapine concentration provides clear evidence that clozapine N-demethylation becomes saturated at higher plasma clozapine concentrations and adds urgency to the requirement for dose adjustment should smoking habit change. A clozapine: norclozapine ratio greater then 2 suggests either a nontrough sample, or that clozapine N-demethylation has become saturated.

    Original languageEnglish
    Pages (from-to)438-447
    Number of pages10
    JournalTherapeutic Drug Monitoring
    Volume32
    Issue number4
    DOIs
    Publication statusPublished - Aug 2010

    Keywords

    • therapeutic drug monitoring
    • adherence
    • smoking habit
    • clozapine TDM
    • norclozapine
    • plasma
    • clozapine: norclozapine ratio
    • ATYPICAL ANTIPSYCHOTICS
    • SCHIZOPHRENIC-PATIENTS
    • N-DESMETHYLCLOZAPINE
    • SMOKING-CESSATION
    • CLINICAL PHARMACOKINETICS
    • LIQUID-CHROMATOGRAPHY
    • SERUM
    • CONSTIPATION
    • OLANZAPINE
    • CIPROFLOXACIN

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