Clozapine plasma measurements

It s hard to prescribe safely without clozapine plasma measurements... 

Many antipsychotics show great interindividual variation in plasma levels and so analysis of therapeutic levels can be important clinically as well as in the research laboratory. In addition, nonresponse to the drugs may actually be due to excessive levels of neuroleptics, a paradoxical situation that requires analysis to identify (Rockland, 1986). Several methods using FID were cited in the previous edition of the Handbook of Neurochemistry but ECD and NPD have both shown utility for the typically low therapeutic levels (Cooper, 1988). GC-FID has been used to analyze levels of clozapine in blood, gastric, and urine samples in fatal cases of overdose with this drug (Ferslew et al., 1998), and olanzapine has been measured in blood and urine samples by GC-NPD in overdoses (Stephens et al., 1998). 4-(4-Chlorophenyl)-4-hydroxypiperidine, a metabolite of haloperidol, was analyzed in urine, plasma, brain, and liver from haloperidol-treated rats by GC-ECD, after derivatization with PFBC under aqueous conditions (Fang et al., 1996). 

The plasma concentrations of clozapine and its metabolite norclozapine (N-desmethylclozapine) have been measured in samples from 3775 patients (2648 men, 1127 women) (308). Step-wise backward multiple regression analysis (37% of the total sample) of log plasma clozapine concentration against log clozapine dose (mg/day), age (years), sex (male = 0, female = 1), cigarette smoking (non-smokers = 0, smokers = 1), body weight (kg), and plasma clozapine/norclozapine ratio (MR) showed that these co-variates explained 48% of the observed variation... 

McCarthy, P.T. Hughes, S. Paton, C. Measurement of clozapine and norclozapine in plasma/serum by high-performance liquid chromatography with ultraviolet detection. Biomed.Chromatogr., 1995, 9, 36-41... 

Preliminary studies in 5 patients found that their mean plasma clozapine levels were unchanged by citalopram. Another study in 8 patients found similar results. However, a patient who was stable taking clozapine developed sedation, hypersalivation and confusion shortly after he started to take citalopram 40 mg daily. When total clozapine serum levels were measured they were found to be 1097 nanograms/mL. The citalopram dose was reduced to 20 mg daily, the symptoms resolved over the following 2 weeks, and the total clozapine level dropped to 792 nanograms/mL. ... 

Draw a timeline, correlating doses plasma clozapine measurements ( clozapine levels ) with side effects and efficacy... 

It may take a few weeks to reach the right dose, based on efficacy, side effects and plasma clozapine measurements (Box 37.2)... 

Take trough sanple for plasma clozapine measurement, 10-12 hours post-dose... 

Norclozapine is the principal plasma metabolite of clozapine. Its half-life is longer than clozapine s, so measurement is useful for assessing adherence. 

It can be difficult to dispute clozapine toxicity as the cause of death at an inquest, with the associated implication that clozapine dosage was inappropriate. This is because blood clozapine and norclozapine often rise after death, e.g. clozapine x5 norclozapine x4. If you have regularly (e.g. yearly in apparently successful therapy) measured plasma clozapine in life, this places you in a much stronger position to answer questions about the possible role of clozapine in a death. 

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