Article
Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients: Influence of patient-related variables

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Abstract

Steady-state plasma concentrations of clozapine and norclozapine, its major metabolite, as well as their sum and ratio (norclozapine/clozapine), were evaluated in 50 in- and outpatients taking clozapine and naturalistically recruited. Drug plasma concentrations were measured by means of a reversed-phase high-performance liquid chromatography (RPLC) method with an ultraviolet detection. Daily doses (milligrams per kilogram of body weight) of clozapine correlated positively with clozapine plasma parameters, except with the norclozapine/clozapine ratio, in all patients. When the patients were divided in subgroups with respect to gender, the corresponding plasma concentrations were no longer dose-related in men. A lack of significant correlation was observed also in patients (n=23) co-treated with typical neuroleptics. Conversely, dose–concentration correlations were significant in either smoker or nonsmoker patients. No significant relationship between body weight and clozapine plasma parameters was reported. Further, we observed (1) a trend towards higher medians of clozapine or total analytes in women than those reported in men (P=.09 and .07); (2) no significant difference in plasma levels obtained in subjects younger than 34 years and subjects 34 years old or older; (3) a trend towards higher norclozapine and clozapine plus norclozapine levels (P=.05 and .08) in nonsmoker than smoker patients; (4) no significant difference between clozapine plasma parameters measured in patients co-medicated with typical neuroleptics and in patients receiving clozapine alone.

Introduction

Clozapine, an atypical antipsychotic drug that is used for treating negative symptoms of schizophrenia resistant to typical neuroleptics (Kane et al., 1988), has proven to be effective also in a wide range of psychotic states, including mood disorders with psychotic features (Calabrese et al., 1991, Calabrese et al., 1996, McElroy et al., 1991, Zarate et al., 1995, Cassano et al., 1997, Young et al., 1997; for review, see Ciapparelli et al., 2000). Several psychotic patients resistant to treatments with typical neuroleptics or developing extrapyramidal side effects (EPS) have been found to respond to clozapine and to tolerate it better Meltzer et al., 1989a, Meltzer et al., 1989b, Conley and Buchanan, 1997. A delayed response to clozapine (10–24 weeks or longer), as compared with that of typical neuroleptics, has been however observed (Meltzer et al., 1989b). As a consequence, compliance problems are frequent in patients taking clozapine. Therefore, the variability of responsiveness to this drug, together with its side effects, in particular its potential for agranulocytosis Alvir et al., 1993, Gerson et al., 1994, has led to focus on its therapeutic monitoring to optimize dosing strategies. In fact, higher levels of clozapine and, in particular, of its metabolite norclozapine in serum or plasma of treated patients, have been related to agranulocytosis (Centorrino et al., 1995).

Plasma levels of clozapine and norclozapine usually display great interindividual differences (Volpicelli et al., 1993), so that it seems currently important to evaluate the effects of patient-related variables on plasma clozapine and norclozapine concentrations. Previous reports on the effects of dose, sex, age, body weight, and smoking habit on clozapine plasma levels from treated patients have been carried out, but the ensuing findings are controversial Haring et al., 1989, Haring et al., 1990, Perry et al., 1991, Hasegawa et al., 1993, Szymanski et al., 1996, Jann et al., 1997, Lane et al., 1999. Lane et al. (1999) suggest that the inappropriate use of parametric statistical tests, employed in previous investigations, might have contributed to such discrepancies, since clozapine plasma levels are skewed to the right and not normally distributed. These authors suggest to normalize clozapine plasma level values by transforming them in their natural log (ln) before applying parametric statistical tests. An alternative method for evaluating frequencies that are not normally distributed consists of the use of nonparametric statistical analyses. Further, some studies were retrospective Haring et al., 1989, Haring et al., 1990, Lane et al., 1999; others followed a controlled prospective design (Hasegawa et al., 1993).

In the present study, which followed a naturalistic design, we investigated a sample of 50 patients, in treatment with clozapine, at a clinically determined dosage to evaluate the variability of clozapine, norclozapine plasma levels, as well as the norclozapine/clozapine ratio and sum of norclozapine plus clozapine concentrations (total analytes). The presumed influence of dose, body weight, gender, age, and smoking habit on clozapine plasma parameters was also evaluated in this patient sample. Since we admitted to the study also patients who were receiving typical neuroleptics in combination with clozapine, we examined the possible influence of these compounds on clozapine metabolism. Statistical analyses were performed by means of nonparametric tests (Mann–Whitney test). We decided to account for the drug ratio and sum, since these parameters are important indices of clozapine metabolism. In particular, the sum of clozapine plus norclozapine divided by dose/weight is related to clozapine clearance (Centorrino et al., 1996).

Section snippets

Subjects

Steady-state plasma levels of clozapine and norclozapine were measured in 50 patients (26 men and 24 women) at more than 10 days from the beginning of treatment with clozapine (treatment duration, mean±S.E.M.: 10.6±2.6 months). The steady state was guaranteed by maintaining subjects at the clozapine dosage for at least 7 days (clozapine half-life: 12–26 h) (Ereshefsky et al., 1989). Subject's age ranged between 18 and 78 years (mean±S.E.M.: 36.84±1.96 years); 16 patients were younger than 30

Correlation with daily dose

The present work, which followed a naturalistic design, reports a significant positive correlation between daily dose of clozapine and clozapine plasma parameters. This is in accord with most of the previous studies, either naturalistic Volpicelli et al., 1993, Haring et al., 1989, Haring et al., 1990, Lane et al., 1999 or based on a controlled prospective design Ackenheil, 1989, Hasegawa et al., 1993. Our Spearman r values (rclozapine=.56, P<.0001; rnorclozapine=.49, P<.0005; rsum=.55, P

Conclusion

In conclusion, this paper reports clozapine, norclozapine plasma levels, total analytes, and their ratio (norclozapine/clozapine) obtained in 50 patients treated with clozapine and naturalistically recruited: the reported values are similar to those reported by others. Gender and smoking behavior seem to exert some influence on clozapine plasma parameters, although the naturalistic design of this study limits the possibility to strongly relate the observed data to such parameters. On the other

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