Gender, age, smoking behaviour and plasma clozapine concentrations in 193 Chinese inpatients with schizophrenia

Abstract

What is already known about this subject • Plasma concentrations of clozapine (CLZ) and its active metabolite vary considerably at a given dosage.• A number of patient-related factors have been reported to increase the variability of plasma CLZ concentrations, with gender, age and smoking behaviour representing some of the more important contributing variables • However, results of previous studies concerning these factors have been inconsistent and most studies were conducted in western populations.What this study adds • Using this ethnically unique, relatively large sample, we replicated some findings in western populations, including large interindividual variability of plasma CLZ concentrations, significant effects of gender on plasma CLZ concentrations.• Female patients had significantly higher levels than males and no significant differences in plasma CLZ concentrations were observed between male smokers and nonsmokers, despite the CLZ dosage for smokers being significantly higher. AimTo study the relationship between age, gender, cigarette smoking and plasma concentrations of clozapine (CLZ) and its metabolite, norclozapine (NCLZ) in Chinese patients with schizophrenia. MethodsData from a therapeutic drug monitoring programme were analysed retrospectively. One hundred and ninety-three Chinese inpatients with schizophrenia were assessed using clinical data forms. Steady-state plasma concentrations of CLZ and NCLZ were assayed using high-performance liquid chromatography. Comparisons of dosage and plasma CLZ concentrations were undertaken between males (n = 116) and females (n = 77), younger (Յ40 years, n = 82) and older patients (>40 years, n = 111) and current male smokers (n = 50) and nonsmokers (n = 66). Results(i) Plasma CLZ concentrations demonstrated large interindividual variability, up to eightfold at a given dose; (ii) there were significant effects of gender on plasma CLZ concentrations (relative to dose per kg of body weight) with female patients having significantly higher concentrations than males (30.09 Ϯ 24.86 vs. 19.87 Ϯ 3.55 ng ml -1 mg -1 day -1 kg -1 ; P < 0.001); (iii) there were no significant differences in plasma CLZ concentrations between those patients Յ40 years old and those >40 years; and (iv) there were no significant differences in plasma CLZ concentrations between male smokers and nonsmokers, despite the CLZ dosage for smokers being significantly higher. ConclusionsPlasma CLZ concentrations vary up to eightfold in Chinese patients. Among the patient-related factors investigated, only gender was significant in affecting CLZ concentrations in Chinese patients with schizophrenia, with female patients having higher levels.

Real‐world effectiveness of clozapine in patients with bipolar disorder: results from a 2‐year mirror‐image study

“…The average dose of clozapine used in the present study was lower than the doses used for patients with treatment‐resistant schizophrenia, but doses were comparable to those used in other BD studies (13, 16). The use of lower clozapine doses in our cohort could, in part, have been because it included more females, as females tend to receive lower clozapine dosages because of lower cytochrome P450 1A2 activity (32). Nevertheless, in clinical practice, the doses of antipsychotic agents used tend to be higher in schizophrenia than in BD (33).…”

Converting from brand-name to generic clozapine: A review of effectiveness and tolerability data

“…Third, the influence of factors known to affect clozapine response and plasma drug levels 33 could not be ascertained, including data on smoking status and the use of concomitant psychotropic medications. 32,[34][35][36][37] While plasma clozapine level influences therapeutic response, the potential effect of this and other factors on results of most reviewed studies that did not permit randomization to treatment or control for specific factors is unknown.…”

“…Significant effects of age, sex, ethnicity, smoking status, and concomitant medication use on plasma clozapine concentrations have been consistently documented. [32][33][34][35][36][37] Several of these factors have been considered by some as key predictors of therapeutic outcomes among clozapinetreated patients. 32,34,38 In addition, there is substantial evidence that a serum clozapine concentration of ≥350-420 ng/mL may serve as a useful threshold for therapeutic effect in clozapine-treated patients with refractory schizophrenia, [39][40][41][42][43][44][45] though not all study results are in agreement.…”

Genetic Polymorphism of Glutathione S-transferase T1 (GSTT1) and QT-Interval in Schizophrenia Patients

“…Smokers had a significantly lower plasma concentration of the drugs than nonsmokers (Thanacoody et al 2007;Bigos et al 2008;Berecz et al 2003;Nozawa et al 2008;Carrillo et al 2003). Others, however, have not found such differences (Tang et al 2007;Hasegawa et al 1993).…”