BackgroundWith clozapine, either crushed tablets suspended in an aqueous medium or proprietary suspension is sometimes prescribed as an alternative to tablets, but bioequivalence data are scant.MethodsWe compared clozapine dose, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations after use of either tablets or crushed tablets/suspension in samples submitted for clozapine therapeutic drug monitoring, 1993 to 2017.ResultsThere were 846 patients (1646 samples) given crushed tablets/suspension and 6065 patients (10,779 samples) given tablets. The median dose (mg d−1) was significantly higher in men (500 vs 450) and women (500 vs 400) given crushed tablets/suspension, but the median plasma clozapine and norclozapine concentrations (mg L−1) were significantly lower (men: 0.29 and 0.22 vs 0.39 and 0.28; women: 0.35 and 0.26 vs 0.50 and 0.32, respectively). A subgroup of 480 patients was prescribed either crushed tablets/suspension (1016 samples) or tablets (1259 samples) at different times. The median dose was again significantly higher in men (500 vs 500) and women (500 vs 450), but the median plasma clozapine and norclozapine concentrations were significantly lower (men: 0.29 and 0.22 vs 0.32 and 0.24; women: 0.30 and 0.24 vs 0.38 and 0.29, respectively).ImplicationsPoor adherence, sedimentation of suspension before use, and incomplete dosage are potential contributors to the lower median plasma clozapine and norclozapine concentrations observed after use of either crushed clozapine tablets or suspension as compared with tablets. Those administering crushed tablets/suspension should be aware of these factors.

AimsGuidance on clozapine dosing in treatment‐resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and N‐desmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status and body weight.MethodsA population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993–2017.ResultsThere were 17 787 measurements from 5960 patients (4315 male) aged 18–86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0 L h−1 between 20 and 80 years. Model‐based dose predictions to attain a predose plasma clozapine concentration of 0.35 mg L−1 was 275 (90% prediction interval 125, 625) mg day−1 in nonsmoking, White males weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females, and was 10% higher and 14% lower in otherwise analogous Afro‐Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between 20 and 80 years.ConclusionThe large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain predose clozapine concentration of 0.35 mg L−1. The analysis was, however, limited by the absence of data on clinical outcome and future studies are required to determine optimal predose concentrations specifically in those aged over 65 years.

Antipsychotics and drug-associated liver injury: toward minimum requirements in reporting pharmacovigilance studies.

Background: Guidance on clozapine dosing in treatment refractory schizophrenia is based largely on data from young adult male White patients.Aim: This study aimed to audit the plasma clozapine and N-desmethylclozapine (norclozapine) concentrations attained in male and female patients of different ethnicity and smoking habit. Method:The effect of dose, sex, ethnicity, age, body weight, and smoking habit on plasma clozapine and norclozapine concentrations were studied using data from a therapeutic drug monitoring service, 1993 to 2017.Results: There were 371,610 samples (48,098 patients, 32,855 male). Ethnicity was recorded for 763 Afro-Caribbean, 536 Asian, and 7940 White patients. Males were prescribed significantly higher median doses than females but attained significantly lower median plasma clozapine and norclozapine concentrations. Asian and Afro-Caribbean males were prescribed significantly lower and higher median doses, respectively, than White males but attained significantly higher and lower median plasma clozapine and norclozapine concentrations, respectively. Data from 78,431 samples (23,516 patients) were analyzed using a linear mixed model. The predicted dose to attain a predose plasma clozapine concentration of 0.35 mg/L in a nonsmoking White male aged 40 years, with weight of 70 kg, and plasma clozapine-norclozapine ratio of 1.32 was 344 mg/d (95% confidence interval, 227-526 mg/d). The predicted dose was 33% higher and 20% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. In all cases, the predicted dose was increased by 36% in smokers and decreased by 22% in females. Conclusions:Research is needed to further investigate the complex relationships between dose, sex, ethnicity, plasma clozapine and norclozapine concentrations, and clinical outcome such as weight gain.