Sex, race, and smoking impact olanzapine exposure

Response to antipsychotics is highly variable, which may be due in part to differences in drug exposure. The goal of this study was to evaluate the magnitude and variability of concentration exposure of olanzapine. Patients with Alzheimer's disease (n = 117) and schizophrenia (n = 406) were treated with olanzapine as part of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Combined, these patients (n = 523) provided 1527 plasma samples for determination of olanzapine concentrations. Nonlinear mixed-effects modeling was used to determine the population pharmacokinetics of olanzapine, and patient-specific covariates were evaluated as potential contributors to variability in drug exposure. The population mean olanzapine clearance and volume of distribution were 16.1 L/h and 2150 L, respectively. Elimination of olanzapine varied nearly 10-fold (range, 6.66-67.96 L/h). Smoking status, sex, and race accounted for 26%, 12%, and 7% of the variability, respectively (P < .0001). Smokers cleared olanzapine 55% faster than non/past smokers (P < .0001). Men cleared olanzapine 38% faster than women (P < .0001). Patients who identified themselves as black or African American cleared olanzapine 26% faster than other races (P < .0001). Differences in olanzapine exposure due to sex, race, and smoking may account for some of the variability in response to olanzapine.