Significant predictors for olanzapine pharmacokinetics: a systematic review of population pharmacokinetic studies

IntroductionOlanzapine is widely used for treating schizophrenia and bipolar I disorder. Due to its high pharmacokinetic variability, several population pharmacokinetic studies have been performed to identify factors contributing to the variability and thus facilitate individualized dosing. This review aims to provide a comprehensive overview of published population pharmacokinetic studies and explore potential covariates.MethodsWe systematically searched PubMed, Web of Science, and EMBASE databases from their inception to 31 December 2022. Information on the study design, characteristics, and final parameter estimates was summarized and compared. Monte Carlo simulations provided visual predictive distributions to compare eligible studies. Forest plots were constructed to explore the effects of covariates on olanzapine pharmacokinetics.ResultsA total of 10 population pharmacokinetic and three population pharmacokinetic/pharmacodynamic studies involving infants, children, adolescents, and adults were finally included. The median apparent clearance was 0.253 L/h/kg in adults, 27-43% lower than that of infants and children. Men and smokers increased the apparent clearance of olanzapine by 32% and 34%, respectively. The concentration required to achieve half of the maximum effect for the Positive and Negative Syndrome Scale total score was 24.80 ng/mL, comparable with 22.32 ng/mL for dopamine D-2 receptor occupancy.ConclusionsA higher dosage may be required for men or heavy smokers than for women or nonsmokers to reach the same exposure. Moreover, further population studies are essential to be conducted to clarify the dose-exposure-response relationship of olanzapine.PROSPERO registrationCRD42022368637

Automated summary

This review provides an overview of published population pharmacokinetic studies on olanzapine and explores factors contributing to its pharmacokinetic variability. The results showed that the apparent clearance in adults was 0.253 L/h/kg, 27-43% lower than in infants and children. Men and smokers had higher apparent clearance, increasing it by 32% and 34% respectively. Furthermore, further population studies are needed to clarify the dose-exposure-response relationship of olanzapine.