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

ABSTRACT

Introduction

Olanzapine 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.

Methods

We 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.

Results

A 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 D₂ receptor occupancy.

Conclusions

A 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 registration

CRD42022368637

KEYWORDS:

• olanzapine
• population pharmacokinetics
• nonlinear mixed effect model
• dosage adjustments
• individualized drug therapy

Article highlights

• The pharmacokinetics of olanzapine were found to be significantly influenced by sex and smoking status. Men and smokers increased the CL/F by 32% and 34%, respectively. Thus, achieving equivalent exposure in men or heavy smokers would necessitate a higher dosage compared to women or nonsmokers.

• Infants and children showed 37–75% higher clearance per kilogram of body weight than adults, suggesting that a higher dosage per kilogram of body weight is required for pediatric patients.

• The concentration required to achieve half of the maximum effect for the Positive and Negative Syndrome Scale total score was comparable with dopamine D₂ receptor occupancy, indicating D₂ receptor occupancy has the potential for clinical application that can reflect the corresponding Positive and Negative Syndrome Scale total score.

Acknowledgments

The authors sincerely thank Dr. Can‑Jun Ruan from the Beijing Anding Hospital, Capital Medical University, Beijing, China, for the active discussion on coding. The authors also would like to thank Yue-Ting Chen from Shanghai Chest Hospital and Di-Hong Yang from Cancer Hospital of the University of Chinese Academy of Sciences, for contributing to the graphic visualization. Finally, we would like to thank Editage (www.editage.cn) for assistance in English language editing.

Declaration of interest

Z Jiao has received consulting fees from Takeda, AstraZeneca and Pharmaron. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Data availability statement

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17512433.2023.2219055.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Z Jiao and JH Mao conceptualized the study design and methodology. JH Mao and L Han performed the literature search and data analysis. JH Mao contributed to the plot and the simulation. JH Mao and Z Jiao wrote the original manuscript. L Han, XQ Liu, and Z Jiao reviewed the manuscript. All authors edited and approved the final version of the manuscript.

Additional information

Funding

This paper was not funded.