Insights into the population pharmacokinetics and pharmacodynamics of quetiapine: a systematic review

ABSTRACT

Introduction

Quetiapine exhibits notable pharmacokinetic and pharmacodynamic (PK/PD) variability, the origins of which are poorly understood. This systematic review summarizes published population PK/PD studies and identifies significant covariates accounting for this variability to inform precision dosing.

Methods

We systematically searched the PubMed, Web of Science, and Embase databases and compared study characteristics, model parameters, and covariate effects. Visual predictive distributions were used to compare different models. Forest plots and Monte Carlo simulations were used to assess the influence of covariates.

Results

Six population PK and three population PK/PD studies were included. The median apparent clearance in adults was 87.7 L/h. Strong and moderate cytochrome P450 3A4 inducers increased the apparent clearance approximately fourfold, while strong cytochrome P450 3A4 inhibitors reduced it by 93%. The half-maximum effect concentrations were 82.8 ng/mL for the Brief Psychiatric Rating Scale and 583 ng/mL for dopamine D₂ receptor occupancy. Both treatment duration and quetiapine exposure were associated with weight gain.

Conclusions

Concurrent administration of potent or moderate CYP3A4 inducers and inhibitors need to be avoided in quetiapine-treated patients. When co-medication is required, it is recommended to adjust the dosage based on therapeutic drug monitoring. Additional research is warranted to delineate the dose-exposure-response relationships of quetiapine and active metabolite norquetiapine in pediatrics, geriatrics, hepatically-impaired patients, and women using contraceptives or are pregnant or menopausal.

PROSPERO registration

CRD42023446654

KEYWORDS:

• Drug-drug interaction
• nonlinear mixed effect modeling
• pharmacodynamics
• pharmacokinetics
• population analysis
• quetiapine

Article highlights

• Strong and moderate cytochrome P450 (CYP) 3A4 inducers can increase the apparent clearance of QTP by approximately fourfold, while strong CYP3A4 inhibitors reduced it by 93%.

• Compared to *1/1 carriers, CYP3A41/*22 and *22/*22 carriers exhibited a 25% and 51% decrease, respectively, in the CL/F of QTP.

• The active metabolite norquetiapine exhibits higher PK exposure than QTP, with a 73% higher minimum steady-state concentration and a 28% higher 24-hour area under the curve.

• Both treatment duration and exposure to quetiapine were correlated with weight gain.

• Further research is needed to elucidate the dose-exposure-response relationships of quetiapine and norquetiapine in pediatrics, the elderly, patients with liver impairments, and women who are pregnant, menopausal, or using contraceptives.

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.

Reviewer disclosures

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

Author contributions

All authors contributed to the study conception and design. Z Jiao and JQ Gu formulated the study design and methodology. L Han, JQ Gu and JH Mao executed the literature search and data analysis. L Han conducted the plot and the simulation. L Han and Z Jiao composed the original manuscript. Z Jiao, JH Mao, XQ Liu and JQ Gu undertaken the manuscript review. All authors participated in the editing process and approved the final version of the manuscript.

Acknowledgments

The authors extend their sincere gratitude to Prof. Robert R. Bies from the University at Buffalo School, Prof. Bruce G. Pollock from the University of Toronto, Prof. Geoff Isbister from The University of Newcastle and Dr. Diansong Zhou from the Quantitative Clinical Pharmacology Department at AstraZeneca, for their assistance with coding and providing extra information on the study population. Special thanks go to Yue-Ting Chen and Hao-Ran Dai from Shanghai Chest Hospital for their insightful discussion on coding and writing. Lastly, we acknowledge Editage (www.editage.cn) for providing English language editing services.

Data availability statement

All data generated or analyzed during this study are included in this published article and supplementary file.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17512433.2023.2295428.

Additional information

Funding

This paper was not funded.