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Population pharmacokinetic analyses of tacrolimus in non-transplant patients: a systematic review

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Abstract

Background and objectives

Tacrolimus (TAC) has been increasingly used in patients with non-transplant settings. Because of its large between-subject variability, several population pharmacokinetic (PPK) studies have been performed to facilitate individualized therapy. This review summarized published PPK models of TAC in non-transplant patients, aiming to clarify factors affecting PKs of TAC and identify the knowledge gap that may require further research.

Methods

The PubMed, Embase databases, and Cochrane Library, as well as related references, were searched from the time of inception of the databases to February 2023, to identify TAC population pharmacokinetic studies modeled in non-transplant patients using a non-linear mixed-effects modeling approach.

Results

Sixteen studies, all from Asian countries (China and Korea), were included in this study. Of these studies, eleven and four were carried out in pediatric and adult patients, respectively. One-compartment models were the commonly used structural models for TAC. The apparent clearance (CL/F) of TAC ranged from 2.05 to 30.9 L·h−1 (median of 14.9 L·h−1). Coadministered medication, genetic factors, and weight were the most common covariates affecting TAC-CL/F, and variability in the apparent volume of distribution (V/F) was largely explained by weight. Coadministration with Wuzhi capsules reduced CL/F by about 19 to 43%. For patients with CYP3A5*1*1 and *1*3 genotypes, the CL/F was 39–149% higher CL/F than patients with CYP3A5*1*1.

Conclusion

The optimal TAC dosage should be adjusted based on the patient's co-administration, body weight, and genetic information (especially CYP3A5 genotype). Further studies are needed to assess the generalizability of the published models to other ethnic groups. Moreover, external validation should be frequently performed to improve the clinical practicality of the models.

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Data availability

The datasets supporting the results of this study are included in the article/ supplementary materials and are available upon request to the corresponding author for further inquiries.

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Acknowledgements

The authors would like to thank Wang Ming-Lu from Shengjing Hospital, China Medical University, China, for her invaluable advice and support.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81673510 and 82073936) and Outstanding Scientific Fund of Shengjing Hospital (Nos. M0779). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Department of Pharmacy, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning Province, People’s Republic of China

    Cheng-Bin Wang, Yu-jia Zhang, Ming-Ming Zhao & Li-mei Zhao

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Cheng-bin Wang wrote the main manuscript text and Cheng-bin Wang and Yu-jia Zhang prepared figures and tables. Ming-Ming Zhao and Limei Zhao contributed to critically revising the manuscript. All authors contributed to the work, approved of the submitted version, and voiced their support for the publishing of the manuscript.

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Correspondence to Li-mei Zhao.

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Wang, CB., Zhang, Yj., Zhao, MM. et al. Population pharmacokinetic analyses of tacrolimus in non-transplant patients: a systematic review. Eur J Clin Pharmacol 79, 897–913 (2023). https://doi.org/10.1007/s00228-023-03503-6

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