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Population Pharmacokinetic Analysis for Model-Based Therapeutic Drug Monitoring of Tacrolimus in Chinese Han Heart Transplant Patients

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Abstract

Background and Objective

Tacrolimus has become the first-line immunosuppressant for preventing rejection after heart transplantation. The present study aimed to investigate genetic variants and clinical factors affecting the variability of tacrolimus in Chinese Han heart transplant patients using a population pharmacokinetic approach.

Methods

The retrospective study included 53 hospitalized patients with 547 tacrolimus concentrations for analysis. Nonlinear mixed-effects modeling was used to develop the population pharmacokinetics model for tacrolimus in patients with heart transplants, followed by Monte Carlo simulations to design initial dosing regimens.

Results

In our study, the mutation rate of CYP3A4*18B (C>T) was 27.36%. An oral one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetics of tacrolimus in heart transplant patients. In the final model, the estimated apparent clearance (CL/F) and volume of distribution (V/F) were 532.5 L/h [12.20% interindividual variability, IIV] and 16.87 L (23.16% IIV), respectively. Albumin, postoperative time, and rs2242480 (CYP3A4*18B) gene polymorphisms were the significant covariates affecting CL/F, and creatinine clearance had significant effects on the V/F.

Conclusion

The population pharmacokinetic model of tacrolimus in heart transplant patients can better estimate the population and individual pharmacokinetic parameters of patients and can provide a reference for the design of individualized dosing regimens.

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Authors and Affiliations

  1. Department of Pharmacy, Fujian Medical University Union Hospital, 29 Xin Quan Rd, Gulou, Fuzhou, 350001, Fujian, People’s Republic of China

    Yu Cheng & Hongqiang Qiu

  2. Department of Pharmacy, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, #18 Daoshan Road, Fuzhou, 350001, China

    Jiana Chen & Jinhua Zhang

  3. Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China

    Xiaojuan Lin

  4. College of Pharmacy, Fujian Medical University, Fuzhou, 350004, China

    Yu Cheng & Hongqiang Qiu

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  1. Yu Cheng
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  2. Jiana Chen
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  5. Jinhua Zhang
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Corresponding authors

Correspondence to Hongqiang Qiu or Jinhua Zhang.

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Funding

This work was supported by grants from the Natural Science Foundation of Fujian Province of China (grant no. 2018Y0037, 2021J01761), Fujian Medical Innovation Project (grant no. 2019-CX-19), and Startup Fund for scientific research, Fujian Medical University (grant no. 2019QH1269).

Conflict of interest

The authors report no conflicts of interest.

Ethics approval

This retrospective study involves human participants who were following the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Ethics Committee of Fujian Medical University Union Hospital (2020YF022-01) approved this study.

Consent to participate

Informed consent was obtained from the study participants before study commencement.

Consent to publish

Not applicable.

Author contribution

Conceptualization: Y.C., H.Q., and J.Z. Methodology: Y.C. and X.L. Data curation: Y.C., X.L., and J.C. Formal analysis and investigation: Y.C. and J.C. Writing: Y.C. Supervision: H.Q. and J.Z.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

The coding for this study is available from the corresponding author upon reasonable request.

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Cheng, Y., Chen, J., Lin, X. et al. Population Pharmacokinetic Analysis for Model-Based Therapeutic Drug Monitoring of Tacrolimus in Chinese Han Heart Transplant Patients. Eur J Drug Metab Pharmacokinet 48, 89–100 (2023). https://doi.org/10.1007/s13318-022-00807-3

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