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The pharmacokinetics of tacrolimus in peripheral blood mononuclear cells and limited sampling strategy for estimation of exposure in renal transplant recipients

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Intracellular exposure of tacrolimus (TAC) may be a better marker of therapeutic effect than whole blood exposure. We aimed to evaluate the influence of genetic polymorphism on the pharmacokinetics of TAC in peripheral blood mononuclear cells (PBMCs) and develop limited sampling strategy (LSS) models to estimate the area under the curve (AUC0–12h) in the PBMC of Chinese renal transplant patients.

Methods

Ten blood samples of each of the 23 renal transplant patients were collected 0–12h after 14 (10–18) days of TAC administration. PBMCs were separated and quantified. The TAC level in PBMCs was determined, and pharmacokinetic parameters were estimated by noncompartmental study. The AUC0–12h of TAC in whole blood was estimated by Bayesian approach based on a population pharmacokinetic model established in 65 renal transplant patients. The influence of CYP3A5 and ABCB1 genotypes on exposure was estimated. By applying multiple stepwise linear regression analysis, LSS equations for TAC AUC0–12h in the PMBC of renal transplant patients were established, and the bias and precision of various equations were identified and compared.

Results

We found a modest correlation between TAC exposure in whole blood and PBMC (r2 = 0.5260). Patients with the CYP3A5 6986GG genotype had a higher AUC0–12h in PBMCs than those with the 6986 AA or GA genotype (P = 0.026). Conversely, patients with the ABCB1 3435TT genotype had a higher AUC0–12h in PBMC than those with the 3435 CC and CT genotypes (P = 0.046). LSS models with 1–4 blood time points were established (r2 = 0.570–0.989). The best model for predicting TAC AUC0–12h was C2–C4–C6–C10 (r2 = 0.989). The model with C0.5–C6 (r2 = 0.849) can be used for outpatients who need monitoring to be performed in a short period.

Conclusions

The CYP3A5 and ABCB1 genotypes impact TAC exposure in PBMCs, which may further alter the effects of TAC. The LSS model consisting of 2–4 time points is an effective approach for estimating full TAC AUC0–12h in Chinese renal transplant patients. This approach may provide convenience and the possibility for clinical monitoring of TAC intracellular exposure.

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Funding

This work was supported by the National Natural Science Foundation of China (Grant Number: 81973387).

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Authors and Affiliations

  1. Department of Pharmacy, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Xi-Han Wang, Xiao-Hui Zhai & Bing Chen

  2. Center for Organ Transplantation, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, People’s Republic of China

    Kun Shao, Hui-Min An & Pei-Jun Zhou

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  1. Xi-Han Wang
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  2. Kun Shao
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  3. Hui-Min An
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  4. Xiao-Hui Zhai
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  6. Bing Chen
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Contributions

Bing Chen and Pei-jun Zhou designed the study. Xi-han Wang, Xiao-Hui Zhai, and Bing Chen conducted the genotyping and TAC PK study in the PBMCs of renal transplant patients. Kun Shao and Hui-min An analyzed the clinical data of the patients. Xi-han Wang and Bing Chen analyzed the results and drafted the manuscript. All of the authors read and approved the final manuscript. The authors confirm that the PI for this paper is Bing Chen.

Corresponding authors

Correspondence to Pei-Jun Zhou or Bing Chen.

Ethics declarations

The study was conducted in accordance with the ethical standards of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Ruijin Hospital, which is affiliated with the Shanhai Jiao-Tong University School of Medicine. All the patients who participated in the study provided written informed consent.

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Wang, XH., Shao, K., An, HM. et al. The pharmacokinetics of tacrolimus in peripheral blood mononuclear cells and limited sampling strategy for estimation of exposure in renal transplant recipients. Eur J Clin Pharmacol 78, 1261–1272 (2022). https://doi.org/10.1007/s00228-021-03215-9

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