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Tacrolimus population pharmacokinetics according to CYP3A5 genotype and clinical factors in Chinese adult kidney transplant recipients.
J Clin Pharm Ther. 2017 Aug; 42(4):425-432.JC

Abstract

WHAT IS KNOWN AND OBJECTIVES

Tacrolimus is characterized by a narrow therapeutic index and a considerable inter- and intraindividual pharmacokinetic variability. The aim of our study was to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant of Chinese patients, identify factors especially CYP3A5*3 genetic polymorphism that explain variability, and determine dosage regimens.

METHODS

Pharmacogenomic data obtained from 83 Chinese kidney transplant patients treated with tacrolimus were determined using polymerase chain reaction-restriction fragment length polymorphism analysis. Trough blood concentration data were collected from all of the patients during the 12 months of post-transplantation days and were analysed using the nonlinear mixed-effects modelling program. After building the final model, 1000 bootstraps were performed to validate the final model.

RESULTS AND DISCUSSION

A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. In this study, we observed that POD, HCT and CYP3A5*3 genotype were determinant factors in CL/F and POD related with V/F of tacrolimus significantly. The final model with the clearance covariates was presented as: Cl/F=THETA(1)*EXP(THETA(4)*(83/POD))*(39.1/HCT)**THETA(5)*EXP(THETA(6)*CYP3A5), and the final model with the volume covariates was presented as: Vd/F=THETA(2)*POD**THETA(3). The Ka was fixed to 4.5 h-1 .

WHAT IS NEW AND CONCLUSION

The HCT, CYP3A5*3 genetic polymorphism and POD contributed to the interindividual variability of oral tacrolimus in Chinese adult renal transplant patients.

Authors+Show Affiliations

Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China. Department of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China.Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China.Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China.Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China.

Pub Type(s)

Journal Article
Validation Study

Language

eng

PubMed ID

28401703

Citation

Zhang, H J., et al. "Tacrolimus Population Pharmacokinetics According to CYP3A5 Genotype and Clinical Factors in Chinese Adult Kidney Transplant Recipients." Journal of Clinical Pharmacy and Therapeutics, vol. 42, no. 4, 2017, pp. 425-432.
Zhang HJ, Li DY, Zhu HJ, et al. Tacrolimus population pharmacokinetics according to CYP3A5 genotype and clinical factors in Chinese adult kidney transplant recipients. J Clin Pharm Ther. 2017;42(4):425-432.
Zhang, H. J., Li, D. Y., Zhu, H. J., Fang, Y., & Liu, T. S. (2017). Tacrolimus population pharmacokinetics according to CYP3A5 genotype and clinical factors in Chinese adult kidney transplant recipients. Journal of Clinical Pharmacy and Therapeutics, 42(4), 425-432. https://doi.org/10.1111/jcpt.12523
Zhang HJ, et al. Tacrolimus Population Pharmacokinetics According to CYP3A5 Genotype and Clinical Factors in Chinese Adult Kidney Transplant Recipients. J Clin Pharm Ther. 2017;42(4):425-432. PubMed PMID: 28401703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tacrolimus population pharmacokinetics according to CYP3A5 genotype and clinical factors in Chinese adult kidney transplant recipients. AU - Zhang,H J, AU - Li,D Y, AU - Zhu,H J, AU - Fang,Y, AU - Liu,T S, Y1 - 2017/04/11/ PY - 2016/09/26/received PY - 2017/03/05/accepted PY - 2017/4/13/pubmed PY - 2018/1/27/medline PY - 2017/4/13/entrez KW - CYP3A5*3 KW - haematocrit KW - nonlinear mixed-effects modelling KW - population pharmacokinetics KW - post-operative days KW - tacrolimus SP - 425 EP - 432 JF - Journal of clinical pharmacy and therapeutics JO - J Clin Pharm Ther VL - 42 IS - 4 N2 - WHAT IS KNOWN AND OBJECTIVES: Tacrolimus is characterized by a narrow therapeutic index and a considerable inter- and intraindividual pharmacokinetic variability. The aim of our study was to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant of Chinese patients, identify factors especially CYP3A5*3 genetic polymorphism that explain variability, and determine dosage regimens. METHODS: Pharmacogenomic data obtained from 83 Chinese kidney transplant patients treated with tacrolimus were determined using polymerase chain reaction-restriction fragment length polymorphism analysis. Trough blood concentration data were collected from all of the patients during the 12 months of post-transplantation days and were analysed using the nonlinear mixed-effects modelling program. After building the final model, 1000 bootstraps were performed to validate the final model. RESULTS AND DISCUSSION: A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. In this study, we observed that POD, HCT and CYP3A5*3 genotype were determinant factors in CL/F and POD related with V/F of tacrolimus significantly. The final model with the clearance covariates was presented as: Cl/F=THETA(1)*EXP(THETA(4)*(83/POD))*(39.1/HCT)**THETA(5)*EXP(THETA(6)*CYP3A5), and the final model with the volume covariates was presented as: Vd/F=THETA(2)*POD**THETA(3). The Ka was fixed to 4.5 h-1 . WHAT IS NEW AND CONCLUSION: The HCT, CYP3A5*3 genetic polymorphism and POD contributed to the interindividual variability of oral tacrolimus in Chinese adult renal transplant patients. SN - 1365-2710 UR - https://www.unboundmedicine.com/medline/citation/28401703/Tacrolimus_population_pharmacokinetics_according_to_CYP3A5_genotype_and_clinical_factors_in_Chinese_adult_kidney_transplant_recipients_ L2 - https://doi.org/10.1111/jcpt.12523 DB - PRIME DP - Unbound Medicine ER -