Dataset Information

A new donors' CYP3A5 and recipients' CYP3A4 cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients.

ABSTRACT: The purpose of the current study was to investigate individualized therapy of tacrolimus (Tac), as well as complications after liver transplantation (LT) with the known genetic determinants and clinical factors.In this retrospective study, two cohorts (n=170) from the China Liver Transplant Registry (CLTR) database from July 2007 to March 2015 were included.Both donors' CYP3A5*3 and recipients' CYP3A4*1G had a correlation with Tac pharmacokinetics at four weeks (all P<0.05), except recipients' CYP3A4*1G nearly had an association at week 2 (P=0.055). The model of donors' CYP3A5*3, recipients' CYP3A4*1G, and total bilirubin (TBL), for the prediction of Tac disposition, was better than donors' CYP3A5*3 only at week 1, 2, and 3 (P=0.010, P=0.007, and P=0.010, respectively), but not apparent at week 4 (P=0.297). Besides, when the P value was greater than or equal to 0.6685 after considering the false-positive rate R=10%, the patients were considered to have a faster metabolism, according to the mentioned model. Interestingly, we found that if more than or equal to two alleles A were present in the combination of donors' CYP3A5*3 and recipients' CYP3A4*1G genotype, there was a lower Tac C/D ration at week 1, 2, and 3 (P<0.001, P=0.001, and P<0.001), except at week 4 (P=0.082), and the probability of new-onset hypertension was lesser (P<0.001).These data provided a potential basis for a comprehensive approach to predicting the Tac dose requirement in individual patients and provided a strategy for the effective prevention, early diagnosis of new-onset hypertension in Chinese LT recipients.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5642551 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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A new donors' <i>CYP3A5</i> and recipients' <i>CYP3A4</i> cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients.

Liu Yuan Y Zhang Tao T Zhang Xiaoqing X Ye Ling L Gu Haitao H Zhong Lin L Sun Hongcheng H Song Chenlong C Peng Zhihai Z Fan Junwei J

Oncotarget 20170726 41

<h4>Aim</h4>The purpose of the current study was to investigate individualized therapy of tacrolimus (Tac), as well as complications after liver transplantation (LT) with the known genetic determinants and clinical factors.<h4>Methods</h4>In this retrospective study, two cohorts (n=170) from the China Liver Transplant Registry (CLTR) database from July 2007 to March 2015 were included.<h4>Results</h4>Both donors' <i>CYP3A5</i>*3 and recipients' <i>CYP3A4</i>*1G had a correlation with Tac pharmac ...[more]

PMID: 29050276

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Project description:Tacrolimus exhibits inter-patient pharmacokinetic variability attributed to CYP3A5 isoenzymes and the efflux transporter, P-glycoprotein. Most black renal transplant recipients require higher tacrolimus doses compared to whites to achieve similar troughs when race-adjusted recommendations are used. An established guideline provides tacrolimus genotype dosing recommendations based on CYP3A5*1(W/T) and loss of protein function variants: CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343) and may provide more comprehensive race-adjusted dosing recommendations. Our objective was to develop a tacrolimus population pharmacokinetic model evaluating demographic, clinical, and genomic factors in stable black and white renal transplant recipients. A secondary objective investigated race-based tacrolimus regimens and genotype-specific dosing. Sixty-seven recipients receiving oral tacrolimus and mycophenolic acid ?6 months completed a 12-hour pharmacokinetic study. CYP3A5*3,*6,*7 and ABCB1 1236C>T, 2677G>T/A, 3435C>T polymorphisms were characterized. Patients were classified as extensive, intermediate, and poor metabolizers using a novel CYP3A5*3*6*7 metabolic composite. Modeling and simulation was performed with computer software (NONMEM 7.3, ICON Development Solutions; Ellicott City, Maryland). A 2-compartment model with first-order elimination and absorption with lag time best described the data. The CYP3A5*3*6*7 metabolic composite was significantly associated with tacrolimus clearance (P value < .05), which was faster in extensive (mean: 45.0 L/hr) and intermediate (29.5 L/hr) metabolizers than poor metabolizers (19.8 L/hr). Simulations support CYP3A5*3*6*7 genotype-based tacrolimus dosing to enhance general race-adjusted regimens, with dose increases of 1.5-fold and 2-fold, respectively, in intermediate and extensive metabolizers for comparable exposures to poor metabolizers. This model offers a novel approach to determine tacrolimus dosing adjustments that maintain comparable therapeutic exposure between black and white recipients with different CYP3A5 genotypes.

Dataset Information

A new donors' CYP3A5 and recipients' CYP3A4 cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients.

Publications

A new donors' <i>CYP3A5</i> and recipients' <i>CYP3A4</i> cluster predicting tacrolimus disposition, and new-onset hypertension in Chinese liver transplant patients.

Similar Datasets

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