Using Genetic and Clinical Factors to Predict Tacrolimus Dose in Renal Transplant Recipients

Wang, Ping; Mao, Yong; Razo, Juan; Zhou, Xiaobo; Wong, Stephen T.; Patel, Samir J.; Elliott, Erin N; Shea, Erin; Wu, Alan H.B.; Gaber, A. Osama

doi:10.2217/pgs.10.105

Cited by 44 publications

(35 citation statements)

References 65 publications

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“…35 However, Wang and associates found that CYP3A5 genotype is the most significant genetic factor that affects tacrolimus dosage in renal transplant patients. 36 Barrera-Pulido and associates found that in Spanish liver transplant patients, presence of the A allele for the CYP3A5 gene was related to greater requirements of tacrolimus in the early days after transplant. 37 In Chinese liver transplant patients, Weilin and associates, suggested that the recipients' ABCB1 and the donors' CYP3A5 genotype affect the tacrolimus dosage requirements.…”

Section: Discussionmentioning

confidence: 98%

Association Between Tacrolimus Concentration and Genetic Polymorphisms of CYP3A5 and ABCB1 During the Early Stage After Liver Transplant in an Iranian Population

Rahsaz

Azarpira²,

Nikeghbalian³

et al. 2012

Exp Clin Transplant

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Objectives: Tacrolimus is widely used as an immunosuppressive drug in liver transplant recipients with a narrow therapeutic range and variable individualized pharmacokinetics. Tacrolimus is a substrate of cytochrome P-450 3A enzyme and the drug transporter, P-glycoprotein. Materials and Methods: We determined the genotypic frequencies of cytochrome P-4503A5 (rs776746), and ABCB1 (rs1045642), single nucleotide polymorphisms in a population of 100 Iranian liver transplant patients, and investigated the influence of the above-mentioned single nucleotide polymorphisms on tacrolimus concentrations. At 7 and 30 days after transplant, tacrolimus dosages (mg/kg/d), trough blood levels (T0), and dose-adjusted concentrations (concentration/dosage ratio) were determined. Polymerase chain reaction, followed by restriction fragment length polymorphism analysis, was used for genotyping cytochrome P-4503A5*3 [6986A>G] as well as ABCB1 [3435C>T]. Results: Ninety-five percent of the population showed a cytochrome P-4503A5*3/*3 genotype. ABCB13435TT genotype was observed in 33 cases (33%); whereas 51 cases (51%) carried 3435CT, and 16 cases (16%) carried 3435CC. With regard to the ABCB1 and cytochrome P-4503A5, they showed no influence on tacrolimus dosing requirements at 1 week or 1 month after transplant. No association of any genetic variant with the acute rejection rate was found. Conclusions: Finally, as the liver donor genotype influences tacrolimus pharmacokinetics with regard to expression of cytochrome P-4503A5, far more than the genotype of the recipient; therefore, it should be considered before recommending any personal immunosuppressive treatment based on pharmacogenetics.

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Section: Discussionmentioning

confidence: 98%

Association Between Tacrolimus Concentration and Genetic Polymorphisms of CYP3A5 and ABCB1 During the Early Stage After Liver Transplant in an Iranian Population

Rahsaz

Azarpira²,

Nikeghbalian³

et al. 2012

Exp Clin Transplant

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“…Tacrolimus is a substrate for CYP3A5 and it is well established that individuals carrying one or more *1 alleles have a higher tacrolimus CL and lower trough concentrations [11][12][13][14]17]. Several previous studies have highlighted the differences in CL/F and dose requirements for the CYP3A5*1 carriers compared with individuals with the CYP3A5*3/*3 genotype [24,[30][31][32][33][34]. In a study involving paediatric kidney transplant recipients, tacrolimus CL/F was about 50% higher in children with the CYP3A5*1/*1 or *1/*3 genotype as compared with the CYP3A5*3/*3 genotype [8].…”

Section: Figurementioning

confidence: 99%

Dosing equation for tacrolimus using genetic variants and clinical factors

Passey

Birnbaum

Brundage

et al. 2011

Brit J Clinical Pharma

151

163

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Patients with low tacrolimus troughs are at a higher risk of rejection while those with high troughs are at an increased risk for toxicity. Therefore, achieving the therapeutic range is important.• CYP3A5 genotype and days post transplant have been previously shown individually to be associated with tacrolimus troughs.WHAT THIS STUDY ADDS• This paper presents the first dosing model for tacrolimus using a combination of genetic and clinical factors in adult kidney transplant recipients. It was developed from one of the largest tacrolimus pharmacogenetic studies conducted to date (681 subjects and 11 823 trough concentrations).• We found that CL/F was significantly influenced by days post transplant, CYP3A5 genotype, transplantation at a steroid sparing centre, recipient age and the use of a calcium channel blocker.• Our large sample size enabled us to define the distinct differences in tacrolimus CL/F between three CYP3A5 genotype groups (*1/*1, *1/*3 and *3/*3).• This study is an important step towards using pharmacogenetic information in the clinical setting.AIM To develop a dosing equation for tacrolimus, using genetic and clinical factors from a large cohort of kidney transplant recipients. Clinical factors and six genetic variants were screened for importance towards tacrolimus clearance (CL/F).METHODS Clinical data, tacrolimus troughs and corresponding doses were collected from 681 kidney transplant recipients in a multicentre observational study in the USA and Canada for the first 6 months post transplant. The patients were genotyped for 2 724 single nucleotide polymorphisms using a customized Affymetrix SNP chip. Clinical factors and the most important SNPs (rs776746, rs12114000, rs3734354, rs4926, rs3135506 and rs2608555) were analysed for their influence on tacrolimus CL/F.RESULTS The CYP3A5*1 genotype, days post transplant, age, transplant at a steroid sparing centre and calcium channel blocker (CCB) use significantly influenced tacrolimus CL/F. The final model describing CL/F (l h−1) was: 38.4 ×[(0.86, if days 6–10) or (0.71, if days 11–180)]×[(1.69, if CYP3A5*1/*3 genotype) or (2.00, if CYP3A5*1/*1 genotype)]× (0.70, if receiving a transplant at a steroid sparing centre) × ([age in years/50]−0.4) × (0.94, if CCB is present). The dose to achieve the desired trough is then prospectively determined using the individuals CL/F estimate.CONCLUSIONS The CYP3A5*1 genotype and four clinical factors were important for tacrolimus CL/F. An individualized dose is easily determined from the predicted CL/F. This study is important towards individualization of dosing in the clinical setting and may increase the number of patients achieving the target concentration. This equation requires validation in an independent cohort of kidney transplant recipients.

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“…Some clinical factors and genetic factors play critical roles in determining TAC pharmacokinetics (PK) [9][10][11] . Tacrolimus is known to be transported by P-glycoprotein (MDR1 or ABCB1) and metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5.…”

Section: Introductionmentioning

confidence: 99%

“…There are also reports that polymorphisms in genes that participate in the pharmacodynamic (PD) pathway, including IL-2, IL-6, and IL-18, and genes involved in the immune system, for instance TLR4, can influence TAC pharmacokinetics [20][21][22] . The existing algorithms, including genetic and clinical factors, for TAC dose prediction only account for 40% to 60% of TAC dose variations [9,23] . The rest of the variations may be caused by unknown genetic factors that are involved in TAC pharmacodynamics, the immune system, or other related pathways.…”

Section: Introductionmentioning

confidence: 99%

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

Liu

Zhang

et al. 2017

Acta Pharmacol Sin

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The highly variable pharmacokinetics and narrow therapeutic window of tacrolimus (TAC) has hampered its clinical use. Genetic polymorphisms may contribute to the variable response, but the evidence is not compelling, and the explanation is unclear. In this study we attempted to find previously unknown genetic factors that may influence the TAC dose requirements. The association of 105 pathway-related single nucleotide polymorphisms (SNPs) with TAC dose-adjusted concentrations (C0/D) was examined at 7, 30 and 90 d post-operation in 382 Chinese kidney transplant recipients. In CYP3A5 non-expressers, the patients carrying the IL-3 rs181781 AA genotype showed a significantly higher TAC logC0/D than those with the AG genotype at 30 and 90 d post-operation (AA vs AG, 2.21±0.06 vs 2.01±0.03, P=0.004; and 2.17±0.06 vs 2.03±0.03, P=0.033, respectively), and than those with the GG genotype at 30 d (AA vs GG, 2.21±0.06 vs 2.04±0.03, P=0.011). At 30 d, the TAC logC0/D in the grouped AG+GG genotypes of CTLA4 rs4553808 was significantly lower than that in the AA genotype (P=0.041) in CYP3A5 expressers, but it was higher (P=0.008) in the non-expressers. We further validated the influence of CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437 on the TAC C0/D; other candidate SNPs were not associated with the differences in TAC C0/D. In conclusion, genetic polymorphisms in the immune genes IL-3 rs181781 and CTLA4 rs4553808 may influence the TAC C0/D. They may, together with CYP3A5 rs776746, CYP3A4 rs2242480 and rs4646437, contribute to the variation in TAC dose requirements. When conducting individualized therapy with tacrolimus, these genetic factors should be taken into account.

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Using Genetic and Clinical Factors to Predict Tacrolimus Dose in Renal Transplant Recipients

Cited by 44 publications

References 65 publications

Association Between Tacrolimus Concentration and Genetic Polymorphisms of CYP3A5 and ABCB1 During the Early Stage After Liver Transplant in an Iranian Population

Association Between Tacrolimus Concentration and Genetic Polymorphisms of CYP3A5 and ABCB1 During the Early Stage After Liver Transplant in an Iranian Population

Dosing equation for tacrolimus using genetic variants and clinical factors

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

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