Consequences of Genetic Polymorphisms for Sirolimus Requirements After Renal Transplant in Patients on Primary Sirolimus Therapy

Sirolimus (SRL) is a substrate for cytochromes P-450 3A and P-glycoprotein, the product of the MDR1 gene. We postulated that single nucleotide polymorphisms (SNPs) of these genes could be associated with inter-individual variations in SRL requirements. We then evaluated in 149 renal transplant recipients the effect of polymorphisms CYP3A4*1/*1B, CYP3A5*1/*3 and MDR1 SNPs in exon 12, 21 and 26 on SRL concentration/dose (C/D) ratio 3 months after sirolimus introduction. SRL C/D ratio was significantly higher in patients treated with calcineurin inhibitors. The CYP3A4*1B and CYP3A5*1 alleles were present in 17% and 21% of patients, respectively. When treated with a SRL-based therapy and low-dose steroids, patients carrying the CYP3A4*1B or the CYP3A5*1 alleles required significantly more SRL to achieve adequate blood trough concentrations (p < 0.01 and p < 0.02, respectively). None of the MDR1 SNPs was associated with the SRL concentration/dose ratio. These findings suggest that the variations in SRL requirements are secondary to both genetic and non-genetic factors including pharmacokinetic interactions. In patients with SRL-based therapy, genotyping of the CYP3As genes may help to optimize the SRL management in transplant recipients.     

Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients

BACKGROUND: A body-weight-based dose of tacrolimus often results in marked individual diversity of blood drug concentration. Tacrolimus is a substrate for cytochrome P450 (CYP) 3A5 and p-glycoprotein encoded by CYP3A5 and MDR1 (ABCB1), respectively, having multiple single nucleotide polymorphisms. In this study, we genotyped CYP3A5 A6986G, MDR1 G2677(A/T), and C3435T polymorphisms and investigated the association between these polymorphisms and the pharmacokinetics of tacrolimus in renal transplant recipients. METHODS: Thirty consecutive recipients were enrolled in this study. The pharmacokinetics of tacrolimus was analyzed on day 28 after transplant, when the daily dose was adjusted to the target trough level of 10-15 ng/mL. The polymerase chain reaction-restriction fragment length polymorphism and direct sequence method were used for genotyping the CYP3A5 and MDR1 polymorphisms, respectively. RESULTS: The single tacrolimus dose per body weight was significantly higher in CYP3A5 *1 carriers than CYP3A5 *3/*3 carriers (0.143+/-0.050 vs. 0.078+/-0.031 mg/kg, P<0.001). The dose-adjusted trough level and the area under the concentration-time curve (AUC0-12) were significantly lower in CYP3A5 *1 carriers than CYP3A5 *3/*3 carriers (0.040+/-0.014 vs. 0.057+/-0.024 ng/mL/mg/kg, P=0.015 and 0.583+/-0.162 vs. 0.899+/-0.319 ng.hr/mL/mg/kg, P=0.004), respectively. The MDR1 polymorphism was not associated with any pharmacokinetic parameters. CONCLUSIONS: Kidney transplant recipients with the CYP3A5 *1 allele required a higher daily tacrolimus dose compared with those with the CYP3A5 *3/*3 genotype to maintain both the target trough level and AUC0-12, suggesting that this polymorphism is useful for determining the appropriate dose of tacrolimus.     

Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation

OBJECTIVE: Tacrolimus is an immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp, encoded by MDR1) play an important role in the absorption and metabolism of tacrolimus. The objective of this study was to evaluate whether or not CYP3A5*1/*3 or MDR1 C3435T polymorphisms are associated with the tacrolimus concentration per dose. METHODS: CYP3A5 and MDR1 genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis in 118 Chinese renal transplant patients receiving tacrolimus. Whole blood trough tacrolimus concentration was measured by enzyme-linked immunosorbent assay and dose-adjusted concentration (ng/mL per mg/kg/d) was calculated at 1 wk, 1 month, and 3 months after transplantation. RESULTS: The dose-adjusted concentration of CYP3A5*1/*1 and *1/*3 patients was significantly lower than *3/*3 patients (32.8 +/- 17.7 and 41.6 +/- 15.8 vs. 102.3 +/- 51.2 at 1 wk; 33.1 +/- 7.5 and 46.4 +/- 12.9 vs. 103 +/- 47.5 at 1 month; 35.3 +/- 20.9 and 59.0 +/- 20.6 vs. 150 +/- 85.3 at 3 months after transplantation respectively). At 1 wk, 46% of the CYP3A5*1 allele carriers had a tacrolimus concentration lower than 5 ng/mL and 77% lower than 8 ng/mL, whereas 20% of the *3/*3 patients had a concentration higher than 20 ng/mL. There was a mild difference between *1/*1 homozygotes and *1/*3 heterozygotes at 1 and 3 months after transplantation. No difference was found among the MDR1 genotypes. CONCLUSION: CYP3A5*1/*3 polymorphisms are associated with tacrolimus pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods could be employed prospectively to help initial dose selection and to individualize immunosuppressive therapy.     

Impact of CYP3A5 and MDR1(ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients

OBJECTIVE: The objective of this study was to assess the influence of CYP3A5 and MDR1 genetic polymorphisms on tacrolimus pharmacokinetics in Japanese renal transplant recipients. METHOD: The pharmacokinetic parameters of tacrolimus were calculated in steady-state on day 28 after transplantation. Polymerase chain reaction-restriction fragment length polymorphism and direct sequence methods were used for CYP3A5 and MDR1 polymorphisms, respectively. RESULTS: The dose-adjusted area under the concentration-time curve (AUC0-12) was significantly lower among CYP3A5*1 carriers than those bearing CYP3A5*3/*3. (0.570 +/- 0.105 vs 0.865 +/- 0.343 ng.h/mL per mg/kg, P = .00322). The daily tacrolimus dose per body weight was significantly higher in CYP3A5*1 carriers than those of CYP3A5*3/*3 carriers (0.271 +/- 0.110 vs 0.150 +/- 0.056 mg/kg, P = .00016). In this study, a distinction was made between carriers of CYP3A5*1/*1+*1/*3 and CYP3A5*3/*3 to investigate the influence of the MDR1 C3435T mutation on tacrolimus pharmacokinetics. The MDR1 C3435T polymorphisms did not affect any tacrolimus pharmacokinetic parameter in either group. CONCLUSIONS: Renal transplant recipients who were CYP3A5*1 carriers required a higher dose of tacrolimus than CYP3A5*3/*3, indicating a significantly lower dose-adjusted AUC0-12 of tacrolimus. In contrast, MDR1 C3435T polymorphism was not an important factor in tacrolimus pharmacokinetics.     

Influence of CYP3A5 and MDR1(ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in Chinese renal transplant recipients

The aims of this study were to investigate the influence of CYP3A5 and MDR1 genetic polymorphisms on tacrolimus pharmacokinetics in Chinese renal transplant recipients, so as to help rational administration in clinical practice. We calculated pharmacokinetic parameters of tacrolimus from blood concentrations in steady state at day 28. Polymerase chain reaction restriction fragment length polymorphisms were used for CYP3A5 and MDR1 analysis. The results showed that the dose-adjusted area under the concentration time curve (AUC_0-12) and renal clearance showed a significant difference between CYP3A5*1 carriers and the CYP3A5*3/*3 genotype (P < .01). In the following study, a distinction was made between carriers of CYP3A5*1/ vs CYP3A5*3/*3 seeking to investigate the influence of the MDR13435T>C polymorphism on tacrolimus pharmacokinetics. MDR1 3435T>C polymorphism did not affect any tacrolimus pharmacokinetic parameter in either group. Renal transplant recipients who were CYP3A5*1 carriers required a higher dose of tacrolimus than CYP3A5*3/*3, indicating a significantly lower dose-adjusted AUC_0-12 of tacrolimus. In contrast, MDR1 3435T>C polymorphism was not an important factor in tacrolimus pharmacokinetics. Pharmacogenetic methods may be used prospectively to aid dose selection and individualize immunosuppressive therapy.     

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

Tacrolimus is a substrate for P-glycoprotein (P-gp) and cytochrome (CYP) P4503A. P-gp is encoded by the multiple drug resistance gene MDR1 and CYP3A is the major enzyme responsible for tacrolimus metabolism. Both MDR1 and CYP3A5 genes have multiple single nucleotide polymorphisms. The objective of this study was to evaluate whether the MDR1 exon21 and exon26 polymorphisms and the CYP3A5 polymorphism are associated with tacrolimus disposition in pediatric heart transplant patients. At 3, 6 and 12 months post transplantation, a significant difference in tacrolimus blood level per dose/kg/day was found between the CYP3A5 *1/*3 (CYP3A5 expressor) vs. *3/*3 (nonexpressor) genotypes with the *1/*3 patients requiring a larger tacrolimus dose to maintain the same blood concentration. There were no significant differences in tacrolimus blood level per dose/kg/day between MDR1 exon21 G2677T and exon 26 C3435T at 3 months, but both were found to have a significant association with tacrolimus blood level per dose/kg/day at 6 and 12 months. We conclude that specific genotypes of MDR1 and CYP3A5 in pediatric heart transplant patients require larger tacrolimus doses to maintain their tacrolimus blood concentration, and that this information could be used prospectively to manage patient's immunosuppressive therapy.     

Tacrolimus dose requirement in relation to donor and recipient ABCB1 and CYP3A5 gene polymorphisms in Chinese liver transplant patients.

The aim of this study was to investigate whether the heterogeneity in tacrolimus dose requirement is associated with ABCB1 and CYP3A5 gene polymorphisms in Chinese liver transplant patients during the first month after transplantation. ABCB1 and CYP3A5 genotyping was performed using the polymerase chain reaction restriction sites polymorphism-based procedure in Chinese liver transplant recipients (n = 50) and their corresponding donors (n = 50). Tacrolimus whole-blood trough concentrations were measured by immunoassays on the IMx analyzers (Abbott Diagnostics Laboratories, Abbott-Park, IL). Doses required to achieve target blood concentrations and dose-adjusted trough concentrations (concentration/dose [C/D] ratios) were compared among patients according to allelic status of ABCB1 and CYP3A5. The ABCB1 3435CC was observed in 23 subjects (23%), whereas 64 (64%) carried 3435CT and 13 (13%) carried 3435TT. The CYP3A5*1/*1 was observed in 13 subjects (13%), 50 (50%) carried *1/*3, and 37 (37%) carried*3/*3. The tacrolimus C/D ratios were obviously lower in recipients carrying ABCB1 3435CC genotype. For CYP3A5, recipients who received organs from CYP3A5*3/*3 donors had higher C/D ratios. But the donors' ABCB1 and recipients' CYP3A5 genotype did not affect the recipients' pharmacokinetics. Analysis of the combination of recipients' ABCB1 and donors' CYP3A5 genotypes revealed that the tacrolimus C/D ratios were significantly lower in the ABCB1 3435CC-carrying recipients, regardless of donors' CYP3A5 genotype. In conclusion, our finding suggests that the recipients' ABCB1 and donors' CYP3A5 genotype affect the tacrolimus dose requirements. ABCB1 C3435T polymorphism is a major determinant of tacrolimus trough concentration in Chinese liver transplant recipients, and recipients with 3435CC genotype will require higher dose of tacrolimus.     

Impact of cytochrome P450 3A and ATP-binding cassette subfamily B member 1 polymorphisms on tacrolimus dose-adjusted trough concentrations among Korean renal transplant recipients

Background

Tacrolimus is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), encoded by the CYP3A and ATP-binding cassette subfamily B member 1 (ABCB1) genes, respectively. This study was aimed to investigate the impact of CYP3A and ABCB1 polymorphisms on the tacrolimus pharmacokinetics and clinical outcomes in Korean renal transplant recipients.

Methods

We analyzed data from a cohort of 70 renal transplant recipients receiving tacrolimus. CYP3A4*4, CYP3A4*5, CYP3A4*18, CYP3A5*3, ABCB1 C1236>T, ABCB1 G2677>T/A, and ABCB1 C3435>T polymorphisms were genotyped and correlated to dose-adjusted tacrolimus trough concentration at months 1, 3, 6, and 12 after transplantation.

Results

Patients with the CYP3A5*3 alleles showed higher dose-adjusted tacrolimus concentrations for 12 months and higher trough levels until 6 months after transplantation. ABCB1 polymorphisms and haplotypes were not associated with tacrolimus concentrations. In a multivariate analysis, the presence of ≥1 CYP3A5*3 allele was a significant independent variable affecting dose-adjusted tacrolimus concentrations. Glomerular filtration rate, acute rejection, opportunistic infection, and graft survival were not affected by CYP3A5 polymorphisms. Calcineurin inhibitor toxicity, which showed higher tendency in patients with CYP3A5*1 alleles, might be associated with higher tacrolimus dose per kilogram.

Conclusions

The CYP3A5 genotype is a major factor in determining the dose requirement of tacrolimus, and genotyping may be of value in individualization of immunosuppressive therapy of renal transplant patients.     

Genetic polymorphisms of CYP3A5 genes and concentration of the cyclosporine and tacrolimus

OBJECTIVE: CYP3A is the major enzyme responsible for metabolism of the calcineurin inhibitors cyclosporine (CsA) and tacrolimus. Our objective was to determine the relationship between genetic polymorphisms of CYP3A5 with respect to interindividual variability in CsA and tacrolimus pharmacokinetics. METHODS: Kidney transplant recipients receiving CsA (n = 137) or tacrolimus (n = 30) were genotyped for CYP3A5*3 and *6 by a PCR/RFLP method. The patients were grouped according to the CYP3A5 genotype. Dose-adjusted trough levels were correlated with the corresponding genotype. RESULTS: At 3, 6, and 12 months, the tacrolimus dose-adjusted trough levels (dose-adjusted C0) showed a statistically significant difference between the group of CYP3A5*3/*3 (n = 19) and the group of CYP3A5*1 allele carriers. The former was higher than the latter. The CsA dose-adjusted C0 and the actual C0 did not display a significant relation (P < .05) between the group of CYP3A5*3/*3 and the group of CYP3A5*1 allele carriers. CONCLUSION: Patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target concentrations compared to those with the CYP3A5*1 allele.     

受者CYP3A5基因多态性对肾移植术后早期血他克莫司浓度的影响

目的 研究细胞色素P450 3A酶系中CYP3A5基因多态性对肾移植术后早期血他克莫司(Tac)浓度的影响.方法 90例肾移植患者均采用Tac、霉酚酸酯和泼尼松预防排斥反应.患者于术后第2～3天开始口服Tac,初始剂量为0.15 mg·kg-1·d-1.用酶联免疫吸附试验法测定血Tac浓度谷值,记录术后1个月内的数据,并据此调整药物剂量,使Tae浓度谷值维持在5～10μg/L.根据患者服用Tac的剂量,计算浓度/剂量比值(C/D),并记录患者每日血肌酐的下降速度.用聚合酶链反应-限制性片段长度多态性法进行CYP3A5基因多态性的检测.结果 CYP3A5基因型为野生型纯合子(*1/*1型)者9例,突变型纯合子(*3/*3型)者41例,突变型杂合子(*1/*3)者40例.*3/*3型者的初次Tac浓度谷值为(9.8±3.1)μg/L,明显高于基因型为*1/*1型和*1/*3型者(P＜0.05,P＜0.05).术后2周内,*3/*3型者的C/D最高,*1/*3型者次之,*1/*1型者最低.前者与后二者相比较,差异有统计学意义(P＜0.05,P＜0.05).术后第1周,*3/*3型者血肌酐的下降速度最快,每天下降(127.4±59.6)μmol/L,高于*1/*3型者和*1/*1型者(P＜0.05,P＜0.05).结论 CYP3A5基因型对肾移植术后1个月内血Tac的浓度谷值有一定影响.     

CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines from an Experimental Study

Genetic polymorphisms in biotransformation enzyme CYP3A5 (6986G > A, CYP3A5*3; 14690A > G, CYP3A5*6) and drug transporter ABCB1 (1236C > T; 2677G > T/A; 3435C > T) are known to influence tacrolimus (Tac) dose requirements and trough blood levels in stable transplant patients. In a group of 19 volunteers selected with relevant genotypes among a list of 221 adult renal transplant candidates, we evaluated whether consideration of CYP3A5 and ABCB1 genetic polymorphisms could explain the interindividual variability in Tac pharmacokinetics after the first administration of a standard dose (0.1 mg/kg body weight twice a day). Lower area under the time versus blood concentration curves (AUC) or lower trough concentrations were observed among CYP3A5 expressors (n = 9) than among nonexpressors (n = 10) using two different analytical methods for Tac determination (liquid chromatography with tandem mass spectrometry (LC-MS/MS) and immunoassay). The median AUC(0-infinity) was 2.6- and 2.1-fold higher in nonexpressors for LC-MS/MS and immunologic methods, respectively. No difference was observed in Tac pharmacokinetic parameters in relation to ABCB1 polymorphisms. In conclusion, our study confirms the very significant effect of CYP3A5 polymorphism early after the first administration of Tac. It also provides a strong argument for a doubling of the loading dose in patients early identified a priori on the transplantation list as possessing at least one CYP3A5*1 allele.     

Genetic polymorphisms and individualized tacrolimus dosing

Background

Genetic polymorphisms of metabolism enzymes or intestinal drug transporters may affect pharmacokinetic responses to immunosuppressive drugs in renal transplant recipients. We sought to identify the frequency of genetic polymorphisms and their importance for individualization of tacrolimus doses.

Patients and Methods

We performed an observational study in 35 renal transplant recipients treated with tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus concentrations were determined by immunoanalysis (IMx method; Abbott Diagnostics, Abbott Park, Ill), on 11 blood samples per patient during the first 6 weeks after renal transplantation. For each patient, we calculated the mean value and its standard error (SEM) of the concentration/dose ratio (ng/mL/mg) of tacrolimus. The pharmacogenetic analysis included single nucleotide polymorphisms (SNPs) in the CYP3A5 (CYP3A5*3 (A6986G), CYP3A5*6 (G14690A), MDR1 (C3435T and G2677T/A) and PXR (C-25385T) genes.

Results

Of the patients, 62.8% (n = 22) were men and the overall mean age was 55 years (95% confidence interval, 48.7-62.7). The SNP distribution was: CYP3A5*3: G/G = 82.9%, A/G = 17.1%; CYP3A5*6: G/G = 88.6%, G/A = 11.4%; MDR1 C3435T: C/C = 25.7%, C/T = 62.9%, T/T = 11.4%; for MDR1 G2677T/A: G/G = 22.9%, G/T = 65.7%, T/T = 11.4% and for PXR: C/T = 85.7%, T/T = 14.3%. Tacrolimus concentration/dose ratios in heterozygote patients for CYP3A5*3 genotypes was >120% lower than for the homozygote CYP3A5*3 genotype (0.65 ± 0.04 vs 1.45 ± 0.05; P < .0001). Wild-type MDR1 (3435 C/C) genotype patients showed up to 40% lower concentration/dose ratios compared with heterozygote and homozygote genotypes (C/C; 1 ± 0.07 vs C/T; 1.4 ± 0.06 vs T/T; 1.37 ± 0.09; P < .0001).

Conclusion

Intestinal absorption and metabolism of tacrolimus was significantly affected by the SNPs in the CYP3A5 and MDR1 genes, which may offer a useful tool to optimize tacrolimus dosing after renal transplantation.     

Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation

We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C(0) )/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C(0) /dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28±26.45, 59.12±24.00, 62.43±41.12, and 57.01±17.34 vs. 112.37± 76.60, 123.21±59.57, 163.34±76.23, and 183.07±107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose-corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01±17.34 vs. 100.09±24.78; P=0.016). Only the ABCB1 TGC (3435-2677-1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR=4.73; CI: 1.3-16.7; P=0.02). Our findings indicate that the CYP3A4*1B-CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.     

肾移植受者CYP3A5基因多态性对术后他克莫司药物代谢的影响

目的 研究肾移植受者细胞色素P450 3A(CMP3A)酶系中的CYP3A5基因多态性对术后他克莫司(Tac)药物代谢的影响,并探讨测定CYP3A5基因型的方法 .方法 选取97例肾移植术后常规使用Tac+吗替麦考酚酯+泼尼松三联免疫抑制方案的受者.用焦磷酸测序法测定受者CYP3A5基因型;用均相酶扩大免疫分析法(EMIT)测定受者全血Tac浓度谷值(C0);比较不同基因型的受者肾移植术后第7天、第14天、1个月、3个月和6个月时的Tac C0,与Tac校正剂量的比值(Tac G0/Tac校正剂量).结果 焦磷酸测序法能够快速准确的测定肾移植受者CYP3A5基因型;97例肾移植受者CYP3A5基因型分别为:CYP3A5+1/*1型17例(17.5%),CYP3A5* 1/*3型35例(36.1%),CYP3A5*3/*3型45例(46.4%).CYP3A5*1/*1型和CYP3A5*1/*3型受者肾移植术后Tac G0/Tac校正剂量均显著低于CYP3A5*3/*3型受者.结论 肾移植受者CYP3A5基因型对Tac药物代谢具有显著的影响.采用焦磷酸法测定肾移植受者CYP3A5基因多态性,有助于确定不同个体移植术后理想的Tac起始剂量,实现Tac个体化用药.     

Influence of CYP3A5 gene polymorphisms of donor rather than recipient to tacrolimus individual dose requirement in liver transplantation

BACKGROUND: Tacrolimus is a widely used immunosuppressant in organ transplantation, but it is characterized by a narrow therapeutic index and high interindividual variations of its pharmacokinetics. Tacrolimus is a substrate for CYP3A. It has been conjectured that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations. The objective of this study was to evaluate the contribution of polymorphisms of the donor and recipient CYP3A5 gene on tacrolimus disposition in liver transplantation. METHODS: Fifty-three liver transplant recipients treated with tacrolimus were enrolled in this study. Tacrolimus dosage and blood trough concentration were investigated at 1 week, 2 weeks, and 1 month after transplantation. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was applied to determine the genotype of CYP3A5 gene. RESULTS: The concentration/dose (C/D) ratios in patients with *1/*1(*1/*3) genotype donor were significantly lower than in patients with *3/*3 genotype donor at 2 weeks (P = 0.036) and 1 month (P = 0.021), but not at 1 week posttransplantation. Combination analysis showed that such significance still existed between CYP3A5 expressor group and nonexpressor group for both donor and recipient genotype. Also differences of C/D ratio between CYP3A5 expressor and nonexpressor donors in nonexpressor recipients were larger than those between recipients in nonexpressor donors. CONCLUSION: The large interindividual variation of tacrolimus dose requirement is influenced by the metabolic activity of CYP3A5. Polymorphisms of the donor CYP3A5 gene seem to contribute more to such variation than the recipient. A larger population and further studies are needed to explore the exact mechanisms for tacrolimus pharmacokinetics.     

Pharmacogenetics of tacrolimus and sirolimus in renal transplant patients: from retrospective analyses to prospective studies

The promises of pharmacogenetics are to elucidate the inherited basis of differences between individual responses to drugs in order to identify the right drug and dose for each patient. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters led to the hypothesis that genetic factors may be implicated in the interindividual variability of the pharmacokinetic or pharmacodynamic characteristics of immunosuppressive drugs, major side effects, and efficacy. The purpose of this study was to provide a short overview of recent results obtained in the field of pharmacogenetics of tacrolimus and sirolimus, both substrates of the cytochrome P450 3A (CYP3A) enzymes and of the efflux pump P-glycoprotein, the product of the Multidrug Resistance-1 (MDR1) genes. A number of retrospective studies that demonstrated a link between the polymorphisms governing the CYP3A5 protein expression, with more conflicting results with the MDR1 gene polymorphisms, related to the daily dose necessary to achieve adequate blood tacrolimus levels. The CYP3A5 polymorphisms have also been associated with sirolimus pharmacokinetics. One challenge is to investigate the combined effect of a number of different polymorphisms in various genes to define genetic backgrounds with different pharmacokinetic profiles using high throughput technologies. Another challenge is to move toward prospective randomized studies to explore whether a pharmacogenetic approach, taking into account a limited number of polymorphisms prior to drug treatment, could be used on an individual basis to guide initial dosing of a given drug. The last challenge is based on "target" pharmacogenetics to investigate the role of the polymorphisms of other genes implicated in the efficacy and/or safety of the drug.     

Higher number of tacrolimus dose adjustments in kidney transplant recipients who are extensive and intermediate CYP3A5 metabolizers

Kidney transplant recipients carrying the CYP3A5*1 allele have lower tacrolimus troughs, and higher dose requirements compared to those with the CYP3A5*3/*3 genotype. However, data on the effect of CYP3A5 alleles on post-transplant tacrolimus management are lacking. The effect of CYP3A5 metabolism phenotypes on the number of tacrolimus dose adjustments and troughs in the first 6 months post-transplant was evaluated in 78 recipients (64% Caucasians). Time to first therapeutic concentration, percentage of time in therapeutic range (TTR), and estimated glomerular filtration rate (eGFR) were also evaluated. Fifty-five kidney transplant recipients were CYP3A5 poor metabolizers (PM), 17 were intermediate metabolizers (IM), and 6 were extensive metabolizers (EM). Compared to PMs, EMs/IMs had significantly more dose adjustments (6.1 vs. 8.1, p = .015). Overall, 33.82% of trough measurements resulted in a dose change. There was no difference in the number of tacrolimus trough measurements between PMs and EM/IMs. The total daily tacrolimus dose requirements were higher in EMs and IMs compared to PMs (<.001). TTR was ∼50% in the PMs and EMs/IMs groups. CYP3A5 EM/IM metabolizers have more tacrolimus dose changes and higher dose requirements which increases clinical management complexity. Larger studies are needed to assess the cost and benefits of including genotyping data to improve clinical management.     

Impact of ABCB1 (MDR1) haplotypes on tacrolimus dosing in adult lung transplant patients who are CYP3A5 *3/*3 non-expressors

BACKGROUND: The influence of ABCB1 (MDR1) polymorphisms on tacrolimus dosing has been questioned in previous studies with contradictory findings, possibly due to the association between CYP3A5 polymorphisms and tacrolimus dosing. The objective of this study was to assess the effect of ABCB1 haplotypes from 3 distinct polymorphic sites on the tacrolimus level/dose [L/D] in lung transplant patients limited to CYP3A5 *3/*3 non-expressors. METHOD: A total of 91 lung transplant patients treated primarily with tacrolimus and prednisone were enrolled, and clinical information on drug dosing and blood levels was collected. The [L/D] was calculated for patients receiving tacrolimus at 1, 3, 6, 9 and 12 months post transplant. ABCB1 polymorphisms at C1236T, G2677T, and C3435T were assessed by PCR amplification and DNA sequencing. Haplotypes were estimated by Arlequin ver.2.00. Haplotype effects on tacrolimus [L/D] were assessed by two-way ANOVA. RESULTS: Of the 10 haplotypes, CGC, TTT and CGT accounted for 44.1%, 40.7% and 7.6% of the total haplotypes, respectively. The tacrolimus [L/D] value in the CGC-CGC patients was significantly lower than in patients with CGC-TTT and TTT-TTT genotypes at the first month (mean [L/D]=1.45 versus 3.10 and 3.97 ngxmL(-)(1) /mg/day), and throughout the first post transplant year. CONCLUSION: This study demonstrates that ABCB1 haplotypes derived from three common polymorphisms are associated with tacrolimus dosing in lung transplant patients when eliminating the confounder CYP3A5 genotype.     

肾移植术后他克莫司神经毒性与CYP3A5基因多态性的相关性研究

目的 总结CYP3A5基因多态性检测与肾移植患者术后他克莫司神经系统毒性的相关性.方法 回顾性分析我院2017年至2020年116例肾移植术后应用他克莫司的患者.采用DNA直接测序法检测患者CYP3A5基因多态性,观察不同基因的患者术后不同时间段的他克莫司药物浓度及神经毒性反应.结果 肾移植术后使用他克莫司的患者神经毒...     

Effect of CYP3A5 Genotype on Renal Allograft Recipients Treated With Tacrolimus

Objective

Tacrolimus concentrations are associated with CYP3A5 genotype. The purpose of this study was to evaluate the outcomes and drug concentrations/doses among a posttransplant population with various CYP3A5 genotypes within 12 months.

Methods

Sixty seven kidney recipients receiving immunosuppression with tacrolimus + mycophenolate mofetil + prednisolone were grouped according to their CYP3A5 genotypes (*1/*1; *1/*3; *3/*3). The initial dose of tacrolimus (0.15 mg/kg/d) was adjusted according to achieve a target therapeutic window. All patients underwent a protocol biopsy at 1 month posttransplantation. We assayed serum creatinine and tacrolimus blood trough concentrations to calculate the concentration per dosage during follow-up. We also investigated the incidence of acute rejection episodes and the nephrotoxicity of tacrolimus according to the renal biopsy.

Results

There was no significant difference among serum creatinine concentrations. Tracrolimus blood concentrations showed a significant difference at day 7 and 1 month with no significant difference at 3, 6, or 12 months among the three groups. The CYP3A5*3/*3 group showed the largest concentration per dosage (C/D) and CYP3A5*1/*1, the smallest C/D. There was a significant difference among the three groups. The occurrence of an acute rejection episode within 3 months showed a significant difference among the three groups but not from 3 to 12 months after transplantation. Nephrotoxicity was greatest among the CYP3A5*3/*3 group.

Conclusion

CYP3A5 influenced the blood concentrations of tacrolimus. Our study suggested to choose the initial dosage according to the CYP3A5 genotype to obtain a better outcome and reduce the incidences of acute rejection episodes and nephrotoxicity.