Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients

Trofe‐Clark, Jennifer; Brennan, Daniel C.; West-Thielke, Patricia; Milone, Michael C.; Lim, Mary Ann; Neubauer, Robin; Nigro, V.; Bloom, Roy D.

doi:10.1053/j.ajkd.2017.07.018

Cited by 63 publications

(79 citation statements)

References 58 publications

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“…In expressers, CYP3A5 comprises ~50% of all CYP enzymes . African Americans are more likely than whites to be CYP3A5*1 expressers (rates of 0.76‐0.85 vs 0.25, respectively), and African Americans therefore may require higher doses of tacrolimus to achieve therapeutic trough levels . Although differences in CYP expression are well described, the use of preemptive CYP genotyping has not been routinely implemented in transplant centers.…”

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confidence: 99%

Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

et al. 2019

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INTRODUCTION One factor impacting tacrolimus interpatient variability is the presence of CYP3A5 polymorphisms. Low tacrolimus concentration-to-dose ratios (CDRs), or rapid metabolizers (RMs), have been associated with poor graft function outcomes and higher biopsy-proven acute rejection (BPAR) rates in a predominantly white population. Pretransplant CYP genotyping is not routinely conducted, and therefore only a small number of studies have assessed the use of tacrolimus CDRs as a surrogate for metabolism. We explored differences in outcomes between patients with low tacrolimus CDRs and high tacrolimus CDRs (i.e., nonrapid metabolizers [NRMs]) in a diverse patient population. OBJECTIVE To determine the relationship between tacrolimus CDRs and graft and patient outcomes in kidney transplant recipients at a large transplant center between 2006 and 2016. METHODS Inclusion criteria consisted of adult kidney transplant recipients who received rabbit antithymocyte globulin induction followed by a maintenance regimen of tacrolimus, mycophenolate, and prednisone. The primary end point was BPAR at 1 year. Secondary end points included graft survival, patient survival, and toxicities. Determination of clusters was conducted using the two-step cluster analysis with a defined two-cluster distribution. Kaplan-Meier survival curves were created using the log-rank test. RESULTS The NRM cluster consisted of 322 patients with a mean CDR of 2.91 ng/ml/mg. The RM cluster consisted of 932 patients with a mean CDR of 1.14 ng/ml/mg. The BPAR at 1 year posttransplant was 3.7% in the NRM cluster and 3.6% in the RM cluster (p=0.95). Death at 5 years was higher in the NRM group compared with the RM group for unknown reasons (p=0.03). Differences in the incidence of posttransplant toxicities were not statistically significant at any time point, except for increased rates of cutaneous cancer at 5 years and cardiovascular disease overall in the NRM group. CONCLUSION Tailoring tacrolimus therapy early posttransplant based on CDR is not supported by the findings in this study.

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confidence: 99%

Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

et al. 2019

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“…CYP3A5*1 expressers demonstrate approximately 30% higher tacrolimus peak compared to nonexpressers to achieve comparable trough levels. This wide fluctuation and swing in tacrolimus pharmacokinetics may explain the higher incidence of DGF in CYP3A5*1 expressers compared to nonexpresser . Expectedly, any evaluation of the impact of tacrolimus on DGF should consider the day of tacrolimus initiation.…”

Section: Discussionmentioning

confidence: 99%

Impact of CYP3A5 genomic variances on clinical outcomes among African American kidney transplant recipients

Asempa

Rebellato

Hudson

et al. 2017

Clinical Transplantation

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Little is known about the impact of CYP3A5 polymorphisms on transplantation outcomes among African American (AA) kidney transplant recipients (KTRs). To assess this issue, clinical outcomes were compared between AA CYP3A5*1 expressers and nonexpressers. This retrospective cohort study analyzed AA KTRs. Biopsy-proven acute rejection (BPAR), delayed graft function (DGF), glomerular filtration rate (GFR), infections, and tacrolimus dosing requirements were examined in 106 immunologically high-risk AA kidney transplant patients over a 2-year follow-up period. In CYP3A5*1 expressers compared to nonexpressers, the incidence of BPAR was significantly higher in the first 6 months (13% vs 0%; P = .016) compared to 24 months (13% vs 7%; P = .521). Tacrolimus total daily dose at first therapeutic level was significantly higher in CYP3A5*1 expressers (12 mg/day) compared to nonexpressers (8 mg/day; P < .001). Compared to CYP3A5*1 nonexpressers, DGF incidence was significantly higher among CYP3A5*1 expressers (27.6% vs 6.7%; P = .006). By contrast, median GFR was significantly higher in CYP3A5*1 expressers compared to nonexpressers (54.5 mL/min vs 50.0 mL/min; P = .003) at 24 months. The findings from this retrospective study suggest that AAs with CYP3A5*1 expression require 50% more tacrolimus and have an increased incidence of DGF and acute rejection.

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“…The main result of this study was that the genotype-guided TAC dose group increased the proportion of Thai KT patients with TAC [26][27][28] Further RCTs are needed to confirm an effect of the extended-release TAC formula on renal outcomes in different CYP3A5…”

Section: Discussionmentioning

confidence: 86%

“…An alternative approach is to either adjust the other immunosuppressive drugs so that high dose TAC could be avoided early in the time after transplantation or usage of other drugs, for example, diltiazem, that have interaction by decreasing TAC clearance resulting in the need for a lower TAC dosage. Additionally, recent studies demonstrated the distinct pharmacokinetics between extended‐release TAC and immediate‐release TAC formulas, therefore requiring different TAC doses in various CYP3A5 polymorphisms and ethnicities . Further RCTs are needed to confirm an effect of the extended‐release TAC formula on renal outcomes in different CYP3A5 genotypes.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype‐guided doses in renal transplantation patients

Anutrakulchai

Pongskul

Kritmetapak

et al. 2019

Brit J Clinical Pharma

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Aims Although cytochromeP450(CYP)3A5 gene polymorphism affects personalized tacrolimus doses, there is no consensus as to whether CYP3A5 genotypes should be determined to adjust the doses. The aims were to compare the therapeutic ranges and clinical outcomes between the conventional and genotype‐guided tacrolimus doses. Methods This randomized controlled study compared 63 cases of the conventional tacrolimus dose group (0.1 mg/kg/day) with 62 cases of the genotype‐guided doses group of 0.125, 0.1 and 0.08 mg/kg for CYP3A5*1/*1, *1/*3, and *3/*3 genotypes for the initial 3 days of kidney transplantation. After day 3, dose adjustment occurred in both groups to achieve therapeutic concentrations. Results The genotype‐guided group had an increased proportion of patients with tacrolimus concentrations in the therapeutic range at the steady state on day 3 (40.3 vs 23.8%, P = .048). A lower proportion of over‐therapeutic concentration patients was noted in the genotype‐guided group in the CYP3A5*3/*3 genotype (9.7 vs 27%, P = .013). Unexpectedly, more delayed graft functions (DGFs) were in the genotype‐guided group (41.9 vs 22.2%, P = .018) especially in the CYP3A5*1/*1 participants who might have had an aggravated DGF by a longer ischaemic time and higher serum donor creatinine levels than in the control group. There were no significant differences of glomerular filtration rates or graft or patient survivals over a median 37‐month follow‐up period. Conclusions Determination of the CYP3A5 genotype improved therapeutic range achievement. CYP3A5*1/*1 patients who have high risks of DGF should be closely monitored because of an increased risk of DGF and reduced glomerular filtration rate with high tacrolimus doses.

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Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients

Abstract: Registered at ClinicalTrials.gov, with study number NCT01962922.

Cited by 63 publications

References 58 publications

Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

Impact of CYP3A5 genomic variances on clinical outcomes among African American kidney transplant recipients

Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype‐guided doses in renal transplantation patients

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