MyDrugGenome

Rationale

This DGI pertains to the interaction between the cytochrome P450 3A5 (CYP3A5) gene and tacrolimus. Extensive literature indicates that patients with specific genetic differences in the CYP3A5 gene may require an increased dose of tacrolimus in order to prevent acute rejection in solid organ, stem cell, and bone marrow transplants.

Results Interpretation

Genetic Variant Information

The CYP3A5 gene encodes an enzyme that is involved in the metabolism of tacrolimus.  There are different CYP3A5 gene versions, or variants, and each has a different effect on how well tacrolimus works in the body.  The version termed *3 does not produce a functional CYP3A5 enzyme to metabolize tacrolimus.  The version termed *1 results in a functional CYP3A5 enzyme.  Patients who carry at least ONE copy of the *1 version in CYP3A5 may require a higher dose of tacrolimus to achieve therapeutic effect.  Studies have shown patients with a *1 CYP3A5 version may be at increased risk for acute transplant rejection while taking a standard dose of tacrolimus. (See Supporting Evidence)

Quality of Results

Genotyping for CYP3A5 was performed within a high complexity, certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement act of 1988. This validated clinical Laboratory Developed Test is carried out with strict adherence to protocols outlined by the College of American Pathology.  The performance of the assay is closely monitored and the accuracy of the results is determined to be  >98%.

Quality of Results for CYP3A5 Gene Variants

Supporting Evidence

Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers

Tang HL, Xie HG, Yao Y, Hu YF. Pharmacogenetics and Genomics. 2011;  21(11): 713–720

Background: CYP3A5 genetic polymorphisms contribute to marked interindividual differences in the metabolism of and response to tacrolimus in humans.

Objective: This study was aimed to clarify the impact of the CYP3A5*3 variant on tacrolimus dose requirements and acute rejection rates in patients with organ transplantation.

Methods: A literature search was performed up to August 2009 by using the Cochrane library, PubMed, Medline, and EMBase.

Results: Twenty-three studies (a total of 1779 patients) were included in this meta-analysis. Eighteen studies (1443 patients) were involved in renal transplantation and five studies (336 patients) in liver transplantation. Results of meta-analysis demonstrated that, in renal transplant patients, despite the presence of significant heterogeneity, CYP3A5 expressers required higher mean tacrolimus daily doses by 0.045 mg/kg (95% confidence interval (CI), 0.033–0.056) than nonexpressers. Furthermore, sub-analysis of the time of posttransplantation showed that CYP3A5 expressers required higher daily doses than nonexpressers by 0.010, 0.084, 0.041, 0.037, and 0.044 mg/kg at week 2, and at month 1, 3, 6, and 12, respectively. Subset analysis of the ethnicity of organ recipients indicated that mean tacrolimus daily doses were 0.056, 0.037, and 0.077 mg/kg higher in CYP3A5 expressers than non- expressers for white, Chinese, and Japanese patients, respectively. In contrast, for liver transplant patients, higher tacrolimus daily doses were required not only in CYP3A5 expressers of the organ donors than nonexpressers by 0.024 mg/kg (95% CI, 0.019–0.028), but also in CYP3A5 expresser of the organ recipients than nonexpresser by 0.012 mg/kg (95% CI, 0.005–0.018). However, a significant difference in the acute organ rejection rate was observed only at one month (odds ratio, 3.27; 95% CI, 1.57–6.81; P=0.002).

Conclusion: Tacrolimus daily dose requirements may vary with the presence of the CYP3A5*3 variant, ethnicity of the organ recipients, and the time of posttransplantation. In addition, the acute organ rejection rate may be higher in CYP3A5 expressers than nonexpressers over the first month after transplantation.Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.

Optimization of Initial Tacrolimus Dose Using Pharmacogenetic Testing

E Thervet, M A Loriot, S Barbier, et al. Clinical Pharmacology & Therapeutics (2010) 87, 6: 721–726

Abstract: Retrospective studies have demonstrated that patients who are expressors of cytochrome P4503A5 (CYP3A5) require a higher tacrolimus dose to achieve a therapeutic trough concentration (C₀). The aim of this study was to evaluate this effect prospectively by pretransplantation adaptation. We randomly assigned 280 renal transplant recipients to receive tacrolimus either according to CYP3A5 genotype or according to the standard daily regimen. The primary end point was the proportion of patients within the targeted C₀. Secondary end points included the number of dose modifications and the delay in achieving the targeted C₀. In the group receiving the adapted dose, a higher proportion of patients had values within the targeted C₀ at day 3 after initiation of tacrolimus (43.2% vs. 29.1%; P = 0.03); they required fewer dose modifications, and the targeted C₀ was achieved by 75% of these patients more rapidly. The clinical end points were similar in the two groups. Pharmacogenetic adaptation of the daily dose of tacrolimus is associated with improved achievement of the target C₀. Whether this improvement will affect clinical outcomes requires further evaluation.

The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients.

Haufroid V, Mourad M, Van Kerckhove V, Wawrzyniak J, De Meyer M, Eddour DC, Malaise J, Lison D, Squifflet JP, Wallemacq P.  Pharmacogenetics. 2004 Mar;14(3):147-54.

Abstract

Cyclosporine and tacrolimus are immunosuppressive drugs largely used in renal transplantation. They are characterized by a wide inter-individual variability in their pharmacokinetics with a potential impact on their therapeutic efficacy or induced toxicity. CYP3A5 and P-glycoprotein appear as important determinants of the metabolism of these drugs. The objective of this study was to investigate the effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood concentrations in stable transplant patients. Stable renal transplant recipients receiving cyclosporine (n = 50) or tacrolimus (n = 50) were genotyped for CYP3A5*3 and *6, and MDR1 C1236T, G2677T/A and C3435T. Dose-adjusted trough blood levels (ng/ml per mg/kg body weight) as well as doses (mg/kg body weight) required to achieve target blood concentrations were compared among patients according to allelic status for CYP3A5 and MDR1. Dose-adjusted trough concentrations were three-fold and 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1/*3 patients for tacrolimus and cyclosporine, respectively. In the case of tacrolimus, the difference was even more striking when considering CYP3A5*1/*1 patients showing dose-adjusted trough concentrations 5.8-fold lower than CYP3A5*3/*3 patients. For both drugs, no association was found between trough blood concentrations or dose requirement and MDR1 genotype. Multiple regression analyses showed that CYP3A5*1/*3 polymorphism explained up to 45% of the variability in dose requirement in relation to tacrolimus use. Given the importance of rapidly achieving target blood concentrations after transplantation, further prospective studies should consider the immediate post-graft period and assess the influence of this specific polymorphism. Beside non-genetic factors (e.g. steroids dosing, drugs interactions), CYP3A5 pharmacogenetic testing performed just before transplantation could contribute to a better individualization of immunosuppressive therapy.

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

Zheng H, Webber S, Zeevi A, Schuetz E, Zhang J, Bowman P, Boyle G, Law Y, Miller S, Lamba J, Burckart GJ. Am J Transplant. 2003 Apr;3(4):477-83.

Abstract

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.