CYP3A5 gene polymorphisms and their impact on dosage and trough concentration of tacrolimus among kidney transplant patients: a systematic review and meta-analysis

Khan, Abdul Rafay; Raza, Ali; Firasat, Sadaf; Abid, Aiysha

doi:10.1038/s41397-019-0144-7

Cited by 42 publications

(40 citation statements)

References 36 publications

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“…In a recently published meta-analysis, the effect-size of CYP3A5 polymorphism on the risk of rejection was estimated in Asian and European kidney transplant populations (Khan et al, 2020). In European populations no significant association was found with rejection episodes between expressers and nonexpressers (OR: 1.12; p = 0.47).…”

Section: Cyp3a5 and Outcomementioning

confidence: 99%

The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

et al. 2020

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Tacrolimus is metabolized by CYP3A4 and CYP3A5 enzymes. Patients expressing CYP3A5 (in Caucasian patients about 15% of the population but more frequent in African Americans and Asians) have a dose requirement that is around 50% higher than non-expressers to reach the target concentration. CYP3A5 expressers can be considered fast metabolizers. The trough concentration/dose (C 0 /D) ratio of tacrolimus has recently been proposed as a prognostic marker for poor outcome after kidney transplantation. Patients with a low C 0 /D ratio (also referred to as fast metabolizers) seem to have more tacrolimus-related nephrotoxicity, more BK-viremia, and a lower graft survival. At first sight, the expression of CYP3A5 and a low C 0 /D ratio seem to be overlapping factors, both pointing towards patients in whom a higher tacrolimus dose is needed to reach the tacrolimus target concentration. However, there are important differences, and these differences may explain why the impact of the C 0 /D ratio on long term outcome is stronger than for CYP3A5 genotype status. Patients with a low C 0 /D ratio require a high tacrolimus dose and are exposed to high tacrolimus peak concentrations. The higher peak exposure to tacrolimus (and/or its metabolites) may explain the higher incidence of nephrotoxicity, BK-viremia and graft loss. A potential confounder is the concurrent maintenance treatment of corticosteroids, as steroids are sometimes continued in patients at high immunological risk. Steroids induce the metabolism of tacrolimus via pregnane X receptor mediated increased CYP3A4 expression, resulting in lower tacrolimus C 0 /D ratio in high risk patients. Also non-adherence may result in lower C 0 /D ratio which is also associated with poor outcome. The C 0 /D ratio of tacrolimus does seem to identify a group of patients with increased risk of poor outcome after kidney transplantation. Our recommendation is to monitor tacrolimus peak concentrations in these patients, and if these are high then target slightly lower pre-dose concentrations. Another possibility would be to switch to a prolonged release formulation or to dose the drug more frequently, in smaller doses, to avoid high peak concentrations.

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Section: Cyp3a5 and Outcomementioning

confidence: 99%

The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

et al. 2020

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“…For these subpopulations, LCPT may be useful because of its specific pharmacogenomic characteristics affecting pharmacokinetics of tacrolimus. [2][3][4][5][6][10][11][12] LCPT appears to be a cost-effective strategy, given the relatively low ICER values. In general, when a decision maker's WTP for 1 additional successfully treated patient exceeds the ICER, the technology should be reimbursed and made available.…”

Section: Discussionmentioning

confidence: 99%

“…2 Since release of the current clinical guidelines by the Kidney Disease Improving Global Outcomes in 2009, advances in sequencing technologies and a growing body of genome-wide association studies have identified genotypes affecting CYP3A enzymes associated with pharmacokinetic differences in tacrolimus-centered immunosuppression that should be considered when prescribing. 2 Black patients are much more likely than Caucasian patients to express the CYP3A5*1 wild-type allele associated with increased tacrolimus clearance and variability (ie, rapid metabolizers), [2][3][4][5][6] and they may also experience low drug levels immediately following transplantation, delaying therapeutic tacrolimus levels. 7 Because of this enzyme, Black patients often need higher doses to reach therapeutic levels, which leads to higher peak concentrations of tacrolimus.…”

Section: What This Study Addsmentioning

confidence: 99%

“…4,6,[10][11][12] Prevalence of the CYP3A5*1 expression is also higher in East Asian populations-specifically Chinese, Japanese, and Korean-than in European populations. 3,5 Orally administered tacrolimus is available as an immediate-release capsule taken twice daily (IR-Tac; Prograf, Astellas Pharma US, Inc.); an extended-release capsule taken once daily (Astagraf XL, Astellas Pharma US, Inc., and Advagraf abroad); and an extended-release tablet taken once daily (LCPT; Envarsus XR, Veloxis Pharmaceuticals, Inc.). LCPT employs a MeltDose drug delivery technology that uses small particle size to alter pharmacokinetic properties, resulting in increased bioavailability and broader absorption in the gastrointestinal tract with a lower peak and less peak-to-trough fluctuation compared with IR-Tac.…”

Section: What This Study Addsmentioning

confidence: 99%

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Cost-effectiveness of once-daily vs twice-daily tacrolimus among Hispanic and Black kidney transplant recipients

Hurwitz

Grizzle

Tyler³

et al. 2021

JMCP

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BACKGROUND:Tacrolimus is a first-line immunosuppressive therapy to prevent rejection and graft failure in kidney transplant recipients. Once-daily extended-release tacrolimus tablets (LCPT) have been shown to be efficacious, particularly for Hispanic and Black patient subpopulations who are rapid metabolizers, but is more costly than twice-daily immediate-release tacrolimus (IR-Tac). OBJECTIVE:To evaluate the cost-effectiveness of LCPT during the first year of treatment vs IR-Tac in kidney transplant recipients who are Hispanic or Black. METHODS:A decision analytic model from a US payer perspective was developed using (1) subgroup outcomes data pooled from two phase 3 clinical trials that compared LCPT and IR-Tac, and (2) direct costs from real-world data sources (ie, costs of LCPT and IR-Tac treatments, biopsy-proven acute rejection, treatment-related serious adverse events [SAEs], graft failure, and consequent dialysis). The primary outcome was cost per successfully treated patient, defined as having a functioning graft after 1 year and without treatment-related SAEs. Probabilistic sensitivity analyses established distributions for cost and outcomes estimates, and a series of one-way sensitivity analyses identified parameters that had the most effect on results.

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“…We instead used the C/D ratio, which is more practical than pharmacogenetic testing for identifying rapid metabolizers. Several studies have demonstrated the utility of the C/D ratio for classifying patients and exploring the relationship between the C/D ratio and outcomes [ 9 , 21 , 22 , 35 , 36 ], and a recent meta-analysis provided strong evidence that kidney transplant recipients can be grouped into metabolizer subgroups using the C/D ratio [ 37 ]. For this analysis, we used the C/D ratio at day 30 to determine metabolizer phenotype.…”

Section: Discussionmentioning

confidence: 99%

Effect of Concentration/Dose Ratio in De Novo Kidney Transplant Recipients Receiving LCP-Tacrolimus or Immediate-Release Tacrolimus: Post Hoc Analysis of a Phase 3 Clinical Trial

et al. 2020

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CYP3A5 gene polymorphisms and their impact on dosage and trough concentration of tacrolimus among kidney transplant patients: a systematic review and meta-analysis

Cited by 42 publications

References 36 publications

The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients

Cost-effectiveness of once-daily vs twice-daily tacrolimus among Hispanic and Black kidney transplant recipients

Effect of Concentration/Dose Ratio in De Novo Kidney Transplant Recipients Receiving LCP-Tacrolimus or Immediate-Release Tacrolimus: Post Hoc Analysis of a Phase 3 Clinical Trial

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