CYP3A5andCYP3A4, but notABCB1polymorphisms affect tacrolimus dose-adjusted trough concentrations in kidney transplant recipients

BACKGROUND Recent studies have identified new candidate polymorphisms in the genes related to CYP3A activity or calcineurin inhibitor dose requirements in kidney transplant recipients. These genes and polymorphisms are CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (rs35599367-C>T; *22); POR [P450 (cytochrome) oxidoreductase] (rs1057868-C>T; *28); and PPARA (peroxisome proliferator-activated receptor alpha) (rs4253728-G>A). We investigated the impact of these polymorphisms on sirolimus (SRL) in vitro hepatic metabolism, SRL trough concentrations (C0), and SRL adverse events in kidney transplant recipients. METHODS The clinical study included 113 stable kidney transplant patients switched from a calcineurin inhibitor to SRL (SRL C0 measured at 1, 3, and 6 months thereafter). We investigated SRL metabolism in vitro using human liver microsomes derived from individual donors (n = 31). Microsomes and patients were genotyped by use of Taqman® allelic discrimination assays. The effects of polymorphisms and covariates were studied using multilinear regression imbedded in linear mixed-effect models or logistic regressions. RESULTS In vitro, the CYP3A4*22 allele resulted in approximately 20% lower metabolic rates of SRL (P = 0.0411). No significant association was found between CYP3A4, CYP3A5, or PPARA genotypes and SRL dose, C0, or C0/dose in kidney transplant patients. POR*28 was associated with a minor but significant decrease in SRL log-transformed C0 [CT/TT vs CC, β = −0.15 (0.05); P = 0.0197] but this did not have any impact on the dose administered, which limited the relevance of the finding. After adjustment for nongenetic covariates and correction for false discovery finding, none of the single-nucleotide polymorphisms tested showed significant association with SRL adverse events. CONCLUSIONS These recently described polymorphisms do not seem to substantially influence the pharmacokinetics of SRL or the occurrence of SRL adverse events in kidney transplant recipients.

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Which Kidney Transplant Recipients Can Benefit from the Initial Tacrolimus Dose Reduction?

BioMed Research International ◽

10.1155/2018/4573452 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Kinga Krzyżowska ◽

Aureliusz Kolonko ◽

Piotr Giza ◽

Jerzy Chudek ◽

Andrzej Więcek

Keyword(s):

Risk Factors ◽

Dose Reduction ◽

Kidney Transplant ◽

Multiple Logistic Regression Analysis ◽

Hemoglobin Concentration ◽

Blood Levels ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Related Factors ◽

Tacrolimus Dose

Background. Observational data suggest that the fixed initial recommended tacrolimus (Tc) dosing (0.2 mg/kg/day) results in supratherapeutic drug levels in some patients during the early posttransplant period. The aim of the study was to analyze a wide panel of patient-related factors and their interactions which increase the risk for first Tc blood level > 15 ng/ml. Materials and Methods. We performed a retrospective analysis of 488 consecutive adult kidney transplant recipients who were initially treated with triple immunosuppressive regimen containing tacrolimus twice daily. The analysis included the first assessment of Tc trough blood levels and several demographic, anthropometric, laboratory, and comedication data. Results. The multiple logistic regression analysis showed that age > 55 years, BMI > 24.6 kg/m2, blood hemoglobin concentration > 9.5 g/dl, and the presence of anti-HCV antibodies independently increased the risk for first Tc level > 15 ng/ml. The relative risk (RR) for first tacrolimus level > 15 ng/ml was 1.88 (95% CI 1.35–2.64, p<0.001) for patients with one risk factor and 2.81 (2.02–3.89, p<0.001) for patients with two risk factors. Conclusions. Initial tacrolimus dose reduction should be considered in older, overweight, or obese kidney transplant recipients and in subjects with anti-HCV antibodies. Moreover, dose reduction of tacrolimus is especially important in patients with coexisting multiple risk factors.

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