Abstract
The pharmacokinetic variability of tacrolimus can be partly explained by CYP3A5 activity. Our objective was to evaluate a tacrolimus sparing policy on renal graft outcome according to CYP3A5 6986A>G genetic polymorphism. This retrospective study included 1114 recipients with a median follow-up of 6.3 years. Genotyping of the 6986A>G allelic variant corresponding to CYP3A5*3 was systematically performed. One year after transplantation, tacrolimus blood trough concentration (C0) target range was 5–7 ng/mL. However, daily dose was capped to 0.10 mg/kg/day regardless of the CYP3A5 genotype. A total 208 CYP3A5*1/- patients were included. Despite a higher daily dose, CYP3A5*1/- recipients exhibited lower C0 during follow-up (p < 0.01). Multivariate analysis did not show any significant influence of CYP3A5*1/- genotype (HR = 0.70, 0.46–1.07, p = 0.10) on patient-graft survival. Glomerular Filtration Rate (GFR) decline was significantly lower for the CYP3A5*1/- group (p = 0.02). The CYP3A5*1/- genotype did not significantly impact the risk of biopsy-proven acute rejection (BPAR) (HR = 1.01, 0.68–1.49, p = 0.97) despite significantly lower C0. Based on our experience, a strategy of tacrolimus capping is associated with a better GFR evolution in CYP3A5*1/- recipients without any significant increase of BPAR incidence. Our study raised some issues about specific therapeutic tacrolimus C0 targets for CYP3A5*1/- patients and suggests to set up randomized control studies in this specific population.
Highlights
Therapeutic drug monitoring, which most often consists of tacrolimus through blood concentration (C0) measurements [7], is routinely used in clinical practice to optimize the balance between the risk of graft rejection and drug toxicity
Concerning the graft outcomes, we found a significant association between intra patient of 15 for an increase of 10%; variability (IPV) of tacrolimus and patient-graft survival
Concerning estimated glomerular filtration rate (eGFR), we found a better modelization using a square root transformation of time according to Bayesian information criterion (BIC) values
Summary
Tacrolimus is the worldwide cornerstone of immunosuppression after kidney transplantation [1,2] This drug displays a narrow therapeutic index and may cause numerous adverse events if plasmatic concentrations are slightly above or below the appropriate range. Underexposure to tacrolimus increases the risk of graft rejection [3] whereas overexposure is associated with nephrotoxicity [4], infection, and metabolic complications such as diabetes or dyslipidemia [5]. These adverse events may affect graft and patient survivals as well as their quality of life [6]. Therapeutic drug monitoring, which most often consists of tacrolimus through blood concentration (C0) measurements [7], is routinely used in clinical practice to optimize the balance between the risk of graft rejection and drug toxicity
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