Optimization of Initial Tacrolimus Dose Using Pharmacogenetic Testing

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 (C(0)). 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 C(0). Secondary end points included the number of dose modifications and the delay in achieving the targeted C(0). In the group receiving the adapted dose, a higher proportion of patients had values within the targeted C(0) at day 3 after initiation of tacrolimus (43.2% vs. 29.1%; P = 0.03); they required fewer dose modifications, and the targeted C(0) 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 C(0). Whether this improvement will affect clinical outcomes requires further evaluation.

Dosing equation for tacrolimus using genetic variants and clinical factors

“…Individuals who carry one or more CYP3A5*1 alleles express the CYP3A5 enzyme [28,29]. Tacrolimus is a substrate for CYP3A5 and it is well established that individuals carrying one or more *1 alleles have a higher tacrolimus CL and lower trough concentrations [11][12][13][14]17]. Several previous studies have highlighted the differences in CL/F and dose requirements for the CYP3A5*1 carriers compared with individuals with the CYP3A5*3/*3 genotype [24,[30][31][32][33][34].…”

“…A recent randomized trial studied CYP3A5 genotype guided tacrolimus dosing in kidney transplant recipients [17]. In the genotype guided group, patients with one or more CYP3A5*1 alleles received an initial tacrolimus dose of 0.3 mg kg -1 day -1 and those without a *1 allele received a dose of 0.15 mg kg -1 day -1 .…”

Emerging Role of Pharmacogenetic in Organ Transplantation

“…Recently, the first study to show the prospective adaptation of tacrolimus daily dose based on CYP3A5 patient's genotype, confirmed that pre-transplant genetic screening increased significantly the proportion of patients reaching the therapeutic target range. In fact, in this multi-center randomized controlled trial, patients receiving tacrolimus daily dose according to their CYP3A5 genotype, achieved the target concentration more rapidly with lesser dose modification and in an higher percentage ( >75%) when compared to those in whom tacrolimus was managed with a concentrationcontrol strategy [21]. ABCB1 polymorphisms do not seem to influence tacrolimus pharmacokinetic and research into this association has yielded mixed results [22,23].…”

Pharmacogenetics of Immunosuppressive Drugs in Renal Transplantation

“…Some studies found that the weighted mean apparent oral clearance was 48% lower in CYP3A5 nonexpressors than CYP3A5 expressors (range, 26%-65%) (Barry & Levine, 2010). Recently, a study with 280 transplant recipients concludes that patients receiving a pharmacogenetic adaption of the daily dose of tacrolimus were associated with improved achievement of the target C 0 (Thervet et al, 2010).…”

“…This plasmatic clearance is higher in those individuals with genotype CYP3A5*1/*3 regarding those CYP3A5*3/*3 (Haufroid et al, 2006). In fact, CYP3A5*1 is responsible from about 60% of tacrolimus hepatic metabolism (Dai et al, 2006;Thervet et al, 2010), so it is of great interest studying it in order to establish optimal doses that reach quickly the efficient blood concentrations, avoiding toxicity but also assuring the necessary concentrations to avoid rejection. The studies performed so far indicate the need to administrate higher tacrolimus doses in patients CYP3A5*1/*1.…”