A prospective, open-label, observational clinical cohort study of the association between delayed renal allograft function, tacrolimus exposure, and CYP3A5 genotype in adult recipients.
BACKGROUND
Tacrolimus, a calcineurin inhibitor with a macrolide lactone structure, is currently used as a cornerstone immunosuppressive drug in solid organ transplantation. It is metabolized by hepatic and intestinal cytochrome P450 (CYP) 3A4/3A5 enzymes and is a substrate for P-glycoprotein (ABCB1). The disposition of tacrolimus might be influenced by severe renal allograft dysfunction (eg, in cases of delayed graft function [DGF]). New-onset diabetes after transplantation (NODAT) is a known adverse effect of tacrolimus therapy and has been associated with DGF.


OBJECTIVE
The impact of DGF on tacrolimus C(min) and dose requirements was evaluated in renal transplant recipients in the first postoperative week. The effects of the CYP3A5*3 A6986G polymorphism on initial mean tacrolimus C(min) and dose requirements in the presence and absence of DGF were assessed. This study also tested the hypothesis that if DGF influences early tacrolimus exposure, this would lead to a higher risk for NODAT (defined as the need for glucose-lowering medication for an uninterrupted period of ≥ 26 weeks).


METHODS
This prospective, open-label, observational clinical cohort study enrolled renal allograft recipients aged ≥ 18 years. Tacrolimus was administered as an oral loading dose of 0.2 mg/kg/d and adjusted to achieve a target mean daily tacrolimus C(min) between 12 and 15 ng/mL. C(min) values and oral dose requirements in the first postoperative week were compared between patients with and without DGF. Patients were genotyped for the CYP3A4*1B -290A>G, CYP3A5*3 A6986G, ABCB1 Exon26 C3435T, ABCB1 Exon21 G2677T, and ABCB1 Exon21 G2677A single nucleotide polymorphisms. NODAT that occurred within the first 12 weeks after transplantation was confirmed using an oral glucose tolerance test.


RESULTS
A total of 304 patients were enrolled (184 men, 120 women; mean [SD] age, 52.9 [14.1] years). Through day 3 after transplantation, mean (SD) 12-hour tacrolimus C(min) values were significantly higher in recipients experiencing DGF despite identical loading doses of 0.2 mg/kg. Mean tacrolimus dose requirements were significantly lower in patients with DGF during the first week. After recovery of DGF, mean tacrolimus dose requirements were not significantly different between recipients with and without DGF. In homozygous CYP3A5*3 carriers (n = 252), mean (SD) tacrolimus dose requirements remained significantly lower during DGF, while in CYP3A5*1 carriers with DGF (n = 52), lower mean dose requirements were observed only after postoperative day 4. The proportion of patients in whom NODAT developed was significantly greater in patients with DGF and tacrolimus C(min) >15 ng/mL on the first day after transplantation (27.2%) compared with recipients who remained free of DGF and had C(min) ≤15 ng/mL on day 1 (6.5%) (P = 0.016). On logistic regression analysis, greater recipient age (odds ratio [OR] = 1.044; 95% CI, 1.009-1.080), higher tacrolimus C(min) on day 1 (OR = 1.048; 95% CI, 1.017-1.080), and DGF (OR = 2.968; 95% CI, 1.107-7.959) were associated with an increased risk for NODAT.


CONCLUSIONS
In this open-label, observational study, DGF was associated with higher initial mean tacrolimus C(min) values and lower daily dose requirements predominantly in CYP3A5 nonexpressers.
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium. Dirk.Kuypers@uz.kuleuven.ac.be
Dirk R J
DR
Kuypers
Hylke
H
de Jonge
Maarten
M
Naesens
Yves
Y
Vanrenterghem
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D051799:Delayed Graft Function / Q000139:chemically induced* / Q000188:drug therapy; D003920:Diabetes Mellitus / Q000097:blood / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011184:Postoperative Period; D011446:Prospective Studies; D016559:Tacrolimus / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus