CLINICAL IMMUNOSUPPRESSION - KIDNEY EARLY

C. Wang¹, L. Liu², J. Li³, S. Deng¹, J. Li¹, J. Fei², Q. Fu¹, C. Xiao⁴, X. Yuan^2
1Organ Transplant Center, The First Affiliated Hosptial, Sun Yat-sen University, Guangzhou/CHINA, ²Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou/CHINA, ³Institute Of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou/CHINA, ⁴Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou/CHINA

Body: Introduction CYP3A5 is one of the cytochrome P450 determining the systemic clearance of tacrolimus. Besides antihypertensive effect, diltiazem is commonly used as a conservation agent of cyclosporine A and tacrolimus in kidney transplantation (KTx), especially in developing countries. Both CYP3A5*3 genotype and diltiazem have been demonstrated to affect tacrolimus pharmacokinetics. This study was designed to investigate the effect of diltiazem on tacrolimus use in KTx patients with different CYP3A5*3 genotypes in the early period after operation. Methods CYP3A5*3 genotype was examined prior to KTx. CYP3A5 expresser was defined as patients with CYP3A5*1/1 and CYP3A5*1/3 genotypes, and CYP3A5 non-expresser was defined as patients with CYP3A5*3/3 genotype. Sixteen CYP3A5 expressers and 16 non-expressers were enrolled in this study. Eight CYP3A5 expressers and eight non-expressers were assigned to diltiazem group, in which patients received diltiazem treatment, at the dose of 30 mg every 8 hours. The others were assigned to non-diltiazem group as control without diltiazem treatment. All the patients were prescribed to tacrolimus + mycophenolate mofetil + steroids immunosuppressive therapy. In the control group, tacrolimus was initiated as a dose of 0.05~0.075 mg/kg (0.1~0.15 mg/kg/day), and was gradually adjusted to its therapeutic window. In diltiazem group, in order to reach therapeutic window directly, the initial dose of tacrolimus was adjusted based on a regression model including the variables of CYP3A5 genotype and accompanying diltiazem. This regression model had been deducted from our previous retrospective study. The following parameters were compared: tacrolimus trough level (C0)after initial dose, percentage of out-of-window C0 after first dosing, dose adjustment times to reach therapeutic window, tacrolimus dose when reaching therapeutic window, acute rejection rate within two weeks after KTx, and serum creatinine (sCr) at day 14 post transplant. Results In CYP3A5 expressers, the initial single dose of tacrolimus was 0.061 ± 0.006 mg/kg in diltiazem group, and was 0.060 ± 0.004 mg/kg in the control (p>0.05). Diltiazem significantly increased tacrolimus C0 after initial dose when compared to the control (7.3 ± 1.37 vs 4.0 ± 1.58 ng/ml, p<0.05). The percentage of out-of-window C0 after first dosing was zero and 75% in diltiazem and control group, respectively (p<0.05). Dose adjustment times to reach therapeutic window was zero and 1.13 ± 0.83 in the two groups (p<0.05). Tacrolimus dose when reaching therapeutic window was 0.061 ± 0.006 mg/kg and 0.075 ± 0.012 mg/kg in diltiazem and control group, respectively (p<0.05). Acute rejection occurred in one patient in the control group, and none in diltiazem group (p>0.05). The sCr at day 14 after transplant was 119.5 ± 25.4 and 119.5 ± 31.1 μmol/L in these groups (p>0.05). In CYP3A5 non-expressers, all the above parameters were not significantly different between diltiazem group and control group (p>0.05). ConclusionCombined with diltiazem, tacrolimus could directly reach its therapeutic window at the first dosing in CYP3A5 expressers. Meanwhile, the targetconcentration level maintains stable at a lower dose without adjustment. The interaction between CYP3A5 and diltiazem may contribute to this facilitation.

Disclosure: All authors have declared no conflicts of interest.