Clinical Trial in Assigning of Tacrolimus Dosage Regimen According to CYP3A5 Genotype in Kidney Transplant Recipients

Objective

1. To determine the clinical outcome of tacrolimus treatment in kidney transplant recipients between genotype guided dosage regimen group and conventional group
2. To determine the influence of CYP3A5 polymorphism on clinical outcome of kidney transplantation recipients Review article Kidney transplantation is the most appropriated treatment in end stage renal failure patients in order to improve quality of life. National health security office of Thailand estimates the cost of kidney transplantation around 250,000 to 400,000 baht per patient. However, patients have to take immunosuppressive drugs such as cyclosporine, tacrolimus, azathioprine, mycophenolate, prednisolone etc. to prevent graft rejection. Tacrolimus is a common immunosuppressive drug used worldwide. However, tacrolimus has narrow therapeutic level and needs regularly therapeutic monitor because of inter-individual variation in dosage regimen. Achieving and maintaining target concentration of tacrolimus are related to tacrolimus toxicity and graft rejection. Not only age, body weight and drug interaction but also genetic factor in metabolic pathway of tacrolimus plays an important role in tacrolimus blood level.

Cytochrome P450 3A4 (CYP3A4) and CYP3A5 are the main enzyme responsible for metabolism of tacrolimus. Unlike CYP3A4, CYP3A5 is more polymorphic and expression of enzyme is controlled by CYP3A5 gene variants. CYP3A5*3, an A to G transition (A6986G) within intron 3 results in the production of a truncated protein, is the most common allele variant. From previous study of our group, the allele frequency of CYP3A5*3 was 66% which is lower than those reported in the Caucasian population (85%). Prevalence of CYP3A5*1/*1, CYP3A5*1/*3, CYP3A5*3/*3 in 400 healthy Thai volunteers are 13.75%, 42.75% and 43.50%, respectively (unpublished data).

Patients who carried CYP3A5*1/*1 or CYP3A5*1/*3 allele showed tacrolimus clearance higher than CYP3A5*3/*3 patients (0.679 ± 0.195 vs 0.355 ± 0.091 L/h/kg). Therefore, CYP3A5*3/*3 patients received 48% lower dose of tacrolimus than CYP3A5*1/*1 or CYP3A5*1/*3 patients in order to achieve the same therapeutic range.

From our previous study showed the mean dose of tacrolimus required for the induction phase was significantly higher (P= 0.006) in the CYP3A5*1/*1 group at 0.142±0.050 mg/kg/day than that required by patients who carried either the CYP3A5*1/*3 group of 0.097±0.040 mg/kg/day or the CYP3A5*3/*3 group of 0.077±0.020 mg/kg/day. Tacrolimus maintenance dose required for CYP3A5*1/*1 group of 0.12±0.03 mg/kg/day was 1.3 times higher (P<0.0001) than used for the CYP3A5*1/*3 at 0.09±0.03 mg/kg/day and 2.4 times higher than the CYP3A5*3/*3 group of 0.05±0.02 mg/kg/day.