Tacrolimus Concentrations in Hematopoetic Stem Cell Transplantation Patients Are Related to Cytochrome P450 3A5 Gene Polymorphisms.

Objective: Tacrolimus, a commonly used potent immunosuppressive drug in hematopoetic stem cell transplantation (SCT), has large individual variation in concentrations and a relatively narrow therapeutic range. It is metabolized mainly by cytochrome P450 (CYP) 3A which has genetic polymorphisms influencing enzymatic activities; CYP3A5*1 and *3 genotypes represent expressor and non-expressor, respectively. In the present study, we investigated whether the tacrolimus concentration per dose is associated with CYP3A5 gene polymorphisms.

Methods: 51 Japanese SCT patients (21 AML, 12 ALL, 9 CML, 3 NHL, 1 HL, 2 ATL, 1 MM, 2 AA), receiving tacrolimus were studied. DNA was extracted from peripheral blood samples. CYP3A5 genotype was analyzed by PCR-restriction fragment length polymorphism (RFLP) using specific primers and a restriction enzyme, SspI. Blood tacrolimus concentrations were measured twice a week by a commercially available EIA kit.

Results: The frequency of the CYP3A5 *1/*1, *1/*3 and *3/*3 genotype was 7.8, 31.4, and 60.8% of 51 patients, respectively, and the genotype distribution was not different significantly from that of 121 Japanese healthy volunteers (2.5, 38.8, and 58.8%, respectively). The frequency of CYP3A5 genotypes of white Americans is reported to be 2.2, 12.0 and 86.0%, respectively, indicating the ethnic difference of distribution. The dose-adjusted concentrations of tacrolimus 5 to 7 days following SCT were significantly higher in CYP3A5 *3/*3 patients than in CYP3A5 *1/*1 and *1/*3 patients (691.7±298.0 ng/ml per mg/kg vs. 451.8±153.8 ng/ml per mg/kg, P=0.0017). The dose needed to achieve the target concentration (10 to 15 ng/ml) between 40 to 60 days following SCT, when the blood concentrations of tacrolimus tended to be stable in most patients, is significantly lower in CYP3A5 *3/*3 patients than in CYP3A5 *1/*1 and *1/*3 patients (0.008±0.005 mg/kg vs.0.016±0.006 mg/kg, P<0.001). Above grade two adverse events related to tacrolimus were observed only in CYP3A5 *3/*3 patients (3 patients in grade 4 and 1 patient in grade2), suggesting the contribution of a higher concentration to renal toxicity by tacrolimus.

Conclusion: The tacrolimus concentration per dose in SCT patients is influenced by the CYP3A5 gene polymorphism. This is the first report showing the relationship between CYP3A5 gene polymorphism and the tacrolimus concentration in SCT patients to the best of our knowledge. Information of CYP3A5 genotype may be helpful to determine the initial tacrolimus dose adequate for each patient.