Switching Immunosuppression From Cyclosporine to Tacrolimus in Kidney Transplant Recipients Based on CYP3A5 Genotyping

Background: Kidney transplant recipients on long-term cyclosporine (CsA) therapy may develop multiple adverse drug events, and immunosuppression conversion from CsA to tacrolimus (Tac) is an option. Genetic variations, especially cytochrome P450 ( CYP ) 3A5*3 , affects Tac dosing. However, little information is available to guide the conversion with regards to patients' pharmacogenomics. We aimed to investigate whether CYP3A5 , CYP3A4 , and ABCB1 genotyping could contribute to a more precise and individualized initial dosing of Tac at the time of immunosuppressant conversion. Methods: Genotypes of 5 candidate genes ( CYP3A5*3 , CYP3A4*1G , ABCB1C1236T , ABCB1C3435T , and ABCB1G2677T/A ) were investigated by polymerase chain reaction and restriction fragment-length polymorphism methods in 46 adult kidney transplant recipients requiring immunosuppressant conversion from CsA to TAC. Associations between these functional genetic polymorphisms and the dose-adjusted trough concentrations of CsA and Tac were evaluated, retrospectively. Results: Based on the linear regression analysis, CYP3A5 expressers (*1/*1 and *1/*3) had lower Tac dose-adjusted trough concentrations on days 7, 14, 21, and 28, and they required 1.40- to 1.75-fold higher daily dose to reach the target concentration compared with nonexpressers (*3/*3) on day 28 [0.07 (0.06–0.09) mg/kg/d versus 0.05 (0.02–0.06) mg/kg/d, P = 0.001]. CYP3A4*1G or ABCB1 genetic polymorphisms had no effect on the Tac dose-adjusted trough concentrations. Conclusions: Our preliminary study supports the use of CYP3A5 genotyping to guide the initial dosing of Tac when converting the immunosuppression therapy from CsA to Tac.