242.7: Influence of CYP3A5 Polymorphisms on Tacrolimus Dosing in Renal Transplant Recipients

Abstract

Introduction: Tacrolimus is a commonly used immunosuppressant after kidney transplantation it has narrow theraupetic range and demonstrates wide interindividual variability in pharmacokinetics leading to potential under immunosuppression or tacrolimus toxicity genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailibility between individuals. Aim of the study: Ti evaluate pharmacogenomic effect of CYP3A5 gene polymorphisms on tacrolimus dosing in renal transplant recipients. Materials and Methods: Present study we investigated pharmacogenomics associations of common CYP3A5 polymorphisms with requirements of tacrolimus in renal transplant patients: □INCLUSION CRITERIA - 50 patients on tacrolimus based triple immunosuppression were genotyped for cyp3A5 polymorphism most allels- *1/*1,*1/*3,*3/*3 alleles. □EXCLUSION CRITERIA- those patients on CYP inducers or inhibitors were excluded demographic data, weight based tacrolimus doses, serum tacrolimus level at 1 month, 3 months 1 year and present tacrolimus trough level were collected. Data was statistically analysed. Results: Mean age of the recipients was 33.41+/-10.2,72% were males mean tacrolimus level at 1 month was 8ng/ml (7-10ng/ml) at 1 month post transplant cyp *1/*1 was 5.75+_0.95,tac level in cyp3a5 *1/*3 was 9.52∔_1.42,CYP3A5*3/*3 -10.26+_1.02 with significant P VALUE <0.01 among patients with high tac level 36% were poor metabolisers,50% intermediate metabolizers,none of the extensive metabolisers had higher tacrolimus level. At>3 months of transplantation tac level in cyp3a5 *1/*1 was 5.75∔0.95, cyp3a5 *1/*3 was 6.33∓1.17, cyp3a5 *3/*3 was 6.78∔-0.8 with significant P value < 0.01. 56% developed tac toxicity - 84%(*3/*3) poor metabolisers, 14.3% in intermediate *1/*3 metabolisers.125 developed rejections in first three months of transplant,90.755 were extensive metabolisers Discussion: Tacrolimus toxicity as well as rejection due to sub theraupetic levels influence graft outcomes. bioavailibility of tacrolimus varies widely due to gene polymorphisms of CYP3A5 gene. CYP3A5*1/*1 had lower tac level in blood resulting higher rates of rejection requiring 1.5 to 2 times higher dose compared to poor metabolisersand intermediate metabolizers. Poor metabolizers *3/*3 had tacrolimus related toxicity at similar dose adjusted tac levels, indicating lower dose for maintanence (0.06mg/kg). Conclusion: Genotyped based dosing may improve achievement of theraupetic drug concentrations with reduced drug related complications in the era of personalised medicine.