Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients

Solid organ transplant recipients would greatly benefit from pharmacogenetic evaluation since immunosuppressive drug regimens consist of multiple medications with narrow therapeutic ranges and toxic adverse event profiles. Tacrolimus is a potent immunosuppressive agent utilized for rejection prophylaxis. Intensive pharmacokinetic monitoring must be performed following organ transplantation to ensure therapeutic drug concentrations due to its highly variable pharmacokinetics profile and narrow therapeutic index. Tacrolimus is a substrate for CYP450 3A and for the membrane transporter p-glycoprotein (Pgp). Polymorphisms in the gene encoding for CYP3A5 have been extensively studied and have been found to influence the dosing of tacrolimus. The effect of ABCB1 gene polymorphisms (which encodes for Pgp) upon tacrolimus pharmacokinetics has been more difficult to establish. This study will determine if haplotypes derived from three frequent polymorphisms in the ABCB1 gene (C1236T, G2677T, C3435T) can predict the degree of drug interaction between tacrolimus (CYP3A5/Pgp substrate) and ketoconazole (CYP3A5/Pgp inhibitor) in patients who are CYP3A5 nonexpressors. This prospective pharmacokinetic and pharmacogenomic study will enroll 20 stable renal transplant recipients with the CYP3A5 *3/*3 genotype and grouped by ABCB1 haplotype (CGC vs TTT). Pharmacokinetics of tacrolimus will be assessed on 2 occasions with and without ketoconazole coadministration separated by 1 week. The order of study occasions will be randomized in a crossover design. The results of this study may identify a genomic marker for predicting drug-drug interactions. Knowing this information a priori will aid clinicians in modifying drug dosing and alleviate patients of the burden of significant drug toxicities.