Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients
Status:
Completed
Trial end date:
2011-09-01
Target enrollment:
Participant gender:
Summary
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.