Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients
Condition: Kidney Transplantation
Intervention: Tacrolimus + Ketoconazole, Then Tacrolimus alone; Tacrolimus alone, Then Tacrolimus + Ketoconazole
Intervention description: Pharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + ketoconazole 200 mg every 12 hours x 3 doses.; Pharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h)
Intervention MeSH terms: Ketoconazole; Tacrolimus
Phase: Phase 4
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: kidney transplantation; tacrolimus; P-glycoprotein; ABCB1; genotyping

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Kidney transplant recipient

          -  > 6 months posttransplant

          -  Serum creatinine < 1.6 mg/dL

          -  Currently taking a stable dose of tacrolims

        Exclusion Criteria:

          -  On medications known to interact with tacrolimus or ketoconazole

          -  Multi-organ transplant recipient

          -  Serum creatinine >1.5 mg/dL