Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients
Condition: Kidney Transplantation
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      Two mL of blood will be obtained for pharmacogenomic screening for CYP3A5 and ABCB1
      genotypes. Patients with the CYP3A5*3/*3 genotype will be consented for the pharmacokinetic
      portion of the study. Volunteers from this patient cohort will participate in 2 overnight
      visits to the General Clinical Research Center (GCRC).

      Patients will report to the GCRC on the evening before each study visit. They will be
      required to fast from midnight the night before until 1 hour after tacrolimus administration,
      which will be in the morning approximately at 8 am.

      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. Each patient will take their take their usual oral dose of tacrolimus and
      have whole blood levels obtained immediately before (C0) and at 0.5, 1, 1.5, 2, 3, 4, 6 hours
      after the tacrolimus dose. They will then receive tacrolimus by intravenous infusion, a
      therapeutic dose over four hours. The IV dose will take the place of the patients' usual
      evening dose of tacrolimus. Additional blood will be drawn for tacrolimus at 0.25, 0.5, 1,
      1.5, 2, 3, 4, 6, 8, 12, 18 hours after the intravenous dose. During the ketoconazole visit,
      tacrolimus doses will be decreased by one-half to account for the drug interaction and avoid
      potential tacrolimus-induced toxicities. Ketoconazole 200 mg will be administered orally
      every 12 hours for a total of 3 doses; the first ketoconazole dose will be given 13 hours
      before tacrolimus administration.
    

Intervention name(s): Tacrolimus + Ketoconazole, Then Tacrolimus alone; Tacrolimus alone, Then Tacrolimus + Ketoconazole
Intervention type(s): Drug; Drug
Intervention description(s): 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)
Other intervention name(s): Tacrolimus; Ketoconazole; Tacrolimus; Ketoconazole
Intervention MeSH terms: Ketoconazole; Tacrolimus
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: kidney transplantation; tacrolimus; P-glycoprotein; ABCB1; genotyping