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Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients

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ClinicalTrials.gov Identifier: NCT01288521
Recruitment Status : Unknown
Verified January 2011 by University of Iowa.
Recruitment status was:  Enrolling by invitation
First Posted : February 2, 2011
Last Update Posted : February 2, 2011
American College of Clinical Pharmacy
Information provided by:
University of Iowa

Brief 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.

Condition or disease Intervention/treatment Phase
Kidney Transplantation Drug: Tacrolimus + Ketoconazole Drug: Tacrolimus alone Phase 4

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Utilizing Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients
Study Start Date : October 2008
Estimated Primary Completion Date : June 2011
Estimated Study Completion Date : September 2011

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Tacrolimus + Ketoconazole
single arm cross over design
Drug: Tacrolimus + Ketoconazole
Pharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + keotconazole 200 mg every 12 hours x 3 doses.
Other Name: Ketoconazole (Nizoral)
Drug: Tacrolimus alone
Pharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h)
Other Name: Tacrolimus (Prograf)

Primary Outcome Measures :
  1. Tacrolimus bioavailability (F) [ Time Frame: 2 weeks ]
    Change in tacrolimus bioavailability before and after administration of ketoconazole

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01288521

United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
Sponsors and Collaborators
University of Iowa
American College of Clinical Pharmacy
Principal Investigator: Sony Tuteja, PharmD University of Iowa

Responsible Party: Sony Tuteja, PharmD, University of Iowa
ClinicalTrials.gov Identifier: NCT01288521     History of Changes
Other Study ID Numbers: UIowa0843
First Posted: February 2, 2011    Key Record Dates
Last Update Posted: February 2, 2011
Last Verified: January 2011

Keywords provided by University of Iowa:
kidney transplantation

Additional relevant MeSH terms:
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Cytochrome P-450 CYP3A Inhibitors