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NCT Number: NCT01288521

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.

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Key information

Conditions

Kidney Transplantation

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Tacrolimus + Ketoconazole, Then Tacrolimus alone

Drug

Pharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + ketoconazole 200 mg every 12 hours x 3 doses.

Other names: Tacrolimus, Ketoconazole

Tacrolimus alone, Then Tacrolimus + Ketoconazole

Drug

Pharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h)

Other names: Tacrolimus, Ketoconazole

Primary outcomes

  1. Tacrolimus Bioavailability (F)

    Time frame: baseline and 2 weeks

    Tac bioavailability alone vs. Tac bioavailability with Keto. To determine F we took the ratio of area under the curve of the oral dose divided by the area under the curve of the IV dose. F was determined by fitting a model that considered the plasma concentration of tac with IV vs. oral dosing.

Sponsors and collaborators

Lead sponsor

Sony Tuteja

Other

Collaborators

  • American College of Clinical Pharmacy

Registry information

Official study title

Utilizing Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients

Important dates

Study start
2008
Primary completion
2011
Study completion
2011
First posted
Feb 2, 2011
Registry last updated
Mar 9, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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