Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients

Study Overview
=================
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.

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.

Official Title
-----------------
Utilizing Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients

Conditions
-----------------
Kidney Transplantation

Intervention / Treatment
-----------------
* Drug: Tacrolimus + Ketoconazole, Then Tacrolimus alone
* Drug: Tacrolimus alone, Then Tacrolimus + Ketoconazole


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus + Ketoconazole, Then Tacrolimus alone<br>Participants first received tacrolimus in combination with with ketoconazole. After a 1-2 week washout they received tacrolimus alone. | Drug: Tacrolimus + Ketoconazole, Then Tacrolimus alone<br>* Pharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + ketoconazole 200 mg every 12 hours x 3 doses.<br>* Other names: Ketoconazole;|
| Experimental: Tacrolimus alone, Then Tacrolimus + Ketoconazole<br>The participants first received tacrolimus alone. After a 1-2 week washout period they received tacrolimus in combination with ketoconazole. | Drug: Tacrolimus alone, Then Tacrolimus + Ketoconazole<br>* Pharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h)<br>* Other names: Ketoconazole;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tacrolimus Bioavailability (F) | 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. | baseline and 2 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
kidney transplantation, tacrolimus, P-glycoprotein, ABCB1, genotyping