Kidney Transplantation
Conditions
Keywords
kidney transplantation, tacrolimus, P-glycoprotein, ABCB1, genotyping
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.
Interventions
DRUGTacrolimus + Ketoconazole, Then Tacrolimus alone
Pharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + ketoconazole 200 mg every 12 hours x 3 doses.
DRUGTacrolimus alone, Then Tacrolimus + Ketoconazole
Pharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h)
Sponsors
American College of Clinical Pharmacy
Sony Tuteja
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tacrolimus Bioavailability (F) | 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. |
Countries
United States
Participant flow
Recruitment details
Kidney transplant recipients were recruited from the transplant clinic from 10/2008 to 6/2010.
Pre-assignment details
Assignment to the treatment group was based on CYP3A5 genotype and subjects were eligible only if they had the \*3/\*3 genotype. 22 subjects were consented to participate. Based on genotype, 3 subjects were ineligible to complete the study. Of the 19 eligible subjects, 11 declined to participate. 8 subjects completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus + Ketoconazole, Then Tacrolimus Alone Randomized, cross over design
Tacrolimus + Ketoconazole : Pharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + keotconazole 200 mg every 12 hours x 3 doses.
Tacrolimus alone : Pharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h) | 3 |
| Tacrolimus Alone, Then Tacrolimus + Ketoconazole Randomized, cross over design
Tacrolimus + Ketoconazole : Pharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + keotconazole 200 mg every 12 hours x 3 doses.
Tacrolimus alone : Pharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h) | 5 |
| Total | 8 |
Baseline characteristics
| Characteristic | Tacrolimus Alone, Then Tacrolimus + Ketoconazole | Tacrolimus + Ketoconazole, Then Tacrolimus Alone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 2 Participants | 7 Participants |
| Age, Continuous | 57 years STANDARD_DEVIATION 5.5 | 53 years STANDARD_DEVIATION 12.5 | 55.6 years STANDARD_DEVIATION 8.2 |
| Region of Enrollment United States | 5 participants | 3 participants | 8 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
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.
Time frame: baseline and 2 weeks
Population: Stable kidney transplant recipients
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tacrolimus Alone | Tacrolimus Bioavailability (F) | 0.224 ratio of oral to IV | Standard Deviation 0.107 |
| Tacrolimus + Ketoconazole | Tacrolimus Bioavailability (F) | 0.681 ratio of oral to IV | Standard Deviation 0.308 |
Comparison: The bioavailability of Tac alone vs. Tac +keto was compared using a general linear model including sex and creatinine clearance as covariates.p-value: 0.006Regression, Linear