Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients
| Status: | Completed |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 4/17/2018 |
| Start Date: | October 2008 |
| End Date: | September 2011 |
Utilizing 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.
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.
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.
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.
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
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