Kidney TransplantationPhase 4NCT01288521
Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients
A Phase 4 study testing Tacrolimus + Ketoconazole, Then Tacrolimus alone and Tacrolimus alone, Then Tacrolimus + Ketoconazole in people with Kidney Transplantation, run by Sony Tuteja at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Kidney Transplantation
- What is being tested?
- Tacrolimus + Ketoconazole, Then Tacrolimus alone and Tacrolimus alone, Then Tacrolimus + Ketoconazole
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- Oct 2008to Sep 2011
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Kidney transplant recipient
- > 6 months posttransplant
- Serum creatinine < 1.6 mg/dL
- Currently taking a stable dose of tacrolims
Who cannot join
- On medications known to interact with tacrolimus or ketoconazole
- Multi-organ transplant recipient
- Serum creatinine >1.5 mg/dL
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242
About this study
Official title: 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.
Read more
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.
Read the 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.
- Conditions
- Kidney Transplantation
- Being tested
- Tacrolimus + Ketoconazole, Then Tacrolimus alone, Tacrolimus alone, Then Tacrolimus + Ketoconazole
- Keywords
- kidney transplantation, tacrolimus, P-glycoprotein, ABCB1, genotyping
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tacrolimus + Ketoconazole, Then Tacrolimus aloneDrug
Also called Tacrolimus, Ketoconazole
Pharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + ketoconazole 200 mg every 12 hours x 3 doses.
Tacrolimus alone, Then Tacrolimus + KetoconazoleDrug
Also called Tacrolimus, Ketoconazole
Pharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h)
| Study group | Role | What they receive |
|---|---|---|
| Tacrolimus + Ketoconazole, Then Tacrolimus alone | Experimental | Participants first received tacrolimus in combination with with ketoconazole. After a 1-2 week washout they received tacrolimus alone. Receives: Drug: Tacrolimus + Ketoconazole, Then Tacrolimus alone |
| Tacrolimus alone, Then Tacrolimus + Ketoconazole | Experimental | The participants first received tacrolimus alone. After a 1-2 week washout period they received tacrolimus in combination with ketoconazole. Receives: Drug: Tacrolimus alone, Then Tacrolimus + Ketoconazole |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: baseline and 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Feb 2011 (estimated)
- Study startOct 2008
- Primary completionJun 2011
- Study completionSep 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Kidney TransplantationStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sony Tuteja
- Sponsor type
- University, hospital or other
- Collaborators
- American College of Clinical Pharmacy
- Responsible party
- Sponsor-investigator, Sony Tuteja, University of Iowa
- Investigators
- Sony Tuteja, PharmD, Principal investigator, University of Iowa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01288521
- Sponsor's protocol ID
- 200806718
- Status last verified
- Feb 2018
- First submitted
- 9 Feb 2010
- Last updated
- 9 Mar 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Mar 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Utilizing Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients
- ClinicalTrials.gov ID
- NCT01288521
- Acronym / sponsor ID
- 200806718
- Conditions
- Kidney Transplantation
- Keywords
- kidney transplantation, tacrolimus, P-glycoprotein, ABCB1, genotyping
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Sony TutejaUniversity, hospital or other
- Collaborators
- American College of Clinical Pharmacy
- Study start
- Oct 2008
- Primary completion
- Jun 2011 (actual)
- Study completion
- Sep 2011 (actual)
- First posted
- 2 Feb 2011 (estimated)
- Results
- Posted 9 Mar 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tacrolimus + Ketoconazole, Then Tacrolimus alone | Experimental | Drug: Tacrolimus + Ketoconazole, Then Tacrolimus aloneParticipants first received tacrolimus in combination with with ketoconazole. After a 1-2 week washout they received tacrolimus alone. |
| Tacrolimus alone, Then Tacrolimus + Ketoconazole | Experimental | Drug: Tacrolimus alone, Then Tacrolimus + KetoconazoleThe participants first received tacrolimus alone. After a 1-2 week washout period they received tacrolimus in combination with ketoconazole. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Kidney transplant recipient
- > 6 months posttransplant
- Serum creatinine < 1.6 mg/dL
- Currently taking a stable dose of tacrolims
Key exclusion criteria (3 listed)
- On medications known to interact with tacrolimus or ketoconazole
- Multi-organ transplant recipient
- Serum creatinine >1.5 mg/dL
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Tacrolimus + Ketoconazole, Then Tacrolimus aloneAlso: Tacrolimus, KetoconazolePharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + ketoconazole 200 mg every 12 hours x 3 doses. | Drug | Tacrolimus + Ketoconazole, Then Tacrolimus alone |
| Tacrolimus alone, Then Tacrolimus + KetoconazoleAlso: Tacrolimus, KetoconazolePharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h) | Drug | Tacrolimus alone, Then Tacrolimus + Ketoconazole |
Primary outcome
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Mar 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Biomarker-Guided Mycophenolate Mofetil Elimination in Low-Risk Older Adult Kidney Transplant Recipients
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sony Tuteja, PharmD principal investigator
University of Iowa
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Tacrolimus + Ketoconazole, Then Tacrolimus alone and Tacrolimus alone, Then Tacrolimus + Ketoconazole in people with Kidney Transplantation, run by Sony Tuteja at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Mar 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Mar 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Tacrolimus Bioavailability (F) (time frame: baseline and 2 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Mar 2018.