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Sponsored by: |
Weill Medical College of Cornell University |
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Information provided by: | Weill Medical College of Cornell University |
ClinicalTrials.gov Identifier: | NCT00629122 |
Tacrolimus (Prograf) belongs to a class of medications known as the calcineurin inhibitors. It is a maintenance drug that is used to prevent rejection in kidney, liver, and heart transplant recipients. Calcineurin inhibitors display high pharmacokinetic (the body's effects on a drug) variability and necessitate use of blood tests to ensure that adequate drug levels are present to maintain effectiveness and safety. The amount of oral tacrolimus that is absorbed varies in all patient populations studied. Tacrolimus is metabolized or broken down for elimination by the liver and small intestine via cytochrome P450 (CYP)3A4, CYP 3A5, and p-glycoprotein enzyme systems. Enzyme activity is affected by several single nucleotide polymorphisms (SNPs) in an individuals genetic make-up and differences in expression may contribute to variations in tacrolimus pharmacokinetics. There are number of drug-drug interactions where concomitantly administered medications can increase or decrease this break down of tacrolimus. Early after transplant or at times when tacrolimus cannot be taken by mouth, alternative routes of administration are sought. Although an intravenous (through the vein) product is available, it can be toxic to the kidneys and has been associated with allergic reactions. Studies in lung transplant recipients have utilized sublingual (under the tongue) tacrolimus administration with successful outcomes. Drug delivery via the oral mucosa is an alternative method of systemic drug administration which offers an alternative when oral administration is impractical (gastrointestinal dysmotility, reduced drug absorption, intestinal failure, difficulty in swallowing, or in those with nausea or vomiting). Administration of tacrolimus by the sublingual route allows for direct entry into the systemic circulation and bypasses problems associated with drug absorption and breakdown that take place in the small intestine. In order to learn more about the possible role of sublingual tacrolimus among transplant recipients we will administer tacrolimus sublingually. In addition, we will evaluate differences in expression and bioactivity of SNP polymorphisms and their effects in tacrolimus pharmacokinetics. Patients awaiting kidney transplantation who are listed on the kidney transplant waiting list or those with upcoming living donor transplants at our center will be administered five doses of sublingual tacrolimus followed by five doses of oral tacrolimus. We will evaluate and then compare the pharmacokinetic characteristics of sublingual and oral tacrolimus administration among the study participants. The purpose of this study is to assess the pharmacokinetic and pharmacodynamic parameters of tacrolimus after sublingual and oral administration. A secondary objective is to assess the drug-drug interaction between concomitant therapy with clotrimazole.
Condition | Intervention | Phase |
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Kidney Failure, Chronic |
Drug: Tacrolimus/Clotrimazole Troche Drug: Tacrolimus/Nystatin Suspension |
Phase IV |
Study Type: | Interventional |
Study Design: | Health Services Research, Randomized, Open Label, Uncontrolled, Crossover Assignment, Pharmacokinetics Study |
Official Title: | Pharmacokinetic Evaluation of Sublingual Versus Oral Tacrolimus Administration in Patients Awaiting Kidney Transplantation |
Estimated Enrollment: | 20 |
Study Start Date: | February 2008 |
Estimated Primary Completion Date: | December 2008 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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A: Experimental
Sublingual tacrolimus 1 mg every 12 hours (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus 1 mg every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Nystatin suspension 5 mL every 12 hours (study days 1 - 3 and 6 - 8). |
Drug: Tacrolimus/Nystatin Suspension
Study day 1 (9 am): Initiate sublingual tacrolimus and nystatin suspension x 5 doses. Study day 3 (9 am): Collection of pharmacokinetic parameters around the 5th sublingual tacrolimus dose. Study day 3 (9 pm): Start washout period, no drug administration (tacrolimus, nystatin). Study day 5 (9pm): End washout period. Study day 6 (9am): Initiate oral tacrolimus and nystatin suspension x 5 doses. Study day 8 (9 am): Collection of pharmacokinetic parameters around the 5th oral tacrolimus dose. Study day 15: Participants will be contacted by telephone to assess for any adverse effects. To ensure that dietary intake does not affect the absorption profile of tacrolimus we will ensure that breakfast is given 15 minutes prior to drug administration on the days of pharmacokinetic assessment (study day 3 and 8). |
B: Experimental
Sublingual tacrolimus 1 mg every 12 hours (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus 1 mg every 12 hours (study day 6 - 8). Tacrolimus capsules will be administered by mouth. Clotrimazole troche 10 mg every 12 hours (study day 1 - 3 and 6 - 8). |
Drug: Tacrolimus/Clotrimazole Troche
Study day 1 (9 am): Initiate sublingual tacrolimus and clotrimazole troche x 5 doses. Study day 3 (9 am): Collection of pharmacokinetic parameters around the 5th sublingual tacrolimus dose. Study day 3 (9 pm): Start washout period, no drug administration (tacrolimus, clotrimazole). Study day 5 (9pm): End washout period. Study day 6 (9am): Initiate oral tacrolimus and clotrimazole troche x 5 doses. Study day 8 (9 am): Collection of pharmacokinetic parameters around the 5th oral tacrolimus dose. Study day 15: Participants will be contacted by telephone to assess for any adverse effects. To ensure that dietary intake does not affect the absorption profile of tacrolimus we will ensure that breakfast is given 15 minutes prior to drug administration on the days of pharmacokinetic assessment (study day 3 and 8). |
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
United States, New York | |
NewYork-Presbyterian Hospital | |
New York, New York, United States, 10065 |
Principal Investigator: | Meredith J Aull, Pharm.D. | NewYork-Presbyterian Hospital |
Responsible Party: | NewYork-Presbyterian Hospital ( Meredith J. Aull, Pharm.D. ) |
Study ID Numbers: | 0710009492 |
Study First Received: | February 12, 2008 |
Last Updated: | February 25, 2008 |
ClinicalTrials.gov Identifier: | NCT00629122 |
Health Authority: | United States: Institutional Review Board |
Kidney Transplantation Tacrolimus (Prograf) Pharmacokinetics Sublingual administration Drug interactions (Cytochrome P450 and p-glycoprotein) |
Renal Insufficiency Urologic Diseases Clotrimazole Renal Insufficiency, Chronic Miconazole Tioconazole |
Kidney Failure, Chronic Nystatin Tacrolimus Kidney Diseases PS-K Kidney Failure |
Membrane Transport Modulators Anti-Bacterial Agents Anti-Infective Agents Anti-Infective Agents, Local Immunologic Factors Molecular Mechanisms of Pharmacological Action |
Antifungal Agents Therapeutic Uses Physiological Effects of Drugs Immunosuppressive Agents Ionophores Pharmacologic Actions |