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Pharmacokinetics of Sublingual Versus Oral Tacrolimus in Patients Awaiting Kidney Transplantation

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00629122
First Posted: March 5, 2008
Last Update Posted: December 11, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Meredith Aull, Weill Medical College of Cornell University
  Purpose
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. 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. 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 may allow for direct entry into the systemic circulation and bypasses problems associated with drug absorption and breakdown that take place in the small intestine.

Condition Intervention Phase
Kidney Failure, Chronic Drug: Tacrolimus (Arm B) Drug: Clotrimazole Troche Drug: Tacrolimus (Arm A) Drug: Nystatin Suspension Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Official Title: Pharmacokinetic Evaluation of Sublingual Versus Oral Tacrolimus Administration in Patients Awaiting Kidney Transplantation

Resource links provided by NLM:


Further study details as provided by Meredith Aull, Weill Medical College of Cornell University:

Primary Outcome Measures:
  • C0 (ng/mL) [ Time Frame: Day 3 and Day 8, time 0 (before tacrolimus dose) ]
    Trough concentration

  • Cmax [ Time Frame: Day 3 and Day 8, at time of maximum concentration ]
    Maximum concentration (ng/mL)

  • Tmax [ Time Frame: Day 3 and Day 8, time of maximum concentration ]
    Time to Maximum concentration (hours)

  • Estimated AUC 0-6 [ Time Frame: Day 3 and Day 8, calculated based on concentrations measured between hours 0 and 6 ]
    Area Under the Concentration-Time Curve from 0-6 hours (mg-hr/L)

  • Tacrolimus Powder Dissolution Time [ Time Frame: Day 3, minutes to powder dissolution ]
    Tacrolimus Powder Dissolution Time during Sublingual Administration (minutes)


Secondary Outcome Measures:
  • Drug Interactions and Genotypes [ Time Frame: 2 weeks ]
    Impact of drug interaction between tacrolimus and clotrimazole troche vs. nystatin suspension. Evaluate genotype polymorphisms that influence CYP3A4, CYP3A5, and p-glycoprotein expression to determine impact on sublingual and oral tacrolimus delivery.


Enrollment: 5
Study Start Date: February 2008
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A: Tacrolimus and Nystatin Suspension

Administer sublingual tacrolimus 2 mg every 12 hours (subject weight < 90 kg) or 3 mg every 12 hours (subject weight > 90kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose 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 (Arm A)
Study day 1 (9a): Initiate sublingual (SL) tacrolimus and nystatin suspension x 5 doses; Study day 3 (9a): Collection of pharmacokinetic parameters around the 5th SL tacrolimus dose; Study day 3 (9p): Start washout period, no drug administration (tacrolimus, nystatin); Study day 5 (9p): End washout period; Study day 6 (9a): Initiate oral tacrolimus and nystatin suspension x 5 doses; Study day 8 (9a): Collection of pharmacokinetic parameters around the 5th oral tacrolimus dose; Study day 15: Contact subjects 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).
Other Name: Prograf
Drug: Nystatin Suspension
Study day 1 (9a): Initiate sublingual (SL) tacrolimus and nystatin suspension x 5 doses; Study day 3 (9a): Collection of pharmacokinetic parameters around the 5th SL tacrolimus dose; Study day 3 (9p): Start washout period, no drug administration (tacrolimus, nystatin); Study day 5 (9p): End washout period; Study day 6 (9a): Initiate oral tacrolimus and nystatin suspension x 5 doses; Study day 8 (9a): Collection of pharmacokinetic parameters around the 5th oral tacrolimus dose; Study day 15: Contact subjects 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).
Other Name: Nystatin Swish and Swallow
Experimental: B: Tacrolimus and Clotrimazole Troche

Administer sublingual tacrolimus 1 mg every 12 hours (subject weight < 90 kg) or 2 mg every 12 hours (subject weight > 90 kg) (study day 1 - 3). Tacrolimus capsules will be opened and the contents placed under the participants tongue. Oral tacrolimus at same dose 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 (Arm B)
Study day 1 (9a): Initiate sublingual (SL) tacrolimus and clotrimazole troche x 5 doses; Study day 3 (9a): Collection of pharmacokinetic parameters around the 5th SL tacrolimus dose; Study day 3 (9p): Start washout period, no drug administration (tacrolimus, clotrimazole); Study day 5 (9p): End washout period; Study day 6 (9a): Initiate oral tacrolimus and clotrimazole troche x 5 doses; Study day 8 (9a): Collection of pharmacokinetic parameters around the 5th oral tacrolimus dose; Study day 15: Contact subject 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).
Other Name: Prograf
Drug: Clotrimazole Troche
Study day 1 (9a): Initiate sublingual (SL) tacrolimus and clotrimazole troche x 5 doses; Study day 3 (9a): Collection of pharmacokinetic parameters around the 5th SL tacrolimus dose; Study day 3 (9p): Start washout period, no drug administration (tacrolimus, clotrimazole); Study day 5 (9p): End washout period; Study day 6 (9a): Initiate oral tacrolimus and clotrimazole troche x 5 doses; Study day 8 (9a): Collection of pharmacokinetic parameters around the 5th oral tacrolimus dose; Study day 15: Contact subject 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).
Other Name: Mycelex

Detailed Description:
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.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients awaiting kidney transplantation aged ≥ 18 years

Exclusion Criteria:

  • Patients concurrently treated with medications that interact with tacrolimus (other than clotrimazole)
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00629122


Locations
United States, New York
NewYork-Presbyterian Hospital
New York, New York, United States, 10065
Sponsors and Collaborators
Weill Medical College of Cornell University
Investigators
Principal Investigator: Meredith J Aull, Pharm.D. NewYork-Presbyterian Hospital
  More Information

Responsible Party: Meredith Aull, Assistant Research Professor of Pharmacology in Surgery, Weill Medical College of Cornell University
ClinicalTrials.gov Identifier: NCT00629122     History of Changes
Other Study ID Numbers: 0710009492
First Submitted: February 12, 2008
First Posted: March 5, 2008
Results First Submitted: July 9, 2015
Results First Posted: December 11, 2017
Last Update Posted: December 11, 2017
Last Verified: November 2017

Keywords provided by Meredith Aull, Weill Medical College of Cornell University:
Kidney Transplantation
Tacrolimus (Prograf)
Pharmacokinetics
Sublingual administration
Drug interactions (Cytochrome P450 and p-glycoprotein)

Additional relevant MeSH terms:
Renal Insufficiency
Kidney Failure, Chronic
Kidney Diseases
Urologic Diseases
Renal Insufficiency, Chronic
Tacrolimus
Nystatin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Antifungal Agents
Ionophores
Membrane Transport Modulators