Pharmacokinetics of Sublingual Versus Oral Tacrolimus in Patients Awaiting Kidney Transplantation

This study has been completed.
Sponsor:
Information provided by:
Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT00629122
First received: February 12, 2008
Last updated: November 4, 2010
Last verified: November 2010
  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. 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
Kidney Failure, Chronic
Drug: Tacrolimus/Clotrimazole Troche
Drug: Tacrolimus/Nystatin Suspension
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: 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 Weill Medical College of Cornell University:

Primary Outcome Measures:
  • Pharmacokinetic evaluation (absorption, distribution, elimination, area under the curve) between sublingual and oral administration routes. [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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. [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 20
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

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).

Experimental: B

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).


  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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

No publications provided

Responsible Party: Meredith J. Aull, Pharm.D., NewYork-Presbyterian Hospital
ClinicalTrials.gov Identifier: NCT00629122     History of Changes
Other Study ID Numbers: 0710009492
Study First Received: February 12, 2008
Last Updated: November 4, 2010
Health Authority: United States: Institutional Review Board

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

Additional relevant MeSH terms:
Kidney Failure, Chronic
Renal Insufficiency
Renal Insufficiency, Chronic
Kidney Diseases
Urologic Diseases
Clotrimazole
Miconazole
Nystatin
Tacrolimus
Anti-Infective Agents, Local
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Ionophores
Membrane Transport Modulators
Anti-Bacterial Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 24, 2014