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Pharmacokinetics of Sublingual Versus Oral Tacrolimus in Patients Awaiting Kidney Transplantation

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ClinicalTrials.gov Identifier: NCT00629122
Recruitment Status : Completed
First Posted : March 5, 2008
Results First Posted : December 11, 2017
Last Update Posted : June 12, 2019
Sponsor:
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Tracking Information
First Submitted Date  ICMJE February 12, 2008
First Posted Date  ICMJE March 5, 2008
Results First Submitted Date  ICMJE July 9, 2015
Results First Posted Date  ICMJE December 11, 2017
Last Update Posted Date June 12, 2019
Study Start Date  ICMJE February 2008
Actual Primary Completion Date December 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 2, 2017)
  • 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)
Original Primary Outcome Measures  ICMJE
 (submitted: February 25, 2008)
Pharmacokinetic evaluation (absorption, distribution, elimination, area under the curve) between sublingual and oral administration routes. [ Time Frame: 2 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2017)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2008)
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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetics of Sublingual Versus Oral Tacrolimus in Patients Awaiting Kidney Transplantation
Official Title  ICMJE Pharmacokinetic Evaluation of Sublingual Versus Oral Tacrolimus Administration in Patients Awaiting Kidney Transplantation
Brief Summary 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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Condition  ICMJE Kidney Failure, Chronic
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • 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).

    Interventions:
    • Drug: Tacrolimus (Arm A)
    • Drug: Nystatin Suspension
  • 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).

    Interventions:
    • Drug: Tacrolimus (Arm B)
    • Drug: Clotrimazole Troche
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 2, 2017)
5
Original Estimated Enrollment  ICMJE
 (submitted: February 25, 2008)
20
Actual Study Completion Date  ICMJE December 2009
Actual Primary Completion Date December 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adult patients awaiting kidney transplantation aged ≥ 18 years

Exclusion Criteria:

  • Patients concurrently treated with medications that interact with tacrolimus (other than clotrimazole)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00629122
Other Study ID Numbers  ICMJE 0710009492
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Weill Medical College of Cornell University
Study Sponsor  ICMJE Weill Medical College of Cornell University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Meredith J Aull, Pharm.D. Weill Medical College of Cornell University
PRS Account Weill Medical College of Cornell University
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP