Pharmacokinetics of Sublingual Versus Oral Tacrolimus in Patients Awaiting Kidney Transplantation

NCT00629122 | Completed Phase 4 Results

• 1 other identifier: 0710009492
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Kidney Failure, Chronic

Keywords

Kidney Transplantation; Tacrolimus (Prograf); Pharmacokinetics; Sublingual administration; Drug interactions (Cytochrome P450 and p-glycoprotein)

Outcome Measures

Primary Outcomes (5)

• C0 (ng/mL)

  Trough concentration

  Day 3 and Day 8, time 0 (before tacrolimus dose)

• Cmax

  Maximum concentration (ng/mL)

  Day 3 and Day 8, at time of maximum concentration

• Tmax

  Time to Maximum concentration (hours)

  Day 3 and Day 8, time of maximum concentration

• Estimated AUC 0-6

  Area Under the Concentration-Time Curve from 0-6 hours (mg-hr/L)

  Day 3 and Day 8, calculated based on concentrations measured between hours 0 and 6

• Tacrolimus Powder Dissolution Time

  Tacrolimus Powder Dissolution Time during Sublingual Administration (minutes)

  Day 3, minutes to powder dissolution

Secondary Outcomes (1)

• Drug Interactions and Genotypes

  2 weeks

Study Arms (2)

A: Tacrolimus and Nystatin Suspension

EXPERIMENTAL

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); Drug: Nystatin Suspension

B: Tacrolimus and Clotrimazole Troche

EXPERIMENTAL

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); Drug: Clotrimazole Troche

Interventions

Tacrolimus (Arm B) DRUG

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).

Also known as: Prograf

B: Tacrolimus and Clotrimazole Troche

Clotrimazole Troche DRUG

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).

Also known as: Mycelex

B: Tacrolimus and Clotrimazole Troche

Tacrolimus (Arm A) DRUG

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).

Also known as: Prograf

A: Tacrolimus and Nystatin Suspension

Nystatin Suspension DRUG

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).

Also known as: Nystatin Swish and Swallow

A: Tacrolimus and Nystatin Suspension

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients awaiting kidney transplantation aged ≥ 18 years

You may not qualify if:

• Patients concurrently treated with medications that interact with tacrolimus (other than clotrimazole)

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead

Study Sites (1)

NewYork-Presbyterian Hospital

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

Tacrolimus; Clotrimazole; Deglutition

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Digestive System Physiological Phenomena; Digestive System and Oral Physiological Phenomena

Limitations and Caveats

Small sample size; variable absorption profile; poor vascular access in some subjects; possible enteral absorption of sublingual drug; unable to assess genotype polymorphisms due to the small number of subjects.

Results Point of Contact

• Title: Meredith J. Aull, Pharm.D.
• Organization: Weill Cornell Medical College

mea9008@med.cornell.edu

(212) 746-8720

Study Officials

• Meredith J Aull, Pharm.D.

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: HEALTH SERVICES RESEARCH
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2008
• First Posted: March 5, 2008
• Study Start: February 1, 2008
• Primary Completion: December 1, 2009
• Study Completion: December 1, 2009
• Last Updated: June 12, 2019
• Results First Posted: December 11, 2017

Record last verified: 2019-05

Locations

US (1)