Clinical trial NCT00629122: Pharmacokinetics of Sublingual Versus Oral Tacrolimus in Patients Awaiting Kidney Transplantation
Official title: Pharmacokinetic Evaluation of Sublingual Versus Oral Tacrolimus Administration in Patients Awaiting Kidney Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Kidney Failure, Chronic
Keywords: Kidney Transplantation
Tacrolimus (Prograf)
Pharmacokinetics
Sublingual administration
Drug interactions (Cytochrome P450 and p-glycoprotein)
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
First posted: 2008-03-05
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: HEALTH_SERVICES_RESEARCH

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.

Eligibility 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)

Primary outcomes:
measure: C0 (ng/mL)
timeFrame: Day 3 and Day 8, time 0 (before tacrolimus dose)
measure: Cmax
timeFrame: Day 3 and Day 8, at time of maximum concentration
measure: Tmax
timeFrame: Day 3 and Day 8, time of maximum concentration
measure: Estimated AUC 0-6
timeFrame: Day 3 and Day 8, calculated based on concentrations measured between hours 0 and 6
measure: Tacrolimus Powder Dissolution Time
timeFrame: Day 3, minutes to powder dissolution
Secondary outcomes:
measure: Drug Interactions and Genotypes
timeFrame: 2 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: NewYork-Presbyterian Hospital
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Meredith J Aull, Pharm.D.
role: PRINCIPAL_INVESTIGATOR
References: