Pharmacokinetics of Sublingual Versus Oral Tacrolimus in Patients Awaiting Kidney Transplantation
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. 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 Design
Allocation: Randomized, Control: Uncontrolled, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Health Services Research
Conditions
Kidney Failure, Chronic
Intervention
Tacrolimus/Clotrimazole Troche, Tacrolimus/Nystatin Suspension
Location
NewYork-Presbyterian Hospital
New York
New York
United States
10065
Status
Enrolling by invitation
Source
Weill Medical College of Cornell University
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00629122
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Tacrolimus Binding Protein 1a
A 12-KDa tacrolimus binding protein that is found associated with and may modulate the function of calcium release channels. It is a peptidyl-prolyl cis/trans isomerase which is inhibited by both tacrolimus (commonly called FK506) and SIROLIMUS.
Tacrolimus Binding Proteins
A family of immunophilin proteins that bind to the immunosuppressive drugs TACROLIMUS (also known as FK506) and SIROLIMUS. EC 5.2.1.-
Tor Serine-threonine Kinases
A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that TACROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity.
Kidney Failure
A severe irreversible decline in the ability of kidneys to remove wastes, concentrate URINE, and maintain ELECTROLYTE BALANCE; BLOOD PRESSURE; and CALCIUM metabolism. Renal failure, either acute (KIDNEY FAILURE, ACUTE) or chronic (KIDNEY FAILURE, CHRONIC), requires HEMODIALYSIS.
Tacrolimus
A macrolide isolated from the culture broth of a strain of Streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro.
Clinical Trials
A Study Comparing the Withdrawal of Steroids or Tacrolimus in Kidney Transplant Recipients
This study evaluates two different immunosuppression drug regimens in patients with a recent kidney transplant. Patients initially received a regimen of Sirolimus, Tacrolimus and Predniso...
The purpose of this study is to evaluate two groups of kidney transplant recipients, to determine the proportion of patients that achieve therapeutic blood concentrations of tacrolimus by...
This study is being done to find out which treatment, tacrolimus or sirolimus, leads to better long-term kidney function.
This 2 arm study will compare the efficacy and safety of CellCept, combined with low or standard dose tacrolimus plus corticosteroids, in patients with kidney transplants. Patients will be...
Comparative Study of Modified Release (MR) Tacrolimus/MMF in de Novo Kidney Transplant Recipients
The purpose of this study is to compare the safety and efficacy of Prograf/MMF, Neoral/MMF and Modified Release (MR) Tacrolimus/MMF in de novo kidney transplant recipients.
PubMed Articles
Tacrolimus-Induced Severe Cholestasis Complicating Renal Transplantation.
Tacrolimus, a calcineurin inhibitor, is a potent immunosuppressive agent used by a majority of transplanters across the globe. Its adverse effects include nephrotoxicity, neurotoxicity, new onset diab...
Aim:To evaluate the pharmacokinetics of tacrolimus in Chinese stable liver transplant recipients converted from immediate release (IR) tacrolimus-based immunosuppression to modified release (MR) tacro...
PURPOSE: The purpose of this study was to characterize the effects of clinical and genetic variables on the pharmacokinetics and complications of tacrolimus during the first year...
We evaluated the hypothesis that cytochrome P450 3A5 (CYP3A5) expression can affect intrarenal tacrolimus accumulation. Tacrolimus was administered orally to 24 healthy volunteers who were selected on...
Is there any way to protect from tacrolimus-induced renal and pancreas injury?
BACKGROUND: The aim of this study was to explore effects of erythropoietin and pentoxifylline in tacrolimus-induced pancreatic beta cell and renal injury in rats. METHODS: Rats in group I were given s...
