Pharmacokinetics of Sublingual Versus Oral Tacrolimus in Patients Awaiting Kidney Transplantation

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.

Inclusion Criteria:

- Adult patients awaiting kidney transplantation aged ≥ 18 years

Exclusion Criteria:

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