Determining Equivalence Dose for Oral Versus Sublingual Administration of Tacrolimus in Hepatic Receptors

Study Overview
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Brief Summary
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After liver transplantation one of the most important cost, for both patients and their health insurance system, is immunosuppressive drug therapy. Tacrolimus (FK 506) is considered the cornerstone of immunosuppressive therapy in solid organ transplantation. Oral administration is the usual route, however, sublingual (SL) administration has been recently reported. This method of administration avoids first pass metabolism and allows an alternative route after transplant surgery, particularly in those patients who should extend the period of fasting (prolonged intubation, ileus, etc). Interestingly, in some studies, the dose of tacrolimus SL required to maintain similar plasma concentrations compared with oral administration, is significantly lower, even up to 50%, which can result in considerable savings in short and long term. Among these studies, only one was conducted in liver recipients. This study suggest that SL administration of tacrolimus could allow to obtain similar concentrations compared with oral administration. The design of this study did not assess the existence of differences in the dose required and only included six patients.

Detailed Description
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The patient will be scheduled fasting to liver transplant unit where the pharmacokinetic study was performed. After installation of the venous needle, blood samples will be collected on 4 ml tubes with EDTA as an anticoagulant at the following intervals of time in hours: 0 (immediately before the oral administration of tacrolimus); 0.5; 1.0; 1.5; 2; 4; 6; 9 and 12 h. post-dose. Once the blood samples taken, the tubes will be plugged, invest gently to mix with anticoagulant and stored at -20 ° C until analysis. Subsequently, tacrolimus administration was change to sublingual route and dose was adjusted to obtain similar trough levels to those determined on per oral administration. The capsule be opened and its contents shall be deposited in the sublingual mucosa. To be ensure that drug will be absorted the patient will be instructed to insistently that after sublingual placement of the drug, should not swallow the capsule content for at least 15 minutes. The same pharmacokinetic study described for the oral route will be performed. Breakfast will be administered 2 hours after ingesting the drug and lunch and dinner 6 and 10 hours after respectively. Fluid intake is discretionary.

Official Title
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Determining Equivalence Dose for Oral Versus Sublingual Administration of Tacrolimus in Hepatic Receptors

Conditions
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Evidence of Liver Transplantation, Effects of Immunosuppressant Therapy

Intervention / Treatment
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* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outline of immunosuppression that includes tacrolimus dosing every 12 hours. Stable plasma levels of tacrolimus in 3 consecutive measurements. Stable blood tests: biochemical profile, creatinine and liver profile. Absence of treatment with drugs that have interaction with tacrolimus (antifungal and diltiazem) and use of grapefruit juice. Absence of active bacterial or viral infection and rejection episodes within 8 weeks prior. Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: oral administration of tacrolimus<br>Oral administration of tacrolimus (FK506) in the usal dose and measuring plasmatic levels at hours 0, 0.5, 1, 2, 3, 4 and 6. Measuring AUC. | |
| Active Comparator: sublingual administration of tacrolimus<br>sublingual administration of tacrolimus (FK506) in the dose that allows similar plasmatic level at time 0 compared with the oral administration, and measuring plasmatic levels at hours 0, 0.5, 1 , 2, 3 , 4 and 6. Measuring AUC. | Drug: Tacrolimus<br>* compared oral administration versus sublingual administration of tacrolimus.<br>* Other names: FK506;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare tacrolimus exposure using per oral and sublingual administration employing AUC (Area Under the Curve). | compared oral administration versus sublingual administration of tacrolimus | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare tacrolimus dose necessary to obtain similar trough levels employing per oral and sublingual administration | compared oral administration versus sublingual administration of tacrolimus | 30 days |