Pharmacokinetics of Sirolimus and Tacrolimus in Liver Transplant Recipients With Tacrolimus Toxicity

Study Overview
=================
Brief Summary
-----------------
Pharmacokinetics of Tacrolimus and Sirolimus alone and in combination in liver transplant recipients.

Detailed Description
-----------------
Liver transplant patients receiving tacrolimus, and who experience side effects such as hypertension and renal dysfunction, will be converted to sirolimus with low-dose tacrolimus, or Tacrolimus withdrawal. This study will evaluate allograft function by serial clinical lab testing, the pharmacokinetics of sirolimus and tacrolimus, the glomerular filtration rate (GFR) and the potential side effect of sirolimus, such as marrow suppression and hyperlipidemia. Two pharmacokinetic evaluations are planned: once around the third post-transplant month and another one at about 12 months. Expected outcomes are, a better understanding of sirolimus pharmacokinetic parameters over time in pediatric/adult liver recipients and early efficacy and safety data of the sirolimus as a non-nephrotoxic alternative to tacrolimus.

Official Title
-----------------
Pharmacokinetics of Sirolimus and Tacrolimus in Liver Transplant Recipients With Early Nephrotoxicity and/or Hypertension Due to Tacrolimus

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: Sirolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Recipients of primary liver (cadaver/liver, whole/segmental) transplants 5- 30 years old. Rejection-free post-transplant course for at least 3 months Renal dysfunction (15% decrease in age-adjusted calculated creatinine clearance) Hypertension requiring anti-hypertensive mediations. Informed consent. Weight ≥15 kg. Exclusion Criteria: Rejection or infections within 3 months of enrollment. Intent to continue TAC Active participation in ongoing studies of immunosuppressive agents. Lack of informed consent. Pregnant or breast feeding HIV positive

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus<br> | Drug: Sirolimus<br>* Single dose SRL pharmacokinetics and TAC steady state pharmacokinetics: This phase is applicable to both sets of patients: those with nephrotoxicity and those with hypertension. Patients will receive a single dose of SRL of 2 mg/m2. Blood sampling will be performed over a 24 hour stay in the Children's Hospital of Pittsburgh's Pediatric Clinical and Translational Research Center (PCTRC) - See more at: http://www.chp.edu/research/our-facilities/pctrc, and the sampling for 48 hour and 72 hour PK studies can be done at the outpatient lab. This phase can either be performed immediately after the 12-hour iothalamate GFR evaluation, or a few days later at the convenience of the subject.<br>* Other names: Tacrolimus (FK506);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early and Late Pharmacokinetics of Sirolimus (SRL) | To evaluate early and late pharmacokinetics of Sirolimus (SRL) , and safety and efficacy of conversion from tacrolimus (TAC) to sirolimus in liver transplant recipients who have been stable for at least 3 months, and who have early nephrotoxicity and/or hypertension due to use of tacrolimus. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameters for Tacrolimus and Sirolimus | pharmacokinetics (PK) of SRL after a single dose and after steady state has been achieved; and the pharmacokinetics of tacrolimus once at steady state | 12 months | 
| SRL Can Substitute TAC | Whether Sirolimus can substitute Tacrolimus in the stable post-transplant state, without compromising allograft function | 12 months | 
| SRL Prevent TAC-related Side Effects | Whether SRL can prevent or minimize progression of selected TAC-related side-effects such as renal dysfunction as measured by clearance of iothalamate (Glomerular filtration rate < 80 mL/min/1.73 m2) and hypertension (blood pressure > 140/90 mm Hg) | 1 year |