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

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

Pharmacokinetics of Tacrolimus and Sirolimus alone and in combination in liver transplant recipients.

Study Overview

• Status: Terminated
• Conditions: Hypertension
• Intervention / Treatment: Drug: Sirolimus

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Sirolimus

Drug: Sirolimus; 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.; Other Names: Sirolimus (Rapamycin); 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

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Investigators: Principal Investigator: Rakesh Sindhi, UPitt

Study record dates

Study Major Dates

• Study Start: December 1, 2005
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): January 1, 2010

Study Registration Dates

• First Submitted: June 29, 2010
• First Submitted That Met QC Criteria: October 16, 2012
• First Posted (Estimate): October 17, 2012

Study Record Updates

• Last Update Posted (Actual): March 30, 2023
• Last Update Submitted That Met QC Criteria: March 29, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Calcineurin Inhibitors; Tacrolimus; Sirolimus
• Other Study ID Numbers: 07100379