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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01709136
Recruitment Status : Terminated (Sirolimus usage discontinued since black box warning)
First Posted : October 17, 2012
Results First Posted : April 21, 2016
Last Update Posted : April 21, 2016
Information provided by (Responsible Party):
Rakesh Sindhi, University of Pittsburgh

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

Condition or disease Intervention/treatment Phase
Hypertension Drug: Sirolimus Phase 2 Phase 3

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  (Clinical Trial)
Actual Enrollment : 3 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacokinetics of Sirolimus and Tacrolimus in Liver Transplant Recipients With Early Nephrotoxicity and/or Hypertension Due to Tacrolimus
Study Start Date : December 2005
Actual Primary Completion Date : January 2010
Actual Study Completion Date : January 2010

Resource links provided by the National Library of Medicine

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:, 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)

Primary Outcome Measures :
  1. Early and Late Pharmacokinetics of Sirolimus (SRL) [ Time Frame: 1 year ]
    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.

Secondary Outcome Measures :
  1. PK Parameters for Tacrolimus and Sirolimus [ Time Frame: 12 months ]
    pharmacokinetics (PK) of SRL after a single dose and after steady state has been achieved; and the pharmacokinetics of tacrolimus once at steady state

  2. SRL Can Substitute TAC [ Time Frame: 12 months ]
    Whether Sirolimus can substitute Tacrolimus in the stable post-transplant state, without compromising allograft function

  3. SRL Prevent TAC-related Side Effects [ Time Frame: 1 year ]
    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)

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Ages Eligible for Study:   Child, Adult, Older Adult
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01709136

Sponsors and Collaborators
University of Pittsburgh
Principal Investigator: Rakesh Sindhi UPitt

Responsible Party: Rakesh Sindhi, Professor of Surgery, University of Pittsburgh Identifier: NCT01709136     History of Changes
Other Study ID Numbers: 07100379
First Posted: October 17, 2012    Key Record Dates
Results First Posted: April 21, 2016
Last Update Posted: April 21, 2016
Last Verified: March 2016

Additional relevant MeSH terms:
Vascular Diseases
Cardiovascular Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents