Hypertension
Conditions
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.
Interventions
DRUGSirolimus
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.
Sponsors
University of Pittsburgh
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early and Late Pharmacokinetics of Sirolimus (SRL) | 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
| Measure | Time frame | Description |
|---|---|---|
| SRL Prevent TAC-related Side Effects | 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) |
| PK Parameters for Tacrolimus and Sirolimus | 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 |
| SRL Can Substitute TAC | 12 months | Whether Sirolimus can substitute Tacrolimus in the stable post-transplant state, without compromising allograft function |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus 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 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. | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Sirolimus |
|---|---|
| Age, Categorical <=18 years | 3 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 3 |
| serious Total, serious adverse events | 0 / 3 |
Outcome results
Primary
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.
Time frame: 1 year
Population: Three pharmacokinetics (PK) profiles were performed, one in each of three patients who were enrolled. However, due to FDA blackbox warnings (6/11/2009) about Sirolimus in liver transplant recipients be circumspect (risk of thrombosis and death), the study was terminated early and data analysis was not able to be completed.
Secondary
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
Time frame: 12 months
Population: We were able to preform 3 pharmacokinetics (PK) profiles, one in each of three patients enrolled. However, due to emerging data and blackbox warnings from FDA suggesting that use of Sirolimus in liver transplant recipients be circumspect (risk of thrombosis and death), the study was terminated early and data analysis was not able to be completed.
Secondary
SRL Can Substitute TAC
Whether Sirolimus can substitute Tacrolimus in the stable post-transplant state, without compromising allograft function
Time frame: 12 months
Population: Due to FDA blackbox warnings (6/11/09) about Sirolimus in liver transplant recipients (risk of thrombosis and death), the study was terminated early. Due to the early termination of this study and small number of subjects enrolled (3), data analysis was not able to be completed.
Secondary
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)
Time frame: 1 year
Population: Due to FDA blackbox warnings from FDA (6/11/2009) about Sirolimus in liver transplant recipients (risk of thrombosis and death), the study was terminated early and data analysis was not able to be completed.