Conversion From Brand to Generic Tacrolimus in High Risk Transplant Recipients

Phase 4

Completed

Conditions: Complication of Transplant

Interventions: Drug: Prograf
Drug: Tacrolimus, Sandoz
Drug: Tacrolimus, Reddy Laboratory
Drug: Tacrolimus, Mylan
Drug: Tacrolimus, Accord
Drug: Tacrolimus, Pancea Biotech Limited

Registration Number: NCT02014103

Lead Sponsor: University of Cincinnati

Brief Summary: The prospective study will compare the relative bioavailability at steady-state pharmacokinetics of 6 tacrolimus formulations in a prospective, 6-way cross-over study including CYP3A5 expressors (n=30) and non-expressor (n=30) transplant patients.

Detailed Description: Comparison of the relative bioavailability and steady-state pharmacokinetics of 6 tacrolimus formulations in a prospective, 6-way cross-over study including CYP3A5 expressors (n=30) and non-expressor (n=30) transplant patients. Six tacrolimus formulations will be tested and each patient will receive each formulation once. As we proposed to test bioequivalence in the steady-state, patients will receive the test formulations for one week prior to pharmacokinetic evaluation. The pharmacokinetic evaluation will incorporate limited sampling strategies with a focus on fully characterizing the Cmax out to hour 4 post dose. Subsequent PK sampling and trough blood concentrations will be monitored on a daily basis using dried blood spots that the study subjects will collect by themselves at home. It will be critical that the patients are adherent to their test medication to ensure that they have reached steady state. This will be monitored using test diaries, pill counts and MEMS caps (Medication Event Monitoring System (MEMS), AARDEX Corp, Palo Alto, CA. Bioequivalence will be tested using average bioequivalence metrics. A combination of limited sampling strategy and dry spot analysis in combination with population pharmacokinetic modeling will be utilized to fully characterize the PK profile of these formulations.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 71

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence 1	Tacrolimus, Reddy Laboratory	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 1: Formulation Sandoz, Panacea, Accord, Mylan, Dr. Reddy's, Astellas Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 2	Prograf	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 2: Formulation Accord, Sandoz, Dr. Reddy's, Panacea, Astellas, Mylan Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 1	Tacrolimus, Sandoz	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 1: Formulation Sandoz, Panacea, Accord, Mylan, Dr. Reddy's, Astellas Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 3	Tacrolimus, Reddy Laboratory	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 3: Formulation Dr. Reddys, Accord, Astellas, Sandoz, Mylan, Panacea Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 3	Tacrolimus, Mylan	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 3: Formulation Dr. Reddys, Accord, Astellas, Sandoz, Mylan, Panacea Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 1	Tacrolimus, Mylan	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 1: Formulation Sandoz, Panacea, Accord, Mylan, Dr. Reddy's, Astellas Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 1	Tacrolimus, Pancea Biotech Limited	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 1: Formulation Sandoz, Panacea, Accord, Mylan, Dr. Reddy's, Astellas Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 2	Tacrolimus, Sandoz	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 2: Formulation Accord, Sandoz, Dr. Reddy's, Panacea, Astellas, Mylan Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 2	Tacrolimus, Mylan	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 2: Formulation Accord, Sandoz, Dr. Reddy's, Panacea, Astellas, Mylan Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 1	Tacrolimus, Accord	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 1: Formulation Sandoz, Panacea, Accord, Mylan, Dr. Reddy's, Astellas Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 3	Tacrolimus, Sandoz	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 3: Formulation Dr. Reddys, Accord, Astellas, Sandoz, Mylan, Panacea Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 3	Tacrolimus, Accord	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 3: Formulation Dr. Reddys, Accord, Astellas, Sandoz, Mylan, Panacea Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 4	Tacrolimus, Sandoz	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 4: Formulation Astellas, Dr. Reddy's, Mylan, Accord, Panacea, Sandoz Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 4	Tacrolimus, Reddy Laboratory	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 4: Formulation Astellas, Dr. Reddy's, Mylan, Accord, Panacea, Sandoz Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 5	Tacrolimus, Reddy Laboratory	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 5: Formulation Mylan, Astellas, Panacea, Dr. Reddy's, Sandoz, Accord Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 2	Tacrolimus, Reddy Laboratory	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 2: Formulation Accord, Sandoz, Dr. Reddy's, Panacea, Astellas, Mylan Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 4	Tacrolimus, Mylan	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 4: Formulation Astellas, Dr. Reddy's, Mylan, Accord, Panacea, Sandoz Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 5	Prograf	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 5: Formulation Mylan, Astellas, Panacea, Dr. Reddy's, Sandoz, Accord Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 5	Tacrolimus, Sandoz	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 5: Formulation Mylan, Astellas, Panacea, Dr. Reddy's, Sandoz, Accord Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 5	Tacrolimus, Pancea Biotech Limited	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 5: Formulation Mylan, Astellas, Panacea, Dr. Reddy's, Sandoz, Accord Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 2	Tacrolimus, Accord	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 2: Formulation Accord, Sandoz, Dr. Reddy's, Panacea, Astellas, Mylan Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 2	Tacrolimus, Pancea Biotech Limited	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 2: Formulation Accord, Sandoz, Dr. Reddy's, Panacea, Astellas, Mylan Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 3	Tacrolimus, Pancea Biotech Limited	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 3: Formulation Dr. Reddys, Accord, Astellas, Sandoz, Mylan, Panacea Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 4	Tacrolimus, Accord	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 4: Formulation Astellas, Dr. Reddy's, Mylan, Accord, Panacea, Sandoz Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 4	Tacrolimus, Pancea Biotech Limited	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 4: Formulation Astellas, Dr. Reddy's, Mylan, Accord, Panacea, Sandoz Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 5	Tacrolimus, Mylan	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 5: Formulation Mylan, Astellas, Panacea, Dr. Reddy's, Sandoz, Accord Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 6	Tacrolimus, Reddy Laboratory	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 6: Formulation Panacea, Mylan, Sandoz, Astellas, Accord, Dr. Reddy's Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 6	Tacrolimus, Mylan	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 6: Formulation Panacea, Mylan, Sandoz, Astellas, Accord, Dr. Reddy's Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 6	Tacrolimus, Accord	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 6: Formulation Panacea, Mylan, Sandoz, Astellas, Accord, Dr. Reddy's Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 5	Tacrolimus, Accord	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 5: Formulation Mylan, Astellas, Panacea, Dr. Reddy's, Sandoz, Accord Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 6	Tacrolimus, Sandoz	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 6: Formulation Panacea, Mylan, Sandoz, Astellas, Accord, Dr. Reddy's Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 6	Tacrolimus, Pancea Biotech Limited	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 6: Formulation Panacea, Mylan, Sandoz, Astellas, Accord, Dr. Reddy's Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 1	Prograf	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 1: Formulation Sandoz, Panacea, Accord, Mylan, Dr. Reddy's, Astellas Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 3	Prograf	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 3: Formulation Dr. Reddys, Accord, Astellas, Sandoz, Mylan, Panacea Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 4	Prograf	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 4: Formulation Astellas, Dr. Reddy's, Mylan, Accord, Panacea, Sandoz Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.
Sequence 6	Prograf	Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 6: Formulation Panacea, Mylan, Sandoz, Astellas, Accord, Dr. Reddy's Patients will be receiving the same tacrolimus dose identified at baseline for each formulation.

Primary Outcome Measures

Name	Time	Method
Compare AUC 0-12hr of Each Tacrolimus Formulation in Expressor and Non Expressor Transplant Recipients	Whole blood samples were collected immediately prior to dosing, at 1, 1.5, 1.75, 2, 2.5, 3 and 4 hours following dosing. Subjects were then instructed to performed fingersticks using dried blood spot cards at 8 and 12 hours post dose.	Report the geometric mean and 95% confidence interval for AUC 0-12hr (ng\*hr/ml) for each formulation in expressor and non expressor transplant recipients
Compare Cmax of Each Tacrolimus Formulation in Expressor and Non Expressor Transplant Recipients	Whole blood samples were collected immediately prior to dosing, at 1, 1.5, 1.75, 2, 2.5, 3 and 4 hours following dosing. Subjects were then instructed to performed fingersticks using dried blood spot cards at 8 and 12 hours post dose.	Report the geometric mean and 95% confidence interval for Cmax (ng/ml) for each formulation in expressor and non expressor transplant recipients

Secondary Outcome Measures

Name	Time	Method
To Compare the Safety and Efficacy of Each Tacrolimus Formulation in Stable Transplant Subjects	Assessed at baseline and weekly for 6 weeks at each pharmacokinetic profile	Conduct safety lab testing specific to transplanted organ function and clinical assessments for adverse events.