Conversion From Brand to Generic Tacrolimus in High Risk Transplant Recipients

Evaluation of Clinical and Safety Outcomes Associated With Conversion From Brand-Name to Generic Tacrolimus Products in High Risk Transplant Recipients

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.

Study Overview

• Status: Completed
• Conditions: Complication of Transplant
• Intervention / Treatment: Drug: Prograf; Drug: Tacrolimus, Sandoz; Drug: Tacrolimus, Reddy Laboratory; Drug: Tacrolimus, Mylan; Drug: Tacrolimus, Accord; Drug: Tacrolimus, Pancea Biotech Limited

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.

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

1. 18 years or older
2. Able to participate and willing to give written informed consent/ assent/ consent by parent or legal guardian and to comply with the study visits and restrictions.
3. Subject who has received a primary or secondary transplant.
4. Subject who is at least 6 months post-transplant and on a stable dose of tacrolimus as defined by physician, one tacrolimus trough level within the physician defined target range within past 6 months and one additional trough level during the screening period within 30% of the physician defined target range.
5. BMI less than or equal to 40.

Exclusion criteria

1. Evidence of any acute rejection
2. Subjects who require dialysis within 6 months prior to study entry
3. Recipients of multiple organ transplants
4. Subjects who have tested positive for HBsAG or HIV, or who are recipients of organ from donors who are known to be HBsAG or HIV positive. Virology screening at the time of transplant.
5. HepC positive subjects with liver biopsy proven recurrent disease considered relevant by physician oversight.
6. Subjects with any severe medical condition requiring acute or chronic treatment that in the investigator's opinion would interfere with study participation
7. History of malignancy, treated or untreated, with the past 2 years with the exception of carcinoma in situ or excised basal cell carcinoma, or hepatocellular carcinoma prior to transplant.
8. GFR ≤ 35 ml/min measured as estimated using the MDRD4 formula
9. Subjects with AST, ALT, total bilirubin ≥ 3 X ULN or other evidence of severe liver disease
10. Subjects with white blood cell (WBC) count ≤2,000/ mm3 or with thrombocytopenia (platelet count ≤ 75,000/ mm3), with an absolute neutrophil count of ≤ 1,500/ mm3 or hemoglobin <8g/dL)
11. Subjects with clinically significant infections, requiring therapy, which, in the investigator's opinion, would interfere with the objectives of the study
12. Other mental or physical conditions which in the investigator's opinion, are considered clinically significant
13. Presence of intractable immunosuppressant complications or side effects resulting in dose adjustment of tacrolimus
14. Subjects who have been exposed to an investigational therapy within 30 days prior to enrollment or 5 half-lives of the investigational product, whichever is greater.
15. An anticipated change in the immunosuppressive regimen during subject participation other than that required by the protocol
16. Subject with severe GI disturbance or diarrhea which could interfere with tacrolimus absorption
17. Severe diabetic gastroparesis
18. Initiation of any medications that could interfere with tacrolimus blood levels, including OTC medications, herbal supplements, grapefruit or grapefruit juice.
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive BhCG laboratory test (> 5 mIU/mL)
20. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are: 1) women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner; 2)women whose partners have been sterilized by vasectomy or 3)using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices (IUDs); periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sequence 1; 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.	Drug: Prograf; Administration of each formulation will be determined by sequence.; Drug: Tacrolimus, Sandoz; Administration of each formulation will be determined by sequence.; Other Names: Sandoz tacrolimus; Drug: Tacrolimus, Reddy Laboratory; Administration of each formulation will be determined by sequence.; Other Names: Reddy's Laboratory tacrolimus; Drug: Tacrolimus, Mylan; Administration of each formulation will be determined by sequence.; Other Names: Mylan tacrolimus; Drug: Tacrolimus, Accord; Administration of each formulation will be determined by sequence.; Other Names: Accord Healthcare tacrolimus; Drug: Tacrolimus, Pancea Biotech Limited; Administration of each formulation will be determined by sequence.; Other Names: Panacea Biotech Limited tacrolimus
Active Comparator: Sequence 2; 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.	Drug: Prograf; Administration of each formulation will be determined by sequence.; Drug: Tacrolimus, Sandoz; Administration of each formulation will be determined by sequence.; Other Names: Sandoz tacrolimus; Drug: Tacrolimus, Reddy Laboratory; Administration of each formulation will be determined by sequence.; Other Names: Reddy's Laboratory tacrolimus; Drug: Tacrolimus, Mylan; Administration of each formulation will be determined by sequence.; Other Names: Mylan tacrolimus; Drug: Tacrolimus, Accord; Administration of each formulation will be determined by sequence.; Other Names: Accord Healthcare tacrolimus; Drug: Tacrolimus, Pancea Biotech Limited; Administration of each formulation will be determined by sequence.; Other Names: Panacea Biotech Limited tacrolimus
Active Comparator: Sequence 3; 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.	Drug: Prograf; Administration of each formulation will be determined by sequence.; Drug: Tacrolimus, Sandoz; Administration of each formulation will be determined by sequence.; Other Names: Sandoz tacrolimus; Drug: Tacrolimus, Reddy Laboratory; Administration of each formulation will be determined by sequence.; Other Names: Reddy's Laboratory tacrolimus; Drug: Tacrolimus, Mylan; Administration of each formulation will be determined by sequence.; Other Names: Mylan tacrolimus; Drug: Tacrolimus, Accord; Administration of each formulation will be determined by sequence.; Other Names: Accord Healthcare tacrolimus; Drug: Tacrolimus, Pancea Biotech Limited; Administration of each formulation will be determined by sequence.; Other Names: Panacea Biotech Limited tacrolimus
Active Comparator: Sequence 4; 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.	Drug: Prograf; Administration of each formulation will be determined by sequence.; Drug: Tacrolimus, Sandoz; Administration of each formulation will be determined by sequence.; Other Names: Sandoz tacrolimus; Drug: Tacrolimus, Reddy Laboratory; Administration of each formulation will be determined by sequence.; Other Names: Reddy's Laboratory tacrolimus; Drug: Tacrolimus, Mylan; Administration of each formulation will be determined by sequence.; Other Names: Mylan tacrolimus; Drug: Tacrolimus, Accord; Administration of each formulation will be determined by sequence.; Other Names: Accord Healthcare tacrolimus; Drug: Tacrolimus, Pancea Biotech Limited; Administration of each formulation will be determined by sequence.; Other Names: Panacea Biotech Limited tacrolimus
Active Comparator: Sequence 5; 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.	Drug: Prograf; Administration of each formulation will be determined by sequence.; Drug: Tacrolimus, Sandoz; Administration of each formulation will be determined by sequence.; Other Names: Sandoz tacrolimus; Drug: Tacrolimus, Reddy Laboratory; Administration of each formulation will be determined by sequence.; Other Names: Reddy's Laboratory tacrolimus; Drug: Tacrolimus, Mylan; Administration of each formulation will be determined by sequence.; Other Names: Mylan tacrolimus; Drug: Tacrolimus, Accord; Administration of each formulation will be determined by sequence.; Other Names: Accord Healthcare tacrolimus; Drug: Tacrolimus, Pancea Biotech Limited; Administration of each formulation will be determined by sequence.; Other Names: Panacea Biotech Limited tacrolimus
Active Comparator: Sequence 6; 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.	Drug: Prograf; Administration of each formulation will be determined by sequence.; Drug: Tacrolimus, Sandoz; Administration of each formulation will be determined by sequence.; Other Names: Sandoz tacrolimus; Drug: Tacrolimus, Reddy Laboratory; Administration of each formulation will be determined by sequence.; Other Names: Reddy's Laboratory tacrolimus; Drug: Tacrolimus, Mylan; Administration of each formulation will be determined by sequence.; Other Names: Mylan tacrolimus; Drug: Tacrolimus, Accord; Administration of each formulation will be determined by sequence.; Other Names: Accord Healthcare tacrolimus; Drug: Tacrolimus, Pancea Biotech Limited; Administration of each formulation will be determined by sequence.; Other Names: Panacea Biotech Limited tacrolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare AUC 0-12hr of Each Tacrolimus Formulation in Expressor and Non Expressor Transplant Recipients	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	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.
Compare Cmax of Each Tacrolimus Formulation in Expressor and Non Expressor Transplant Recipients	Report the geometric mean and 95% confidence interval for Cmax (ng/ml) for each 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.

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Collaborators: University of Colorado, Denver; Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Rita R Alloway, PharmD, University of Cincinnati

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: October 21, 2013
• First Submitted That Met QC Criteria: December 17, 2013
• First Posted (Estimated): December 18, 2013

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 10, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: transplant; bioequivalence; tacrolimus; CYP3A5 expressors/non expressors
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: 13-223-SOL-00102; FDA (Other Grant/Funding Number: HHSF223201310224C)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO