Conversion From Brand to Generic Tacrolimus in High Risk Transplant Recipients

Study Overview
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Brief Summary
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Conduct a retrospective study to evaluate the impact of generic conversion in adult transplant recipients on post transplant outcomes one year prior to conversion to one year post conversion. Variables for analysis will include but not limited to incidence of rejection, hospital admission, changes in renal function, changes in transplanted organ function. All tacrolimus levels and dose changes during this period will be collected and compared. Additional pharmacokinetic modeling of this data will be performed for comparison. The prospective study will compare othe 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.

Detailed Description
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Primary hypothesis: - Generic immunosuppressants for which bioequivalence were established in single-dose healthy volunteer studies are also bioequivalent to the brand in stable transplant patients that are considered high-risk such as CYP3A expressors, AA, and diabetics patients under steady-state conditions and there will be no difference in intra-subject variability. Secondary hypotheses: Generic immunosuppressants will be bioequivalent among each other in transplant patients independent of the type of risk (CYP3A5 expression, race, diabetes, age or a combination hereof). All generic immunosuppressants and the brand will be bioequivalent to each other as confirmed in in vitro dissolution studies. Tacrolimus metabolism and clearance will not be affected by the formulation. Alternative bioequivalence metrics such as using narrower acceptance intervals and a population pharmacokinetic approach will confirm bioequivalence among the brand and the six generics in the aforementioned high-risk transplant patient populations. To test these hypotheses, we propose the following four Aims: AIM 1: Using a retrospective cohort design, we will evaluate the clinical and safety outcomes among adult transplant recipients whose tacrolimus dosage was converted from Prograf® to a generic formulation. In a retrospective review, evaluate the impact of generic conversion in adult transplant recipients on post transplant outcomes one year prior to conversion to one year post conversion. Variables for analysis will include but not limited to incidence of rejection, hospital admission, changes in renal function, changes in transplanted organ function. All tacrolimus levels and dose changes during this period will be collected and compared. Additional pharmacokinetic modeling of this data will be performed for comparison. Aim 2: Identification of a single lot with the longest expiration date from each unique manufactured product approved in the United States and conduct systematic dissolution, content uniformity and purity testing on all tacrolimus product. We will conduct systematic dissolution testing of the brand and all currently approved tacrolimus drug formulations using the FDA-recommended dissolution method. We propose to test and compare the 1 mg capsule strength. In addition, we will compare the different formulations in terms of potency, purity and other quality attributes. This work will be carried out in the GMP-compliant facilities of The University of Iowa Pharmaceuticals (uip.pharmacy.uiowa.edu) and at the University of Colorado (iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado, Laboratory Director: U. Christians). Based on these studies, if all lots pass current USP standards, we will proceed to the clinical trial described in Aim 3. Aim 3: 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. The daily monitoring of levels will allow us to specifically address whether the need of additional monitoring upon formulation conversion is necessary. 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, CABioequivalence will be tested using scaled average bioequivalence metrics and analysis of variance as appropriate and intra-individual variability of the formulations will be compared. This will also include the analysis of potential period and sequence effects. 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. In addition, the same study will be conducted in 36 pediatric patients. Aim 4. Subgroup analysis, population pharmacokinetics, and average bioequivalence Aim 4 is an exploratory aim in which we will (A) address the concern that bioequivalence in the general patient population will not translate to special subgroups such as high risk transplant recipients as characterized by genotype, race, age, gender, sensitization (repeat transplant or cytotoxic PRA >35% or calculated PRA >50%), presence of concomitant steroids, presence of diabetes. and (B) test alternative bioequivalence metrics that have been proposed for the analysis for immunosuppressant generics such as narrower acceptance intervals, average bioequivalence was well as population pharmacokinetics.

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

Conditions
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Complication of Transplant

Intervention / Treatment
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* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion criteria 18 years or older 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. Subject who has received a primary or secondary transplant. 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. BMI less than or equal to 40. Exclusion criteria Evidence of any acute rejection Subjects who require dialysis within 6 months prior to study entry Recipients of multiple organ transplants 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. HepC positive subjects with liver biopsy proven recurrent disease considered relevant by physician oversight. Subjects with any severe medical condition requiring acute or chronic treatment that in the investigator's opinion would interfere with study participation 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. GFR ≤ 35 ml/min measured as estimated using the MDRD4 formula Subjects with AST, ALT, total bilirubin ≥ 3 X ULN or other evidence of severe liver disease 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) Subjects with clinically significant infections, requiring therapy, which, in the investigator's opinion, would interfere with the objectives of the study Other mental or physical conditions which in the investigator's opinion, are considered clinically significant Presence of intractable immunosuppressant complications or side effects resulting in dose adjustment of tacrolimus 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. An anticipated change in the immunosuppressive regimen during subject participation other than that required by the protocol Subject with severe GI disturbance or diarrhea which could interfere with tacrolimus absorption Severe diabetic gastroparesis Initiation of any medications that could interfere with tacrolimus blood levels, including OTC medications, herbal supplements, grapefruit or grapefruit juice. 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) 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Sequence 1<br>Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 1: Formulation 3, 5, 6, 4, 2, 1. | Drug: Tacrolimus<br>* Administration of each formulation will be determined by sequence.<br>* Other names: Prograf;|
| Other: Sequence 2<br>Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 2: Formulation 3, 4, 6, 5, 1, 2. | Drug: Tacrolimus<br>* Administration of each formulation will be determined by sequence.<br>* Other names: Prograf;|
| Other: Sequence 3<br>Patients will be randomized to a sequence of administration of the various 6 tacrolimus formulations. Sequence 3: Formulation 4, 3, 5, 1, 6, 2. | Drug: Tacrolimus<br>* Administration of each formulation will be determined by sequence.<br>* Other names: Prograf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare pharmacokinetic parameters of each tacrolimus formulation in transplant recipients | To estimate the ratio of C0, C12, AUC0-12h and Cmax and apply CI testing at steady state between all tacrolimus formulation combinations in transplant subjects. | December 2014 (up to one year) | 

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. | December 2014 (up to one year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bioequivalence, tacrolimus, transplant, CYP3A5 expressors/non expressors