Conversion From Brand to Generic Tacrolimus in High Risk Transplant Recipients

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.

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.