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Purpose: Tacrolimus pharmacokinetic (PK) differences may exist in transplant patient subpopulations. Generic tacrolimus formulations are widely used, but bioequivalence studies (BE) versus reference drug have only been performed in healthy volunteers.
Methods: Prospective, two-center, open-label, randomized, two-period (14 days/period), two-sequence, crossover, steady-state PK study was performed to compare Sandoz generic tacrolimus (TS) versus Prograf® (TP) in stable renal transplant patients. PK parameters were compared (post-hoc analysis) according to gender, African American ethnicity, presence of diabetes, and concomitant steroids. Ratio of tacrolimus AUC0-12h and peak concentration (Cmax) with TS:TP was calculated using geometric mean (GM) of dose-normalized values at days 14 and 28.
Results: Sixty-eight/71 patients provided evaluable PK data. Median time post-transplant was 3.5 years (range 0.6-15.3). Mean (SD) tacrolimus dose was 5.7(4.2) mg/day. Overall, TS:TP ratios for AUC 0-12 was 1.02, 90% confidence intervals (CI) 97,108% and C max was 1.09, 90% CI 101,118%. The 90% CI for ratios of AUC0-12 and C 12 were within 80-125% for all subpopulations, but 90% CI for ratios of C max in the two smallest subpopulations (females, African Americans) and non-diabetics exceeded FDA BE criteria (upper values were 1.27-1.28).
Conclusion: TS and TP subpopulation data was found to be BE by FDA AUC parameter. Future studies must be powered to identify if Cmax differences within subpopulations are genuine. These findings also apply to the branded generic Hecoria ™ which has identical formulation to TS.
| AUC 0-12 Ratio of GM/90% CI | C 12 Ratio of GM/90% CI | |
| Male (n = 40) | 1.02/0.96,1.08 | 1.02/0.94,1.09 |
| Female (n = 28) | 1.01/0.91,1.12 | 1.00/0.86,1.14 |
| Non-African American (n = 44) | 1.07/1.00,1.14 | 1.07/0.98,1.16 |
| African American (n = 24) | 0.94/0.86,1.04 | 0.92/0.82,1.02 |
| No diabetes (n = 38) | 1.04/0.97,1.11 | 1.03/0.96,1.11 |
| Diabetes (n = 30) | 1.01/0.92,1.10 | 1.00/0.88,1.13 |
| No steroids (n = 40) | 1.07/1.00,1.15 | 1.06/0.97,1.14 |
| Steroids (n = 28) | 0.95/0.88,1.04 | 0.97/0.86,1.07 |