A randomized, crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients

Abstract

An exploratory, post hoc analysis was performed using data from a prospective, multicenter, open-label, randomized, two-period (14 d per period), two-sequence, crossover, steady-state pharmacokinetic study comparing generic tacrolimus (Sandoz) vs. reference tacrolimus in stable renal transplant patients receiving their pre-study twice-daily dose. Pharmacokinetic parameters were compared in 68 patients according to gender, African American ethnicity, the presence or absence of diabetes, and use of steroids. The ratios of tacrolimus AUC0-12 h , Cmax , and C12 with generic vs. reference tacrolimus were calculated using the geometric mean (GM) of dose-normalized values at days 14 and 28. Mean (SD) tacrolimus dose at baseline was 5.7 (4.2) mg/d. There were no consistent differences in dose-normalized AUC0-12 h , C12 , Cmax, or tmax between the generic and reference preparations within subpopulations. The 90% confidence intervals (CI) for the ratios of dose-normalized AUC0-12 h and C12 with generic vs. reference tacrolimus were within 80-125% for all subpopulations, as were 90% CIs for Cmax other than for females, African Americans, and non-diabetics, which is not unexpected given the wide variability of tacrolimus Cmax and the small subpopulation sizes. These exploratory results suggest that this generic tacrolimus preparation would be expected to offer comparable bioavailability to the reference drug in these patient subpopulations.

Healthcare utilization and costs with fixed-source versus variable-source tacrolimus in patients receiving a kidney transplant

“…In this study, approximately one-third of tacrolimus users had evidence of a switch between tacrolimus manufacturers, often with a protracted delay in tacrolimus TDM testing after the switch. While studies have shown that patients can be safely managed in a controlled environment over the shortterm using any approved tacrolimus formulation 20 , the literature is devoid of reports that are representative of the realworld setting in which patients may be cycled through products from multiple manufacturers. Even less clear is what happens to these patients over longer time-horizons.…”

“…The therapeutic benefit of tacrolimus TDM (i.e. avoiding toxicity) is well established [8][9][10]12,15,20 . Although there are no guidelines to definitively inform the appropriate frequency of tacrolimus TDM, guidance exists regarding its necessity, particularly after a medication change or a change in a patient's status 14 .…”

Use of Generic Tacrolimus in Elderly Renal Transplant Recipients

“…AUC 0-12 , area under the plasma concentration versus time curve from zero to 12 hr; CI, confidence interval; C max , maximum whole blood concentration; T max , time to C max ; C 0 , concentration before the dose; Tac, tacrolimus. Bioequivalence in different age groups was unfortunately not investigated in the subpopulation analysis of the study by Alloway et al 16,24 The reasons for the observed lack of bioequivalence between the two Tac formulations remain to be investigated, and further studies should examine bioequivalence of NTI drugs in different subpopulations (e.g., age, race, and organ transplanted). Use of generic Tac resulted in a significantly higher systemic drug exposure.…”

Generic Substitution Of Tacrolimus In De Novo Mexican Renal Transplant Recipients: A Single Center Experience

“…Despite this, the variability margins allowed do not ensure bioequivalence for drugs with a narrow therapeutic window, such as immunosuppressive agents.In immunosuppressive drugs and in order to demonstrate the bioequivalence of generic drugs, exhaustive and rigorous studies must be performed in patients with transplantation to prove their effectiveness, as have been conducted in other countries 4,5 .…”