Research Article: A Randomized Pharmacokinetic Study of Generic Tacrolimus Versus Reference Tacrolimus in Kidney Transplant Recipients

Date Published: October , 2012

Publisher: Blackwell Publishing Inc

Author(s): R R Alloway, B Sadaka, J Trofe-Clark, A Wiland, R D Bloom.


Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC0–12h and peak concentration (Cmax) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97–108%, p = 0.486) for AUC0–12h and 1.09 (90% CI 101–118%, p = 0.057) for Cmax. Mean (SD) C0 was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines.

Partial Text

Since expiry of the tacrolimus patent in 2008, generic preparations have become available and have been widely adopted. However, tacrolimus pharmacokinetics are relatively complex with a high degree of inter- and intrapatient variability such that therapeutic drug monitoring is mandatory. Differences between patients (interpatient variability) can be affected by a multitude of factors, including patient demographics, liver function, diurnal variation, concomitant immunosuppressants, gastrointestinal disturbances, coexisting diabetes mellitus and genetic differences in CYP3A4 and P-glycoprotein expression (1). In transplant patients, the key contributors to intrapatient variability in immunosuppressant dosing are usually drug–drug, drug–disease and food–drug interactions. Against this background, careful examination of generic tacrolimus preparations compared to the reference preparation (Prograf®) is essential to ensure that exposure is similar on substitution in stable renal transplant patients.

To our knowledge, this is the first prospective study undertaken specifically to compare the pharmacokinetic characteristics of a generic tacrolimus preparation versus the reference drug in kidney transplant patients. The generic tacrolimus (Sandoz) showed a similar pharmacokinetic profile to reference tacrolimus, as assessed by a comparison of AUC0–12h, Cmax and C0 concentration. These data indicate that the generic tacrolimus preparation is bioequivalent to reference tacrolimus in kidney transplant recipients according to the FDA guidelines. The findings will also apply to the branded generic tacrolimus Hecoria™, which has an identical formulation to the Sandoz generic.




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