Renal transplantation
Immunosuppression
Physiochemical Properties of Generic Formulations of Tacrolimus in Mexico

https://doi.org/10.1016/j.transproceed.2008.03.091Get rights and content

Abstract

Tacrolimus is an important immunosuppressive agent used to prevent allograft rejection after transplantation. Tacrolimus has a narrow therapeutic index; therefore, it is essential that the physicochemical properties of generic formulations be identical to the brand-name formulation, Prograf. In this study, the physicochemical properties of generic tacrolimus formulations were compared with Prograf. The drug dissolution profiles of generic formulations of tacrolimus were different from that of Prograf. Tacrobell and T-Inmun exhibited faster dissolution than Prograf, and Tenacrine, Framebin, and Talgraf showed slower and incomplete drug dissolution, releasing 24% to 51% of tacrolimus within 2 hours. Generic formulations of tacrolimus demonstrated decreased solubility compared with Prograf. The solubility of Prograf was 35.7 μg/mL at 2 hours and 29.5 μg/mL at 24 hours. The solubility of Tenacrine, Framebin, and Talgraf at 2 hours was 5.5, 12.6, and 7.8 μg/mL, respectively, and the solubility decreased to 0.5, 2.3, and 2.1 μg/mL, respectively, at 24 hours. Whereas Prograf demonstrated content uniformity, the content of the generic tacrolimus formulations varied widely. The standard deviation of content for Tenacrine, Tacrobell, and T-Inmun were high at 29.3, 6.9, and 5.6, respectively. Furthermore, the mean percentage of labeled amount of T-Inmun was 84.2% with a relative standard deviation of 6.7% (minimum value; 72.7%; maximum value; 100.7%). These results indicate that generic formulations of tacrolimus tested in this study are not bioequivalent to Prograf, which suggests that their use may be of potential risk to transplant patients.

Section snippets

Materials

The tacrolimus formulations used in this study are listed in Table 1. Prograf was provided by Astellas Pharma Inc. (Tokyo, Japan) and generic tacrolimus formulations were purchased from local markets, including Mexico. All other materials were of analytical reagent grade.

Dissolution

The NTR-6100A dissolution tester (Toyama Sangyo Co., LTD, Osaka, Japan) was utilized for the dissolution studies. Experimental conditions consisted of the USP Apparatus 2 (paddle method) with sinker, employing 900 mL of

Dissolution

The drug dissolution profiles of the five generic formulations of tacrolimus were different from that of Prograf (Fig 1). Tacrobell and T-Inmun exhibited faster dissolution than Prograf, and Tenacrine, Framebin, and Talgraf showed slower and incomplete drug dissolution, releasing 24% to 51% of tacrolimus within 2 hours.

Solubility

Generic formulations of tacrolimus demonstrated decreased solubility compared with Prograf (Fig 2). The solubility of Prograf was 35.7 μg/mL at 2 hours and 29.5 μg/mL at 24

Discussion

Tacrolimus has a narrow therapeutic window; therefore, in clinical practice dosing is optimized by individualizing the dose and maintaining tacrolimus blood levels within a defined range. Toxic side effects, including nephrotoxicity and neurotoxicity, are associated with high tacrolimus blood levels and potential allograft rejection is associated with low blood levels. This study demonstrated that certain generic tacrolimus formulations had greater variations in dissolution, solubility, and

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