Physiochemical Properties of Generic Formulations of Tacrolimus in Mexico J.A. Petan, N. Undre, M.R. First, K. Saito, T. Ohara, O. Iwabe, H. Mimura, M. Suzuki, and S. Kitamura 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 g/mL at 2 hours and 29.5 g/mL at 24 hours. The solubility of Tenacrine, Framebin, and Talgraf at 2 hours was 5.5, 12.6, and 7.8 g/mL, respectively, and the solubility decreased to 0.5, 2.3, and 2.1 g/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. T ACROLIMUS (Prograf) is one of the two main immu- nosuppressive agents currently used to prevent allo- graft rejection and has demonstrated superiority to cyclo- sporine (Neoral) with respect to graft survival and prevention of acute rejection in renal transplant recipients. 1 However, because generic formulations of immunosuppres- sive agents are available, it is important to determine if they are equivalent to the name brand formulations. Although generic formulations of tacrolimus are available in other countries, they are currently not approved for use in the United States. Thus, studies on efficacy and safety of generic tacrolimus formulations have been conducted out- side of the United States. According to the US Food and Drug Administration (FDA), to gain approval, a generic drug must contain the same active ingredients as the innovator drug; be identical in strength, dosage form, and route of administration; have the same indications; be bioequivalent; meet the same batch requirements for identity, strength, purity, and qual- ity; and be manufactured according to the FDA’s good manufacturing practice regulations required for innovator products. 1 Despite this, the World Health Organization has reported several problems in terms of the quality of generic drugs, citing inferior safety, stability, and effectiveness compared with the original product. 2 Bioequivalence studies are generally performed in healthy subjects, but transplant recipients are quite differ- ent from healthy individuals because their renal and hepatic functions are usually altered by illness or concurrent med- ications. 3 Studies have shown that generic formulations of cyclosporine are inferior to the brand-name version despite From the Medical Affairs Astellas Pharma Europe Limited, Munich, Germany; Medical Affairs Astellas Pharma US Inc., Deerfield, Illinois, USA; and Pharmaceutical Research and Tech- nology Laboratories Astellas Pharma Inc., Shizuoka, Japan. Address reprint requests to M. Roy First, MD, Vice President, Research & Development, Global Immunology & Transplanta- tion, Astellas Pharma US, Inc., Three Parkway North, Deerfield, IL 60015. E-mail: roy.first@us.astellas.com © 2008 by Elsevier Inc. All rights reserved. 0041-1345/08/$–see front matter 360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2008.03.091 Transplantation Proceedings, 40, 1439 –1442 (2008) 1439