Product individuality of commercially available low-molecular-weight heparins and their generic versions: therapeutic...

The currently available brand-name low-molecular-weight heparins (LMWHs) in the United States include dalteparin (Pfizer), enoxaparin (Aventis), and tinzaparin (Pharmion). Other products available, in Europe, include certoparin (Novartis), reviparin (Abbott), nadroparin (GlaxoSmithkline), and parnaparin (Alpha-Wasserman). Each of these LMWHs has a characteristic molecular weight profile and biological activity in terms of an anti-FXa and anti-FIIa potency. The mean molecular weight of these drugs ranges from 4.0 kDa to 7.0 kDa and the anti-FXa:anti-FIIa ratio ranges from 1.5 to 3.5. These agents may also be characterized by the presence of specific chemical end groups such as 2-O-sulfo-4-enepyranosuronic acid at the nonreducing terminus (enoxaparin) or 2,5-anhydro-D-mannose at the reducing terminus (dalteparin). Further, the component oligosaccharide chains exhibit product-specific distribution profiles. It is now widely accepted that individual LMWHs are chemically unique agents and cannot be interchanged therapeutically. Each commercial LMWH has been individually developed for specific clinical indications, which are dose and product dependent. Recently, several generic LMWHs have become available in India (Cutenox and Markaparin) and South America (dilutol, clenox, dripanina), and three companies have filed for regulatory approval of a generic version of enoxaparin in the United States. As the primary aim of a generic drug is to reduce cost without compromising patient care, a generic drug is required to be chemically and biologically equivalent to the pioneer drug. Because LMWHs represent complex natural mucopolysaccharide drugs that have undergone chemical and enzymatic modifications, physicochemical and biological information in addition to molecular weight and anti-FXa:anti-FIIa ratio should be used to determine generic equivalency to the branded drug. We have utilized a previously reported approach to systematically compare three generic versions of enoxaparin obtained from India and Brazil with the branded enoxaparin (Lovenox) available in the United States. Testing included molecular and structural profiling, evaluation in clot-based and amidolytic anti-FXa and anti-FIIa assays, and heparinase-I digestion profiles. While the molecular profiles (4.8 +/- 1.8 kD) and anticoagulant potencies as determined by activated partial thromboplastin time (APTT) were comparable for all four agents, the generic products showed variations in the thrombin time (TT) and Heptest assays. Two generic and the branded enoxaparin were readily digested by heparinase-I, losing most of their anticoagulant activity, but one generic product resisted digestion. This may have been due to a unique structural feature in this product. These studies show that, while generic LMWHs may exhibit acceptable molecular weight and anti-FXa profiles, they can exhibit assay-based differences and digestion profiles. Testing in animal models to determine safety, efficacy, and pharmacodynamic parameters may be important to verify equivalence. In order to assure that the generic LMWHs are equivalent to branded LMWHs such that equivalent clinical results are obtained, there is a need to develop clear stepwise guidelines that will establish equivalency in terms of physical, chemical, biochemical, pharmacokinetic, and pharmacodynamic properties for these anticoagulant drugs.