Generic and Branded Low Molecular Weight Heparins Can Be Differentiated Based on Biologic and Pharmacologic Assays.

Several generic versions of the low molecular weight heparins enoxaparin and dalteparin have become available in different parts of the world and several products are currently under review by the FDA. At this time, there are no regulatory guidelines for defining equivalence of complex biologic drugs. Because of their complexity and hybrid nature (biologic and chemical), the available generic versions may not be acceptable by using currently applicable generic criteria. Due to their complex nature, the pharmacologic effect of these may not be similar to the branded product. Therefore, additional methods are needed to equate these drugs with the branded products. In this study, multiple lots of Lovenox or generic enoxaparin such as Lupenox (Lupin Pharma, India), Dripanina (Ariston, Brazil), Dilutol (Lazar, Argentina), Clenox (Pharmayect, Columbia), and Cutenox (Gland Pharma, India) and generic versions of dalteparin such as Daltehep (Gland Pharma, India) were supplemented to human plasma in the absence or presence of protamine sulfate (PS). Anticoagulant activity was measured using the aPTT, Heptest, PiCT assays. Antithrombin and anti-factor Xa activity were assessed by amidolytic assays. Effects on thrombin generation and the activation of thrombin activatable fibrinolytic inhibitor (TAFI) were determined by functional assay. At prophylactic levels of LMWH, no differences in anticoagulant or antiprotease activities were observed between generic and branded LMWHs. At therapeutic concentrations, significantly higher anticoagulant and antiprotease activities were observed with Lovenox. Assay-dependent variations in PS neutralization of antiprotease and anticoagulant activities were observed at higher concentrations of the generic versions of enoxaparin and dalteparin. Significant differences were noted in the effects of these agents on thrombin generation and the activation of TAFI. Current generic LMWHs possess some differences from branded LMWHs in known biologic properties of heparin. Variations in PS neutralization raise the question as to whether the interaction with other plasmatic proteins also differs from that of the branded drug. These results emphasize a need to consider multiple functional parameters when defining bioequivalence of complex biologic drugs and underscore the importance of further pharmacologic studies involving animal models and human clinical trials. Such approaches can be incorporated in the recommendations to develop guidelines for the approval of the generic versions of low molecular weight heparins.