Biochemical and Pharmacological Differentiation of Generic Low Molecular Weight Heparins

Abstract

Generic LMWHs are available in several countries and several products are under review by the FDA. There are no regulatory guidelines for defining equivalence of complex biologic drugs. Multiple lots of Lovenox or generic enoxaparin were supplemented to human plasma in the absence or presence of protamine sulfate (PS). Anticoagulant activity was measured using the aPTT, Heptest, PiCT assays. Anti-thrombin 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 LMWH concentrations. 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.