Differentiating Low-Molecular-Weight Heparins Based on Chemical, Biological, and Pharmacologic Properties: Implications for the Development of Generic Versions of Low-Molecular-Weight Heparins

Abstract

Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.

In situ crosslinkable heparin‐containing poly(ethylene glycol) hydrogels for sustained anticoagulant release

“…The concentration of unmodified LMWH in the blood (Figure 6A) is consistent with standard heparin dosage curves previously described in the literature, with an initial delay from the subcutaneous injection, followed by a maximum and gradual decrease to baseline shortly thereafter. 61 In our experiments, peak concentrations of LMWH were detected within the first hour of injection. In comparison, the subcutaneous injection of maleimide-modified LMWH produced a different concentration curve (Figure 6B).…”

Avaliação da tromboflebite jugular experimental em equinos tratados com heparina

“…A partir da década de 80, heparinas com baixo peso molecular (HBPM) passaram a ser preparadas através da despolimerização química ou enzimática da heparina comercial [1,16,17]. Os fármacos dalteparina, enoxaparina, nadroparina e tinzaparina, disponíveis para uso, apresentam segurança e eficiência no tratamento e prevenção de doenças vasculares tromboembólicas [5].…”

“…As HBPM têm substituído a heparina não fracionada por possuírem menos efeitos indesejáveis como a resposta variável devido à ligação com proteínas plasmáticas ou a trombocitopenia induzida pela heparina (TIH) [1]. Além disso, diversos estudos realizados com modelos de trombose venosa em animais e estudos clínicos em humanos portadores de doenças venosas tromboembólicas mostraram que as HBPM são equivalentes ou até mesmo superiores à heparina não fracionada em relação ao seu efeito antitrombótico e possuem maior segurança por apresentar menor risco hemorrágico [5,14,17,18,19,20,21,22].…”

“…As frações de heparina com baixo peso molecular possuem em média 4000 a 5000 dáltons e apresentam mecanismo de ação semelhante à heparina não fracionada, com maior biodisponibilidade e meia-vida mais longa, metabolizadas quase que exclusivamente por via renal [1,4,9,17]. A principal diferença em sua atividade farmacológica é a capacidade de se ligar mais fortemente ao fator Xa do que à trombina devido à necessidade de cadeias mais longas para se ligar simultaneamente à antitrombina e à trombina [1,9,23].…”

Binding of heparin‐dependent antibodies to PF4 modified by enoxaparin oligosaccharides: evaluation by surface plasmon resonance and serotonin release assay

“…Among chemokines known to bind heparin, platelet-factor 4 (PF4) is the most clinically relevant because interactions between PF4 and heparin fragments are crucial for priming the synthesis of the platelet-activating antibodies responsible for heparin-induced thrombocytopenia (HIT). HIT is a severe and relatively frequent complication of treatments with heparin [4], which results from an atypical immune response involving the synthesis of immunoglobulin G antibodies that bind to PF4 epitopes exposed by conformational changes induced by interactions with sulfated polysaccharides [5,6].the original product in terms of molecular weight range, stability and immunogenicity [8]. HIT is a non-hemorrhagic adverse effect also associated with LMWHs, although the incidence is lower than with UFH.…”