Feasibility Study of Heparin Mass Calibrator as a GPC Calibrator for Heparins and Low Molecular Weight Heparins

Self Cite

The introduction of low-molecular-mass heparins (LMMHs) has added a new dimension to the prophylactic and therapeutic management of thromboembolic disorders. These agents are now globally accepted as drugs of choice for postsurgical prophylaxis of deep vein thrombosis (DVT). Currently, the LMMHs are being developed for various therapeutic and cardiovascular indications. Reviparin is an optimized LMMH prepared by controlled nitrous acid digestion of porcine mucosal heparin. This drug has been developed utilizing validated procedures and exhibits a relatively narrow molecular mass distribution in contrast to most other commercially available LMMHs. The specific activity in the anticoagulant assays is approximately 40 U/mg whereas the specific activity in amidolytic anti-Xa assays is approximately 100 anti-Xa U/mg. Reviparin is capable of producing dose- and time-dependent antithrombotic effects in animal models of thrombosis. Although ex vivo anticoagulant effects are initially observed at dosages that are antithrombotic, this agent has been found to produce sustained antithrombotic effects when ex vivo anticoagulant actions are not measurable. Repeated administration of this LMMH induces progressively stronger antithrombotic effects. This drug has also been found to release tissue factor pathway inhibitor (TFPI) following both intravenous (IV) and subcutaneous (SC) administration. The studies included in this article are designed to provide additional data on the molecular profile using new calibration methods and additional results on pharmacologic studies. In particular, the release of TFPI following IV and SC administration to nonhuman primates is described. The effect of repeated administration of Reviparin mimicking the postsurgical prophylaxis of DVT is also reported in terms of any augmentation of the antithrombotic or hemorrhagic effects of this agent.

Section: Discussionmentioning

confidence: 99%

Biochemical and Pharmacologic Characteristics of Reviparin, a Low-Molecular-Mass Heparin

Jeske

Fareed²,

Eschenfelder³

et al. 1997

Self Cite

“…One means of assessing the molecular weight of polymers such as the heparins is by HPLC-GPC. 25,26 When such an analysis is performed on various versions of the innovator product enoxaparin (Lovenox, Sanofi-Aventis, Paris, France), it is observed that the mean molecular weight of these LMWHs is nearly the same (Fig. 1).…”

Section: Current Generic Versions Of Lmwhmentioning

confidence: 99%

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

Jeske

Walenga

Hoppensteadt

et al. 2008

Self Cite

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.

“…The molecular weight profile was determined by using size exclusion chromatography. 6,7 Fig. 1A and 1B show the molecular profile of the hyper-/oversulfated chondroitin sulfate (HCS-2), isolated contaminant from the recalled heparin batches (HC), contaminant-free heparin (CFH), and their respective mixtures with heparin (HCS-2 þ CFH, HC þ CFH).…”

Section: Isolation and Characterization Of The Heparin Contaminantmentioning

confidence: 99%

Biological Profile of the Hyper/Oversulfated Chondroitin Sulfate Contaminant Isolated from Recalled Heparin

Fareed¹,

Walenga²,

Jeske³

et al. 2008

Self Cite

An unexpectedly high rate of adverse events and deaths were reported from in patients exposed to heparin. Investigations on the quality of heparin revealed an oversulfated chondroitin sulfate (OSCS) contaminant in the heparin. Several reports on the chemical structure and limited biologic actions of OSCS have recently become available. However, no data are available on its anticoagulant and antiprotease effects. Moreover, its interaction with heparin, resulting in the modulation of heparin's anticoagulant activity, is not reported. The isolated contaminant from recalled batches of heparin and several semisynthetic OSCSs were profiled for their in vitro anticoagulant effects. The contaminant and OSCSs both exhibited measurable anticoagulant activity and produced supra-additive effects in the presence of heparin. In addition, in animal models of thrombosis and bleeding, the contaminated heparin produced stronger anticoagulant and bleeding effects than heparin. Thus, in addition to the reported biological actions, the heparin contaminant exerts measurable anticoagulant effects and interacts with heparin to produce supra-additive effects. These studies suggest that the contamination of heparin with OSCS was based on a rational design and prior knowledge of molecular and anticoagulant profiles. These studies also indicate that the OSCS contaminant may itself be heterogeneous and its molecular and biological profiles may vary in different recalled heparins.