Case Study Low-Molecular-Weight Heparins

Standards and the recommended therapeutic dose. The antithrombotic potency and potential bleeding effects of one product cannot be extrapolated to another on the basis of weights in milligrams of anti-Xa or anti-IIa activities [34]. 

The mean plasma anti-factor Xa and anti-factor Ha activities following single 175 IU/kg subcutaneous administration of test and reference formulations is shown graphically in Fig. 8.2 A and B, respectively. The mean maximum plasma anti-Xa activity (Amax) was approximately 0.818 IU/mL at 4 h after tinzaparin injection. Anti-Xa activity fell to undetectable levels by 24—30 h in all subjects. The mean maximum plasma anti-IIa activity was 0.308 IU/mL at 5 h post-dose, and anti-IIa activity fell to undetectable levels by 24 h in all subjects. Inter-subject var- 

Preferred term Tinzaparin Tinzaparin-like LMWH 

Anti-Xa activity has been used extensively for monitoring heparin administration to patients, and remains a necessary feature of the current heparin dose-adjustment paradigm [35]. Moreover, anti-Xa and anti-IIa activity have been used successfully in the exploration of patient covariates which may suggest regimen modifications for certain disease states [35, 36] and subpopulations [37, 38]. These parameters also appear to be sufficient to judge the in-vivo performance of such agents. One reason for the lack of predictability of anti-Xa and anti-IIa activity 

That documentation of pharmaceutical- and bio-equivalence should be provided to regulatory authorities is not at issue. However, the means by which these data can and should be demonstrated remain the subject of discussion. Political, economic and scientific hurdles pervade, and this issue remains unresolved. The imposition of existing small-molecule equivalence criteria on the registration of generic biologic drug products is unlikely to provide an acceptable degree of consumer protection. Likewise, the conventional bioequivalence trial used to infer therapeutic equivalence of different formulations based on the similarity of the phar- 

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