J Clin Pharmacol
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0091270008322911v1
48/10/1189    most recent
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BIOLOGICS

Biomarkers and Coagulation Tests for Assessing the Biosimilarity of a Generic Low-Molecular-Weight Heparin: Results of a Study in Healthy Subjects With Enoxaparin

Karina Kuczka, MD, Sebastian Harder, MD, Bettina Picard-Willems, BSc, André Warnke, BSc, Frank Donath, MD, Pietro Bianchini, PhD, Bruna Parma, PhD and Henning Blume, PhD

From pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, University Hospital Frankfurt, Germany (Dr Kuczka, Dr Harder, Ms Picard-Willems); SocraTec R&D GmbH, Oberursel, Germany (Mr Warnke, Dr Donath, Dr Blume); and OPOCRIN S.p.A. Modena, Italy (Dr Bianchini [deceased], Dr Parma).

Low-molecular-weight heparins (LMWHs) differ considerably in their influence on clotting tests and release of tissue factor pathway inhibitor (TFPI). Biosimilarity therefore becomes an issue when generic forms of LMWHs are developed. So far, no bioequivalence study with a generic LMWH has been reported. A generic enoxaparin (test) was compared with the originator (reference) in 20 volunteers after single-dose subcutaneous administration (40 mg enoxaparin sodium, 4000 IU/mL anti–factor Xa (anti-FXa; activity). Target variables were anti-FXa and anti-FIIa activity, activated partial thromboplastin time (aPTT), prothrombinase-induced clotting time (PiCT), and TFPI over 24 hours. The statistical evaluation of the anti-FXa activity profile demonstrated bioequivalence of test and reference with confidence intervals of area under the plasma concentration-time curve (AUC0-tlast) (93%-99%) and Amax (88%-95%). Confidence intervals of AUC0-tlast (89%-102%) and Amax (90%-103%) of anti-FIIa activity also fulfill bioequivalence criteria. The 90% confidence interval for the maximum concentration of TFPI ranged from 90% to 113%. The claim of similarity was also supported by aPTT and PiCT profiles. Bioequivalence with the originator enoxaparin could be demonstrated by ex vivo inhibition of FXa and FIIa activity, by coagulation tests (aPTT and PiCT), and by in vivo release of TFPI. Whether such data also prove biosimilarity of the generic enoxaparin needs to be determined.

Key Words: Biosimilarity • enoxaparin • factor Xa • tissue factor pathway inhibitor

Address for reprints: Sebastian Harder, MD, Institute for Clinical Pharmacology at the pharmazentrum frankfurt, University Hospital, Frankfurt/Main, Theodor Stern Kai 7, D-60590 Frankfurt am Main, Germany; e-mail: harder{at}em.uni-frankfurt.de.


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