title: Biomarkers and coagulation tests for assessing the biosimilarity of a generic low-molecular-weight heparin: results of a study in healthy subjects with enoxaparin.
abstract: 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 AUC(0-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.
authors: Pharmazentrum frankfurt/ZAFES, Institute for Clinical Pharmacology, University Hospital Frankfurt, Germany.
authors: Karina
authors: K
authors: Kuczka
authors: Sebastian
authors: S
authors: Harder
authors: Bettina
authors: B
authors: Picard-Willems
authors: André
authors: A
authors: Warnke
authors: Frank
authors: F
authors: Donath
authors: Pietro
authors: P
authors: Bianchini
authors: Bruna
authors: B
authors: Parma
authors: Henning
authors: H
authors: Blume
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests / Q000379:methods; D018592:Cross-Over Studies; D004311:Double-Blind Method; D016568:Drugs, Generic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D017984:Enoxaparin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000187:drug effects; D008297:Male; D010314:Partial Thromboplastin Time; D011516:Prothrombin / Q000037:antagonists & inhibitors; D013810:Therapeutic Equivalency
chemical_list: D000925:Anticoagulants; D016568:Drugs, Generic; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D011516:Prothrombin; C025337:Factor IIa