Pharmacodynamic Equivalence of Ovine Enoxaparin to Lovenox®
Condition: Enoxaparin
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This study is designed as a randomized, open-label, 2-way cross-over, single dose study with
      at least 7 days wash-out period. The objective of this study is to demonstrate the
      pharmacodynamic / pharmacokinetic equivalence of ovine enoxaparin to the reference product,
      the originator porcine enoxaparin, Lovenox® from Sanofi, and to assess its safety and
      tolerability in healthy volunteers.
    

Detailed description: 
      Low molecular-weight heparins (LMWHs) are derived from unfractionated heparin (UFH) by
      chemical or enzymatic depolymerization. Enoxaparin is one of the most widely used LMWHs and
      is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine
      intestinal mucosa. In contrast to UFH, enoxaparin has higher and more consistent
      bioavailability after s.c. administration compared with UFH and has longer plasma half-life.

      Because of difficulties in chemical detection of LMWH, conventional pharmacokinetic studies
      cannot be performed. LMWH absorption and elimination are studied using pharmacodynamic
      surrogate markers, i.e. anti-FXa activity. Measurement of this pharmacodynamic activities is
      used to compare the biosimilar/ generic products to the reference LMWH.

      This study is designed as a randomized, open-label, 2-way cross-over, single dose study with
      at least 7 days wash-out period. The objective of this study is to demonstrate the
      pharmacodynamic / pharmacokinetic equivalence of ovine enoxaparin to the reference product,
      the originator porcine enoxaparin, Lovenox® from Sanofi, and to assess its safety and
      tolerability in healthy volunteers.

      The test drug is ovine enoxaparin sodium 60 mg (0.6 mL taken from 1.0 mL vial containing 100
      mg = 10,000 IU anti-FXa), from Metiska Farma. Meanwhile, the reference drug is enoxaparin
      sodium 60 mg (Lovenox® 0.6 mL prefilled syringe containing 60 mg = 6,000 IU anti-FXa) from
      Sanofi, France. The drugs are not similar in appearance: ovine enoxaparin is supplied in
      vials, whereas Lovenox® is supplied as pre-filled syringes, both are given as s.c. injection.
      An unblinded pharmacist will prepare the study drug, and an unblinded medical doctor will
      inject the study drug.

      Study procedures

        1. On day-1 of period 1, subjects will be given in fasting condition, a single s.c.
           injection of the test or the reference drug.

        2. Blood samples to assess PD parameters will be collected in both study periods at the
           following time points: pre-dose, and 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 16, 20,
           and 24 hours after dosing on Day-1 (16 sampling points).

        3. Nine (9) mL of blood will be drawn from vena cubiti with a needle of 19 to 21 gauge with
           a maximum of 1 minute pressure with tourniquet, the first 3 mL of blood will be
           collected in an empty tube (to be thrown away), the second 3 mL of blood will be
           collected in a blood collection tube containing citrate, theophylline, adenosine, and
           dipyridamole (CTAD tube) for anti-FXa and anti-FIIa, and the third 3 mL of blood will be
           collected in a citrate tube for TFPI. In case of failure in blood drawing, the
           phlebotomist should change the site of blood drawing and change the needle used.

        4. Subjects will return to the clinic after a wash-out period of at least 7 days, and on
           day-1 of period 2, they will be crossed over to receive a single s.c. dose of the
           alternate drug.

      Anti-FXa activity will be determined by a chromogenic method using a commercial kit
      (STA-Liquid anti-FXa, Diagnostica Stago S.A.S, France) within 4 hours after sample collection
      at room temperature. Meanwhile, anti-FIIa activity will be measured by a chromogenic method
      using a commercial kit (Biophen anti-FIIa, STA Compact Max, France) within 4 hours after
      sample collection at room temperature, and TFPI levels will be measured using a commercial
      ELISA kit (Abcam PLC, Cambridge, UK).
    

Intervention name(s): Ovine Enoxaparin; Enoxaparin Prefilled Syringe [Lovenox]
Intervention type(s): Drug; Drug
Intervention description(s): The test drug is ovine enoxaparin sodium 60 mg (0.6 mL taken from 1.0 mL vial containing 100 mg = 10,000 IU anti-FXa), from Metiska Farma.; The reference drug is enoxaparin sodium 60 mg (Lovenox® 0.6 mL prefilled syringe containing 60 mg = 6,000 IU anti-FXa) from Sanofi, France.
Other intervention name(s): Ovine Enoxaparin Sodium; Ovine Enoxaparin (Metiska Farma); Active comparator
Intervention MeSH terms: Enoxaparin; Enoxaparin sodium
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized, open-label, 2-way cross-over, single-dose study with at least 7 days wash-out period.
Masking: None (Open Label)
Primary purpose: Other
Keywords: pharmacodynamic equivalence; anticoagulant; antithrombotic