Evaluation of Dose-response, Pharmacodynamic and Pharmacokinetic Bioequivalence of Filgrastim in Healthy Male Volunteers After Single and Multiple-dose Subcutaneous Administration of the Test Injectable Formulation BK0023 vs. Neupogen®
Condition: Healthy Male Subjects
Study type: Interventional
Phase: Phase 1

Summary: 
      Study rationale: Bio-ker has developed the new formulation of filgrastim BK0023 with the same
      active content as Neupogen®. BK0023 is expected to have the same tolerability profile and
      clinical effects as Neupogen® in controlling myelo-toxicity induced by chemotherapy given for
      the treatment of solid and haematological tumours. It is worth noting that the production and
      manufacturing procedures allow to have a reduction of drug cost thus it is likely to have
      pharmacoeconomic advantages.

      The study is aimed at investigating the pharmacodynamic equivalence and the pharmacokinetic
      bioequivalence of the new BK0023 injectable formulation of filgrastim 0.3 mg/mL by Bio-Ker
      S.r.l. vs. the comparator (Neupogen® 0.3 mg/mL, Dompé Biotec S.p.A., Italy). Healthy male
      subjects will receive test and reference at the doses of 2.5 and 5 µg/kg/day for 7
      consecutive days and at the dose of 10 µg/kg/day for 5 consecutive days according to a
      randomised cross-over design. Pharmacodynamics, pharmacokinetics and safety of BK0023
      injectable formulation 0.3 mg/mL and of Neupogen® 0.3 mg/mL, administered in 2 consecutive
      periods with a wash-out of at least 28 days elapsing between the last injection of period I
      and the first of period II, are compared.

      Study design: Single and multiple escalating dose, double-blind, randomised, two-way
      cross-over, pharmacodynamic and pharmacokinetic bioequivalence study.
    

Detailed description: 
      In a first part of the study, 16 healthy male subjects will be included in each dose group
      and will receive test and reference product according to the cross-over design. After the end
      of the second period of each dose group (completion of both cross-over periods for each dose
      group) the pharmacodynamic and pharmacokinetic primary parameters will be calculated. The
      blinding will be temporarily broken by one statistician for the ad interim analysis of
      primary parameters that will be performed after conclusion of the treatment of 16 subjects
      for each dose group (results are not disclosed) with the aim to re-calculate the sample size
      and to conclude the study with the necessary and sufficient number of subjects for each dose
      regimen.

      The study design was chosen according to the internationally recognised guideline for
      pharmacokinetics studies and in accordance with the EMEA guidance on similar medicinal
      products containing recombinant granulocyte-colony stimulating factor (G-CSF), which is
      annexed to the guideline on similar biological medicinal products containing
      biotechnology-derived proteins as active substance: non-clinical and clinical issues. A
      clinical development plan including the study outline was also submitted to EMEA, which
      examined the documentation and gave advice about the present study design .

      A multiple-dose design was chosen instead of a single-dose design, since G-CSF
      pharmacokinetics is non linear due to 2 reasons: non-proportional increase with dose and time
      dependent non-linearity. However, pharmacodynamic equivalence and pharmacokinetic
      bioequivalence will be both tested after the 1st and the last dose of the multiple dose
      treatment.

      Since the effects of r-h-met-G-CSF can be directly measured as pharmacodynamic responses,
      i.e. the increase in the absolute neutrophil count (ANC) and the development of peripheral
      blood cells (CD34+ cells), both parameters will be evaluated for the equivalence testing.

      Dose levels of 2.5 and 5 μg/kg/day were chosen for the pharmacodynamic equivalence, since
      literature data show a clear dose-response relationship in terms of the pharmacodynamic
      parameters over this range. The 10 μg/kg/day dose was chosen to make the investigated range
      relevant with respect to the clinical indications and the usual praxis for Neupogen®.
      Moreover, the subcutaneous administration was chosen, since this administration route is the
      most commonly used in the clinical setting.
    

Intervention name(s): Filgrastim test; Filgrastim reference
Intervention type(s): Drug; Drug
Intervention description(s): 0.3 mg/mL injectable solution in 1 mL vials Manufacturer (Drug Substance): Eurogenetec S.A., B-4102 Seraing, Belgium Manufacturer (Drug Product): Areta International S.r.l., I-21040 Gerenzano, Italy Batch release: Areta International S.r.l., I-21040 Gerenzano, Italy Route of administration: subcutaneous; 0.3 mg/mL injectable solution in 1 mL vials Licensed owner: Dompé farmaceutici S.p.A., Milan, Italy Manufacturer (Drug Product): Hoffmann - La Roche Ltd., Basel, Switzerland and Amgen Manufacturing Limited, Puertorico.
Batch release: Amgen Europe B.V., Breda, Netherlands Route of administration: subcutaneous
Other intervention name(s): r-metHuG-CSF, BK0023; r-metHuG-CSF, Neupogen®
Intervention MeSH terms: Lenograstim
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment