Pharmacokinetic/Pharmacodynamic Study of 3 Subcutaneous Single Dose Epoetin Alfa Formulations in Healthy Volunteers
Condition: Anemia
Study type: Interventional
Phase: Phase 1

Summary: 
      Pharmacokinetic/Pharmacodynamic Study of 3 Epoetin Alfa Formulations in Single Subcutaneous
      Doses Administered to Healthy Volunteers

      SPONSOR Biosidus S.A.
    

Detailed description: 
      TITLE

      Pharmacokinetic/ Pharmacodynamic Study of 3 Epoetin Alfa Formulations in Single Subcutaneous
      Doses Administered to Healthy Volunteers

      SPONSOR

      Biosidus S.A.

      PRINCIPAL INVESTIGATOR

      Guillermo Di Girolamo, M.D., National License No. 56857, domiciled at Congreso 3137 (Calle
      75), San Andrés (1651), Telephone/Fax: 4753 - 8211, e - mail: gdigirolamo@arnet.com.ar

      CO-INVESTIGATORS

      Guillermo Alberto Keller, M.D., National License No.106.860, domiciled at Murgiondo 376,
      CABA. Cell Phone: 1563615376 - e-mail: drguillermokeller@yahoo.com.ar

      Paola Czerniuk, M.D., National License No. 84280, domiciled at Paraguay 3559, Piso 6, Dto A,
      CABA. Cell Phone 1550189563, e - mail: pczerniuk@intramed.net.ar SITE Centro de Medicina
      Integral S.R.L. - Address: Avenida Belgrano 1844, CABA (C1094) - Telephone: (011) 4383 - 5145

      LABORATORY

      Laboratorio de Calidad de Biosidus SA - Constitución 4234 (C1254ABX) Buenos Aires, Argentina
      - Tel. 4909 8000 - Fax 4909 8055

      OBJECTIVES

      Primary: To compare the pharmacokinetic and pharmacodynamic behavior of three formulations of
      epoetin alfa after subcutaneous administration of 40,000 UI:

        -  Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen -
           Cilag GmbH (Reference Formulation, "R")

        -  Hemax® 40,000 UI, lyophilized with albumin, vial, produced by Biosidus SA (Test
           Formulation Number 1, "T1")

        -  Hemax® PFS 40,000 UI, liquid without albumin, prefilled syringe, produced by Biosidus SA
           (Test Formulation Number 2, "T2")

      Secondary: To assess the pharmacological action, through quantification of blood
      reticulocytes at different time points as a surrogate pharmacodynamic marker. Assessment of
      adverse effects and tolerance.

      TRIAL DESIGN

      Open, randomized, 3 - arm, cross - over, sequential, and balanced

      DISCONTINUATION SCHEME

      The sponsor and the investigators can independently discontinue the study at any time if
      there is a mere possibility of or in case of occurrence of a serious adverse effect or
      situation that might affect the volunteer's health. If the Hb exceeds 18 g/ dl confirmed by
      repetition of the analysis at the pre - dose control in each phase, the volunteer will be
      excluded and 1 unit of blood will be collected. If, after the procedure, it is still above 18
      g/ dl, another 0.5 or 1 Unit of blood will be collected, based on medical judgment.

      NUMBER OF VOLUNTEERS

      24 (twenty - four) at first. Since it is a sequential design, if the statistical analysis of
      the first 24 volunteers does not show biosimilarity, 12 additional volunteers will be
      included up to a total of 36 (thirty - six) volunteers.

      DURATION OF THE STUDY

      3 months

      Selection and recruitment period: 2 (two) months

      TIME THE STUDY WILL TAKE

      Visit I: Selecting volunteers, obtaining informed consents, performing baseline tests.

      Visits II, III, and IV: They will consist of 3 hospitalization phases -one for subcutaneous
      administration of Test Formulation Number 1 (T1), another for subcutaneous administration of
      Test Formulation Number 2 (T2), and a third one for subcutaneous administration of Reference
      Formulation (R), with a washout period of no fewer than 28 days between phases.

      Sampling times for erythropoietin quantification in each phase, carried out by Biosidus SA,
      will be: pre - dose and 1, 2, 4, 6, 7, 8, 9, 10, 11, 12, 15, 24, 48, 72, 96, and 120 hours
      post - dose.

      Telephone contact: The Principal Investigator or the healthcare staff assigned by the
      Principal Investigator will contact the volunteer by phone after the volunteer's discharge
      until the last (120 - hour) outpatient collection in order to ask about tolerance to the
      medication and presence of adverse effects.

      Blood samples will be collected for red blood cell, Hb, and reticulocyte counting using flow
      cytometry performed by Biosidus SA, as an erythropoietin surrogate pharmacodynamic marker at
      the following time points: pre - dose (0 hours), 24, 48, 72, 96, 120, and 240 hours.

      Another blood sample will be collected for red blood cell and Hb count after 504 hours (21
      days after the dose), 7 days before starting the next treatment cycle, in order to determine
      whether the volunteer complies with one of the inclusion criteria for the next phase, i.e.
      not exceeding 18 g/ dl of Hg.

      DOSE / ROUTE / REGIME / OF THE INVESTIGATION PRODUCTS

      Single 40,000 UI dose of epoetin alfa. The following formulations will be assessed after
      administering 1 subcutaneous injection on the arm:

        -  Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen -
           Cilag GmbH (Reference Formulation, "R")

        -  Hemax® 40,000 UI, lyophilized with albumin, vial, produced by Biosidus SA (Test
           Formulation Number 1, "T1")

        -  Hemax® PFS 40,000 UI, liquid without albumin, prefilled syringe, produced by Biosidus SA
           (Test Formulation Number 2, "T2")

      There will be 6 randomly assigned sequences:

        1. R - T1 - T2

        2. R - T2 - T1

        3. T1 - R - T2

        4. T1 - T2 - R

        5. T2 - R - T1

        6. T2 - T1 - R

      COMPARISON DRUG

      Erypo ® 40,000 UI, liquid without albumin, prefilled syringe, produced by Janssen - Cilag
      GmbH (Reference Formulation, "R")

      COMPARATIVE PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENT BETWEEN THE FORMULATIONS

      Based on the erythropoietin serum concentration results, at the different sampling times, the
      following variables will be calculated:

        -  AUC0 - 120h: Area under the serum concentration - time curve 0 - 120 h.

        -  AUC0 - ∞: Area under the serum concentration - time curve from time 0 extrapolated to
           infinity (∞).

        -  Cmax: Maximum serum concentration of erythropoietin.

        -  Cmin: Minimum serum concentration of erythropoietin.

        -  Tmax: Time to maximum serum concentration of erythropoietin.

      The difference between Tmax times in each test formulations and the reference formulation
      will be assessed, and the elimination rate constant and half - life of the drug in the body
      will be calculated.

      The average results for each formulation will be presented, as well as each volunteer's
      individual results.

      STATISTICAL ANALYSIS

      CALCULATION OF THE SAMPLE SIZE:

      The size of the sample (n:24) was established based on literature data and information from
      absolute and relative bioavailability studies performed with the drug before by Biosidus SA.
      Since it is a sequential design, if the statistical analysis of the first 24 volunteers does
      not show biosimilarity, 12 additional volunteers will be included up to a total of 36 (thirty
      - six) volunteers.

      ANALYSIS PLAN

      COMPARATIVE PHARMACOKINETIC ANALYSIS BETWEEN FORMULATIONS

        -  AUCT / AUCR: Quotient between the area under the curve of the TEST formulation and the
           area under the curve of the REFERENCE. For the log transformation, the 90% confidence
           interval of the AUC ratio (for AUC0 - 120h and AUC0 - ∞) should be within the range of
           0.80 - 1.25.

        -  CmaxT / CmaxR: Quotient between the Cmax of the Test formulation and the Cmax of the
           Reference. For the log transformation, the 90% confidence interval of the Cmax ratio
           should be within the range of 0.80 - 1.25.

      COMPARATIVE PHARMACODYNAMIC ANALYSIS BETWEEN THE FORMULATIONS

        -  Maximum number of reticulocytesT / Maximum number of reticulocytesR: Quotient between
           the maximum number of reticulocytes in the Test formulation and the maximum number of
           reticulocytes in the Reference.

      Using ANOVA, the possible differences between subjects, treatments, and periods will be
      analyzed.

      Outliers: In order to determine possible outliers, a selective - statistical method will be
      applied.
    

Intervention name(s): Epoetin Alfa 40000 UNT/ML
Intervention type(s): Drug
Intervention description(s): 40.000 UI subcutaneous single dose
Other intervention name(s): Hemax; Hemax PFS; Erypo
Intervention MeSH terms: Epoetin Alfa
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Other