Pharmacokinetic/Pharmacodynamic Study of 3 Subcutaneous Single Dose Epoetin Alfa Formulations in Healthy Volunteers

Anemia

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

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.

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