Pharmacokinetic and Pharmacodynamic Equivalence of Epoetin Hospira and Epogen After Single Subcutaneous Doses to Healthy Male Subjects

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• 作者：Dennis Stalker ; PhD ; ^{dennis.stalker@hospira.com" class="auth_mail" title="E-mail the corresponding author} ; Susan Reid ; MEd ; PMP ; Atulkumar Ramaiya ; PhD ; Wayne A. Wisemandle ; MA ; Nancy E. Martin ; PharmD ; MD
• 关键词：biosimilar ; epoetin alfa ; equivalence ; erythropoietin ; pharmacokinetics ; pharmacodynamics
• 刊名：Clinical Therapeutics
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：38
• 期：8
• 页码：1778-1788
• 全文大小：278 K

文摘

The purpose of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of single 100 U/kg subcutaneous doses of Epoetin Hospira and Epogen in healthy male subjects as part of an overall program to demonstrate biosimilarity of Epoetin Hospira to the reference product Epogen.

Methods

This single-center, open-label, randomized, 2-period, crossover study was conducted in 81 healthy male subjects. Subjects were randomized to Sequence 1, in which they received 100 U/kg of Epoetin Hospira or to sequence 2, in which they received 100 U/kg Epogen subcutaneously in the first study period and the alternative treatment in the second study period. Blood was collected for determination of baseline-adjusted epoetin concentrations (BAECs) for pharmacokinetics and for determination of reticulocyte percentage of total erythrocytes for pharmacodynamics throughout both study periods. The primary PK end points were the geometric mean ratios (GMRs) of the 2 treatments for AUC_0–t and C_max based on the BAEC, and the primary PD end points were the GMRs of the 2 treatments for AUC_0–t and C_max for reticulocyte percentage.

Findings

The GMRs of Epoetin Hospira to Epogen for the BAEC-derived PK parameters were 1.05 for AUC_0–t with a 90% CI of 1.01 to 1.11, and 1.09 for C_max with a 90% CI of 1.01 to 1.18, with both 90% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. The GMRs (Epoetin Hospira/Epogen) for the reticulocyte percentage–derived PD parameters were 1.01 for AUC_0–t with a 95% CI of 0.98 to 1.05, and 1.02 for C_max with a 95% CI of 0.98 to 1.06, with both 95% CIs contained within the prespecified equivalence margin of 0.80 to 1.25. Overall, the adverse events were of similar frequency (11.7% and 13.9% for Epoetin Hospira and Epogen, respectively) and severity between treatments. One subject had a positive anti– recombinant human erythropoietin antibody result by radioimmunoprecipitation assay before dosing and throughout the conduct of the study with negative neutralizing antibodies and with no evidence of clinical deterioration or impact on the pharmacokinetics, pharmacodynamics, or safety.

Implications

The results of this study established the PK and PD equivalence of single 100 U/kg subcutaneous doses of the proposed biosimilar Epoetin Hospira to the reference product Epogen in healthy male subjects and support the overall demonstration of biosimilarity of Epoetin Hospira and Epogen.