Population Pharmacokinetic and Pharmacodynamic Model-Based Comparability Assessment of a Recombinant Human Epoetin Alfa and the Biosimilar HX575

作者：Yan Xiaoyu; Lowe Philip J; Fink Martin; Berghout Alexander; Balser Sigrid; Krzyzanski Wojciech^*

来源：JOURNAL OF CLINICAL PHARMACOLOGY, 2012, 52(11): 1624-1644.

DOI：10.1177/0091270011421911

• Comparability
• erythropoietin
• pharmacokinetics
• pharmacodynamics
• pharmacodynamics-mediated drug disposition

The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic (PK/PD) model and assess the comparability between epoetin alfa HEXAL/Binocrit (HX575) and a comparator epoetin alfa by a model-based approach. PK/PD data-including serum drug concentrations, reticulocyte counts, red blood cells, and hemoglobin levels-were obtained from 2 clinical studies. In sum, 149 healthy men received multiple intravenous or subcutaneous doses of HX575 (100 IU/kg) and the comparator 3 times a week for 4 weeks. A population model based on pharmacodynamics-mediated drug disposition and cell maturation processes was used to characterize the PK/PD data for the 2 drugs. Simulations showed that due to target amount changes, total clearance may increase up to 2.4-fold as compared with the baseline. Further simulations suggested that once-weekly and thrice-weekly subcutaneous dosing regimens would result in similar efficacy. The findings from the model-based analysis were consistent with previous results using the standard noncompartmental approach demonstrating PK/PD comparability between HX575 and comparator. However, due to complexity of the PK/PD model, control of random effects was not straightforward. Whereas population PK/PD model-based analyses are suited for studying complex biological systems, such models have their limitations (statistical), and their comparability results should be interpreted carefully.

• 出版日期2012-11