Premium
Population Pharmacokinetic and Pharmacodynamic Model‐Based Comparability Assessment of a Recombinant Human Epoetin Alfa and the Biosimilar HX575
Author(s) -
Yan Xiaoyu,
Lowe Philip J.,
Fink Martin,
Berghout Alexander,
Balser Sigrid,
Krzyzanski Wojciech
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011421911
Subject(s) - epoetin alfa , pharmacodynamics , medicine , pharmacokinetics , pharmacology , dosing , population , biosimilar , comparability , reticulocyte , hemoglobin , chemistry , mathematics , biochemistry , environmental health , combinatorics , messenger rna , gene
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.