title: Population pharmacokinetic and pharmacodynamic model-based comparability assessment of a recombinant human Epoetin Alfa and the Biosimilar HX575.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, 565 B Hochstetter Hall, State University of New York at Buffalo, Buffalo, NY 14260, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Yan
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lowe
authors.forename: Martin
authors.initials: M
authors.lastname: Fink
authors.forename: Alexander
authors.initials: A
authors.lastname: Berghout
authors.forename: Sigrid
authors.initials: S
authors.lastname: Balser
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krzyzanski
mesh_terms: D061605:Administration, Intravenous; D019540:Area Under Curve; D000068817:Epoetin Alfa; D004906:Erythrocyte Count; D004921:Erythropoietin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006397:Hematinics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency
chemical_list: D006397:Hematinics; D006454:Hemoglobins; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa