A randomized phase I study comparing the pharmacokinetics of a bevacizumab (HD204) biosimilar to European Union- and United States of America-sourced bevacizumab

Abstract

Purpose This first-in-human study was designed to evaluate the pharmacokinetic (PK) equivalence between HD204 and the European Union (EU)-sourced bevacizumab, between HD204 and the United States of America (US)-sourced bevacizumab, and between EU-sourced and US-sourced bevacizumab (NCT 03390673). Methods In this randomized, double-blind, 3-way parallel group, single-dose comparative PK study, healthy male subjects were randomized to receive a single 1 mg/kg intravenous dose of HD204, EU-sourced bevacizumab or US-sourced bevacizumab. PK parameters were calculated using non-compartmental methods. PK equivalence was determined using the pre-defined equivalence margin of 0.8–1.25 in terms of AUC(0-∞) for the pairwise comparisons. Findings Baseline demographics for the 119 randomized subjects were similar across the three groups. The 90% CIs for the ratio of the geometric means of HD204 to US-sourced bevacizumab, HD204 to EU-sourced bevacizumab, and EU-sourced to US-sourced bevacizumab were all within the interval of 80% to 125% for AUC0-inf, thus demonstrating equivalency in the PK properties for all three treatment groups. Similarly, the ratio of the geometric means for AUC0-last and Cmax were all within the 80% and 125% margins, supporting the robustness of the primary findings. All other PK parameters, including the half-life (t1⁄2) clearance (CL), volume of distribution (Vd) and time of maximum concentration (tmax), were comparable. There was no difference between the 3 treatment arms in terms of vital signs, laboratory tests and adverse events. None of the subjects treated with HD204 had positive ADA results. Implications HD204 demonstrates equivalent pharmacokinetic profiles compared to those of both US-sourced and EU-sourced bevacizumab. (NCT 03390673).

Translation of Monoclonal Antibodies Pharmacokinetics from Animal to Human Using Physiologically Based Modeling in Open Systems Pharmacology (OSP) Suite: A Retrospective Analysis of Bevacizumab

“…Since VEGF-A concentration is significantly lower in HV than in patients, this TMDD mechanism was not necessarily expected. According to the manufacturer label, bevacizumab PK is linear in HV for doses ranging from 1 to 10 mg/kg [ 10 ], although a slightly non-linear profile was visible at 1 mg/kg in several studies [ 14 , 15 , 16 , 17 ]. In addition, Li et al used a mixed zero- and first-order model to describe elimination of bevacizumab at 0.5 mg/kg in HV as it provided better description of the data than a linear PK model [ 12 ].…”