Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics

Abstract

Background: Biosimilars provide safety, purity, and potency similar to those of a reference biologic product.

Methods: An array of protein analytical techniques was used to compare the physicochemical properties of proposed biosimilar filgrastim (EP2006), US-approved originator filgrastim, and EU-approved originator filgrastim. Biological characterization involved surface plasmon resonance spectroscopy analyses and in vitro proliferation assays. A randomized, double-blind, two-way crossover, phase I study in healthy volunteers assessed the pharmacodynamics, pharmacokinetics, and safety profiles of EP2006 and US-approved originator filgrastim (administered as a single subcutaneous 10 µg/kg injection).

Results: EP2006 and originator filgrastim (US and EU approved) were highly similar with respect to primary, secondary, and tertiary protein structures; mass, size, purity, charge, and hydrophobicity. No differences in receptor binding affinity were observed, and all samples demonstrated similar in vitro bioactivity. In the phase I study, no statistically significant differences between EP2006 and US-approved originator filgrastim were noted in pharmacodynamic or pharmacokinetic parameters, and all confidence intervals were within the equivalence boundaries. The two products had similar safety profiles.

Conclusion: These studies provide robust evidence of the structural and functional similarity between the proposed biosimilar filgrastim (EP2006) and the US-approved originator filgrastim.

Fig. 1

Overlay of reversed-phase high-performance liquid chromatograms of a Glu-C digest peptide map from biosimilar and originator filgrastim

Fig. 2

1D-{1H}-nuclear magnetic resonance spectra of biosimilar filgrastim (batch DP1), US-approved originator filgrastim (batch NUS1), and EU-approved originator filgrastim (batch NEU1). ppm parts per million. *2,2,3,3-d4 Sodium 3-(trimethylsilyl)propionate (d4-TSP) signal; **signals between 3.4 and 3.9 ppm correspond to formulation components, i.e., are not protein related

Fig. 3

Sensorgram overlay of the receptor binding affinities of biosimilar and originator filgrastim, based on a surface plasmon resonance-based interaction assay using Biacore technology. RU resonance units

Fig. 4

Pharmacodynamic analysis: geometric mean absolute neutrophil count (ANC)–time profiles for biosimilar and US originator filgrastim

Fig. 5

Pharmacokinetic analysis: geometric mean filgrastim concentration–time profiles for biosimilar and US originator filgrastim