Proposed biosimilar pegfilgrastim shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects

• Published in: British journal of clinical pharmacology Vol. 84; no. 12; pp. 2790 - 2801
• Main Authors: Nakov, Roumen, Gattu, Sreekanth, Wang, Jessie, Velinova, Maria, Schaffar, Gregor, Skerjanec, Andrej
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.12.2018
• Subjects: Adult; Biosimilar Pharmaceuticals - pharmacokinetics; Cross-Over Studies; Double-Blind Method; drug development < phase I; Female; Filgrastim - adverse effects; Filgrastim - immunology; Filgrastim - pharmacokinetics; Filgrastim - pharmacology; Healthy Volunteers; Humans; Male; oncology < chemotherapy; Original; pharmacodynamics; pharmacokinetics; Polyethylene Glycols - adverse effects; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - pharmacology; drug development < phase I; pharmacokinetics; oncology < chemotherapy; pharmacodynamics
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.13731

Aims This study aimed to demonstrate that the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Sandoz proposed biosimilar pegfilgrastim (LA‐EP2006) matches reference pegfilgrastim (Neulasta®) in healthy subjects. Safety and immunogenicity were also assessed. Methods The phase I, randomized, double‐blind, two‐period crossover study consisted of two treatment periods separated by an 8‐week washout period. Healthy subjects aged 18–45 were randomized to either proposed biosimilar/reference pegfilgrastim or reference pegfilgrastim/proposed biosimilar. Proposed biosimilar and reference pegfilgrastim were administered on Day 1 of each treatment period (single 6 mg subcutaneous injection). Blood samples for PK/PD analysis were taken predose and ≤336 h postdose. PK/PD similarity was claimed if 90% (PK) and 95% (PD) confidence intervals (CI) for geometric mean ratios of the area under the serum concentration–time curve (AUC) from time of dosing and extrapolated to infinity (AUC0–inf), or to the last measurable concentration (AUC0–last), maximum observed serum concentration (Cmax), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC0–last) and ANC maximum effect attributable to the therapy under investigation (Emax) were completely contained within the predefined margin (0.8 to 1.25). Results Overall, 169 subjects completed the study. PK/PD similarity was demonstrated; 90% CIs of geometric mean ratio of proposed biosimilar/reference for PK: AUC0–inf (1.0559–1.2244), AUC0–last (1.0607–1.2328), Cmax (1.0312–1.1909) and 95% CIs for PD (ANC): AUEC0–last (0.9948–1.0366), Emax (0.9737–1.0169) were completely contained within predefined margin of 0.8 to 1.25. Both biologics had similar safety profiles, were well tolerated and had low incidence of anti‐drug antibodies. No neutralizing or clinically relevant antibodies were detected. Conclusions PK/PD similarity of Sandoz proposed biosimilar pegfilgrastim and reference pegfilgrastim was confirmed. No clinically meaningful differences in safety, tolerability and immunogenicity were observed in healthy subjects. What is Already Known about this Subject Sandoz has developed a proposed biosimilar pegfilgrastim (LA‐EP2006). Physicochemical and functional characterization using state‐of‐the‐art analytical procedures showed Sandoz proposed biosimilar pegfilgrastim to be highly similar to the reference pegfilgrastim (Neulasta®, Amgen). In two confirmatory, randomized, double‐blind, phase III studies in patients with breast cancer (PROTECT‐1 and PROTECT‐2), Sandoz proposed biosimilar pegfilgrastim showed no clinically meaningful differences in efficacy and safety to reference pegfilgrastim (Neulasta®). What this Study Adds This phase I, randomized, double‐blind, two‐period crossover trial was conducted to demonstrate that the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Sandoz proposed biosimilar pegfilgrastim (LA‐EP2006) matches reference pegfilgrastim (Neulasta®) in healthy subjects. PK and PD similarity of Sandoz proposed biosimilar pegfilgrastim and reference pegfilgrastim was confirmed. No clinically meaningful differences in safety, tolerability and immunogenicity were observed in healthy subjects.