Abstract P5-14-16: Pharmacokinetics/pharmacodynamics of Sandoz biosimilar pegfilgrastim compared to both US- and EU-reference pegfilgrastim: A meta-analysis of three clinical studies in healthy subjects
Authors: Nakov Roumen , Wang Jessie , Bellon Anne , Gattu Sreekanth , Arani Ramin 
Published: March 2020

Background. To further evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of Sandoz biosimilar, US-reference and EU-reference pegfilgrastim, a meta-analysis was conducted using data from three Phase I studies.

Methods. All studies were single-dose, double-blind, randomized trials. The first was a three arm parallel-group study, the second a two-way crossover study, and the third a three-way crossover study. Healthy subjects were randomized to receive Sandoz biosimilar pegfilgrastim (all studies), US-reference (studies 1 and 3) or EU-reference (all studies). For each primary PK and primary PD (non-baseline corrected) parameter, geometric mean ratios and 90% confidence intervals (CIs) for the treatment comparisons were calculated using a meta-analysis approach with a fixed-effect model. PK/PD similarity was considered confirmed if the calculated 90% CIs of the ratios were within the pre-defined similarity margins of 0.8–1.25.

Results. This meta-analysis showed that the 90% CIs of the geometric mean ratios (Sandoz biosimilar vs. US-reference, Sandoz biosimilar vs. EU-reference, and US- vs. EU-reference pegfilgrastims) of the primary PK parameters and primary PD parameters (see Table 1) were contained within the pre-defined similarity margins of 0.80–1.25, confirming PK/PD similarity for all pairwise comparisons. Safety and tolerability were similar between Sandoz biosimilar, US- and EU-reference biologic in healthy subjects.

Conclusions. This is the first meta-analysis combining data from three Phase I studies to confirm PK/PD similarity of Sandoz biosimilar to US- and EU-reference pegfilgrastim, and PK/PD similarity between US- vs. EU-reference pegfilgrastim. No clinically meaningful differences in safety or tolerability were observed.

Table 1. Results of the meta-analysis combining PK and PD data obtained with Sandoz biosimilar pegfilgrastim, US-reference pegfilgrastim, and EU-reference pegfilgrastim in healthy subjects included in three clinical studies.ParameterSandoz biosimilar vs. US-reference pegfilgrastimSandoz biosimilar vs. EU-reference pegfilgrastimEU-reference vs. US-reference pegfilgrastimGeometric mean ratio90% CIGeometric mean ratio90% CIGeometric mean ratio90% CILowerUpperLowerUpperLowerUpperPrimary PK parameters using pegfilgrastim serum concentrationsAUC0-last (h*ng/mL)1.06851.01501.12481.07891.03401.12560.98260.93331.0344AUC0-inf (h*ng/mL)1.07041.01841.12511.07511.03171.12040.97940.93181.0294Cmax (ng/mL)1.05161.00141.10431.05151.00981.09500.97590.92911.0250Primary PD parameters using Absolute Neutrophil CountAUEC0-last (h*109/L)0.99930.99091.00781.00430.99711.01151.00210.99371.0105Emax (109/L)0.99760.98681.00851.00350.99431.01271.00900.99811.0201Study one: n=277 (three-arm parallel group study: 93 for biosimilar, 93 for EU-reference pegfilgrastim, and 91 for US-reference)Study two: n=169 (two-way crossover study)Study three: n=496 (three-way crossover study)AUC0-inf, area under the serum concentration–time curve measured from time of dosing and extrapolated to infinity; AUC0-last, area under the serum concentration–time curve measured from time of dosing extrapolated to the last measurable concentration; CI, confidence interval; Cmax, maximum serum concentration; AUEC0-last, area under the effect curve using absolute neutrophil counts over time; Emax, maximum effect attributable to the therapy under investigation; n, number of subjects in study; PD, pharmacodynamic; PK, pharmacokinetic.

Citation Format: Roumen Nakov, Jessie Wang, Anne Bellon, Sreekanth Gattu, Ramin Arani. Pharmacokinetics/pharmacodynamics of Sandoz biosimilar pegfilgrastim compared to both US- and EU-reference pegfilgrastim: A meta-analysis of three clinical studies in healthy subjects [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-16.