Meta‐analysis of Pharmacokinetic/Pharmacodynamic Results of 3 Phase 1 Studies with Biosimilar Pegfilgrastim

Abstract

A meta‐analysis using data from 3 phase 1 studies evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of Sandoz biosimilar versus US‐ and EU‐reference pegfilgrastim. The studies included a single‐dose, double‐blind, 3‐arm, parallel‐group study (study 1); a single‐dose, double‐blind, 2‐way crossover study (study 2); and a single‐dose, double‐blind, 3‐way, 6‐sequence crossover study (study 3). Healthy male and female subjects were randomized to receive the proposed biosimilar (all studies), US‐reference biologic (studies 1 and 3), or EU‐reference biologic (studies 1, 2, and 3). For PK parameters (area under the serum concentration–time curve from time of dosing and extrapolated to infinity, area under the serum concentration–time curve from the time of dosing to the last measurable concentration, and maximum observed serum concentration) and PD parameters (absolute neutrophil count area under the effect curve from the time of dosing to the last measurable concentration and maximum measured absolute neutrophil count) geometric mean ratios and 90% confidence intervals (CIs) for treatment comparisons were calculated using the meta‐analysis approach with a fixed‐effects model. PK/PD biosimilarity was concluded if the 90%CIs were within the equivalence margins of 0.80 to 1.25. The 90%CIs for the geometric mean ratios for the PK/PD parameters were all within the equivalence margins. Safety and tolerability were similar between the proposed biosimilar and the US‐ and EU‐reference pegfilgrastim in healthy subjects. This meta‐analysis of 3 phase 1 studies supports PK/PD similarity of Sandoz biosimilar pegfilgrastim to US‐ and EU‐reference pegfilgrastim. No clinically meaningful differences in safety or tolerability were observed.

Model‐Based Approach to Selecting Pegfilgrastim Dose for Pharmacokinetic and Pharmacodynamic Similarity Studies in Biosimilar Development

“…Second, a difference of 5% in administered dose manifests as a difference of AUC by 14% and 11% at 6 and 2 mg, respectively, indicating that 6 mg has a similar sensitivity to detect differences in dose amount. Last, the PD parameters (AUEC of ANC and ANC max ) observed at 2 and 6 mg were insensitive to changes in linear CL and K d (Figure 4, all panels), which is consistent with the report of Bekkan et al 13 Further, pegfilgrastim PD parameters have been reported to be much less variable than the PK parameters [17][18][19] ; therefore, the sample size required to achieve PD similarity is smaller than that for demonstrating PK similarity. On the other hand, the 2 mg dose has a favorable quality compared with the 6 mg dose in that the pegfilgrastim PK parameters at 2 mg are sensitive to changes in K d (Figure 4b1, b2), presumably because the TMDD CL accounts for a 98% of total CL at 2 mg which is 21% higher than the estimated 77% at 6 mg.…”

“…Given that the model was developed with data from single dose studies, the suitability for simulating PK and PD profiles for crossover studies has not been verified. Another limitation is that variability from simulations was higher than reported from a meta‐analysis of data from more than 600 healthy subjects who participated in three pegfilgrastim PK and PD similarity studies 17 . The increased variability is likely due to the limited number of subjects available for the modeling combined with the complicated model structure that includes receptor‐mediated elimination and interplay between pegfilgrastim exposure and the circulating neutrophil count.…”

“…Another limitation is that variability from simulations was higher than reported from a meta-analysis of data from more than 600 healthy subjects who participated in three pegfilgrastim PK and PD similarity studies. 17 The increased variability is likely due to the limited number of subjects available for the modeling combined with the complicated model structure that includes receptor-mediated elimination and interplay between pegfilgrastim exposure and the circulating neutrophil count. Because of the increased variability the model may not be suitable for simulating studies although it does depict central tendencies adequately to support comparisons across doses, as reported in Table 2.…”

Pooled analysis of three pharmacokinetic studies comparing biosimilar MB02 and reference bevacizumab

“…Gattu et al performed another analysis using data from three phase 1 studies to evaluate the PK and pharmacodynamic characteristics of a pegfilgrastim biosimilar versus the reference product. However, as the designs of the studies were different and the sensitivity of the bioanalytical assay slightly varied among the studies, data from the individual studies could not be pooled directly and a fixed‐effects model was used to perform a combined analysis 26 . Even though different methodologies were used, results from the previously reported meta‐analysis and the present analysis are aligned in the sense of providing further evidence to support the already demonstrated PK similarity of a certain biosimilar versus the reference product.…”