A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01)

Abstract

Aims: The pharmacokinetic (PK) similarity between PF-05280014, a proposed trastuzumab biosimilar, trastuzumab sourced from European Union (trastuzumab-EU) or from United States (trastuzumab-US) was evaluated. Safety and immunogenicity were also assessed.

Methods: In this phase 1, double-blind trial (NCT01603264), 105 healthy male volunteers were randomized 1:1:1 to receive a single 6 mg kg(-1) intravenous dose of PF-05280014, trastuzumab-EU, or trastuzumab-US, and evaluated for 70 days. Drug concentration-time data were analyzed by non-compartmental methods. PK similarity for the comparisons of PF-05280014 to each of trastuzumab-EU and trastuzumab-US, and trastuzumab-EU to trastuzumab-US were determined using the standard 80.00% to 125.00% bioequivalence criteria.

Results: Baseline demographics for the 101 subjects evaluable for PK were similar across all arms. The three products exhibited similar PK profiles with target-mediated disposition. The 90% CIs for the ratios of Cmax , AUC (0 , t last) and AUC(0,∞) were within 80.00% to 125.00% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms with treatment-related AEs reported by 71.4%, 68.6% and 65.7% subjects in the PF-05280014, trastuzumab-EU, and trastuzumab-US arms, respectively. The most common AEs were infusion-related reactions, headache, chills, pyrexia and nausea. The AE term 'pyrexia' was numerically greater in the PF-05280014 arm. All post-dose samples, except 1, tested negative for anti-drug antibodies (ADA).

Conclusions: This study demonstrates PK similarity among PF-05280014, trastuzumab-EU and trastuzumab-US. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab.

Keywords: PF-05280014; biosimilar; immunogenicity; pharmacokinetics; safety; trastuzumab.

© 2014 The British Pharmacological Society.

Figures

Figure 1

Study design. *Time/day on which samples were collected for ADA; samples for PK were collected at all times shown. †Subjects having an unresolved adverse event that was possibly related to ADA formation were asked to return for ADA and drug concentration blood sampling at up to 3 month intervals until the adverse event or its sequelae resolved or stabilized at a level acceptable to the investigator and the sponsor concurs with the investigator's assessment, up to 6 months from the visit on day 71 or the day of early withdrawal. ADA, anti-drug antibodies; PK, pharmacokinetics

Figure 2

Subject disposition. IRR, incomplete dosing due to infusion-related reaction

Figure 3

Individual (A–C) and mean ± SD (D) serum concentration–time profiles of PF-05280014, trastuzumab-EU and trastuzumab-US following a single dose of 6 mg kg−1 in healthy subjects. SD, standard deviation. A, B and C: , median; , individual; D: •, PF-02580014; ▪, trastuzumab-EU; ▴, trastuzumab-US

Figure 4

Individual and mean estimates of (A) Cmax, (B) and (C) AUC(0,∞) of PF-05280014, trastuzumab-EU and trastuzumab-US. AUC(0,∞), area under the concentration–time curve from time 0 extrapolated to infinite time; , area under the concentration-time curve from time 0 to last time point of measurable concentration; Cmax, maximum drug concentration; EU, trastuzumab EU; PF, PF-05280014; US, trastuzumab-US