Lipegfilgrastim: pharmacodynamics and pharmacokinetics for body-weight-adjusted and 6 mg fixed doses in two randomized studies in healthy volunteers

Abstract

Objective:

Two phase I, single-blind (subject blinded to treatment), randomized studies were conducted to assess the pharmacodynamics, pharmacokinetics, safety, and tolerability of lipegfilgrastim compared with pegfilgrastim in healthy adult volunteers.

Methods:

Study 1 consisted of a pilot safety phase (N = 8) during which subjects received a single body-weight-adjusted subcutaneous dose of lipegfilgrastim 25 µg/kg and a dose escalation phase (N = 45) wherein subjects received lipegfilgrastim 50 or 100 μg/kg or pegfilgrastim 100 μg/kg. Study 2 was a single-blind, fixed-dose study (N = 36) comparing subcutaneous lipegfilgrastim 6 mg and pegfilgrastim 6 mg.

Results:

Cumulative exposure (AUC_0–tlast and AUC_0–∞) and peak exposure (C_max) were higher for lipegfilgrastim than pegfilgrastim after both weight-adjusted and fixed dosing. In both studies, the terminal elimination half-life of lipegfilgrastim was 5–10 hours longer than the terminal elimination half-life for pegfilgrastim at the maximum dose, and the time to maximum serum concentration (t_max) was observed later for lipegfilgrastim than for pegfilgrastim. The area over the baseline effect curve (AOBEC) for absolute neutrophil count (ANC) was approximately 30% greater after lipegfilgrastim dosing compared with the same dose of pegfilgrastim at the maximum dose. Both drugs were well tolerated, with a similar occurrence of adverse events between treatment groups. Key limitations of these studies include the small numbers of subjects and differences in dosage regimens between the two studies.

Conclusions:

In these studies, lipegfilgrastim provided a longer-lasting increase in ANC compared with pegfilgrastim at an equivalent dose, without increasing the peak ANC values. This may reflect the higher cumulative exposure and slower clearance (therefore longer body residence) of lipegfilgrastim. These data support the use of single-dose lipegfilgrastim 6 mg in subsequent phase III trials as prophylactic treatment for patients receiving myelosuppressive chemotherapy.

Key words::

• Granulocyte colony-stimulating factor
• human volunteers
• safety
• sustained-release preparations

Transparency

Declaration of funding

This work was funded by Biogenerix/Merckle/Ratiopharm, which are subsidiaries of Teva Pharmaceuticals Inc. since 2010 but were not subsidiaries at the time of these studies.

Declaration of financial/other relationships

A.B., A.L., U.M., and P.B. have disclosed that they are employees of Teva Pharmaceuticals Inc. and own stock in that company. A.A.-B. has disclosed that she is an employee of BioGeneriX GmbH/Teva Pharmaceuticals Inc.

CMRO peer reviewers on this manuscript have no relevant financial relationships to disclose.

Acknowledgments

The authors thank Lisa Grauer MSc of Chameleon Communications for providing editorial support, Amy Zannikos PharmD and Lisa Feder PhD of Peloton Advantage for providing medical writing and editorial support, all of which were funded by Teva Pharmaceuticals Inc.

Notes

*Neupogen is a registered trade name of Amgen Inc., Thousand Oaks, CA, USA

†Neulasta is a registered trade name of Amgen Inc., Thousand Oaks, CA, USA