title: 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 (AUC0-t last and AUC 0-∞) and peak exposure (Cmax) 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 (tmax) 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.
authors.affiliation: Merckle GmbH/Teva Pharmaceuticals Inc. , Ulm , Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Buchner
authors.forename: Andreas
authors.initials: A
authors.lastname: Lammerich
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Abdolzade-Bavil
authors.forename: Udo
authors.initials: U
authors.lastname: Müller
authors.forename: Peter
authors.initials: P
authors.lastname: Bias
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim
keywords: Granulocyte colony-stimulating factor; human volunteers; safety; sustained-release preparations