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PII‐60
Author(s) -
Hilbert J.,
Schnee J.,
Rummerstorfer U.,
Jilma B.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.185
Subject(s) - pharmacodynamics , medicine , antigen , placebo , immunology , monocytosis , pharmacokinetics , tolerability , pharmacology , adverse effect , pathology , bone marrow , alternative medicine
BACKGROUND/AIMS BIWH 3 is a recombinant pyro‐glu monocyte chemotactic protein‐1 (MCP‐1). Based on arteriogenic effects of MCP‐1 in animals, MCP‐1 was developed for critical limb ischemia. This study investigated safety, tolerability, and PK of BIWH 3 after single 1‐hr iv infusions of 20 ng/kg −; 2 μg/kg in healthy males. Since the Duffy Antigen Receptor of Chemokines might be an important scavenger of MCP‐1, BIWH 3 PK was assessed in Duffy positive and negative subjects. METHODS This was a randomized double‐blind dose escalation study. 3 Duffy positive subjects each were enrolled at 20 and 60 ng/kg doses (2:1 active:placebo). At higher doses, 5 Duffy positive and 5 Duffy negative subjects were enrolled at each dose (4:1 active:placebo). Safety and tolerance were assessed for each dose. Plasma samples were collected for PK analysis and for PD of markers of leukocyte, coagulation, platelet and endothelial activation. RESULTS MCP‐1 concentrations increased in a dose‐proportional manner, and were rapidly cleared with a half‐life of 0.4–0.5 h. There were no PK differences between Duffy negative and positive subjects. There was no consistent relationship of any PD markers to the PK of BIWH 3, except for the PD of MCP‐1 induced monocytosis. CONCLUSIONS BIWH 3 was well tolerated by the study subjects in single iv infusions up to 20 μg/kg. Exposure was dose proportional, and didn't change with Duffy antigen status. PK‐PD data were in line with the chemoattracting actions of BIWH 3 on monocytes in vitro and in animal studies. Clinical Pharmacology & Therapeutics (2005) 79 , P52–P52; doi: 10.1016/j.clpt.2005.12.185