Pharmacodynamics and pharmacokinetics of the novel thrombopoietin mimetic peptide RWJ-800088 in humans.
RWJ-800088 is a novel thrombopoietin mimetic peptide for the treatment of thrombocytopenia. The objectives of this study were to evaluate the pharmacokinetics, pharmacodynamics, and safety of ascending doses of RWJ-800088 administered as a single intravenous delivery in a double-blind, placebo-controlled study with five parallel groups of eight healthy human subjects each. Platelet counts and functionality, peripheral stem cells, drug concentrations, and routine laboratory parameters were measured frequently up to day 29, and antibody formation was measured up to days 56-72. At doses > or = 0.75 microg/kg of RWJ-800088, platelet levels showed dose-related elevation as compared to results with placebo. The pharmacokinetic profile was characterized for doses of 2.5 and 3.0 microg/kg, although the dose relationship could not be fully defined. The two highest doses of RWJ-800088 appeared to increase burst-forming units-erythroid and colony-forming unit counts, suggesting some effects on progenitor lineages. RWJ-800088 was well tolerated, with no evidence of antibody formation in this single-dose study. Additional patient studies are warranted to investigate the therapeutic use of this novel peptide.
Liem-Moolenaar
M
M
Centre for Human Drug Research, Leiden, The Netherlands. mmoolenaar@chdr.nl
Cerneus
D
D
Molloy
C J
CJ
End
D
D
Brown
K H
KH
de Kam
M L
ML
Cohen
A F
AF
van Hensbergen
Y
Y
Burggraaf
J
J
D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004921:Erythropoietin / Q000097:blood; D006801:Humans; D007275:Injections, Intravenous; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D010976:Platelet Count; D010982:Platelet-Derived Growth Factor / Q000032:analysis; D013234:Stem Cells / Q000187:drug effects*; D013926:Thrombopoietin / Q000819:agonists* / Q000097:blood; D016212:Transforming Growth Factor beta / Q000097:blood
D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010982:Platelet-Derived Growth Factor; C539273:RWJ 800088; D016212:Transforming Growth Factor beta; D004921:Erythropoietin; D013926:Thrombopoietin