Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies.
Inhibition of cathepsin K (CatK) is a potential new treatment for osteoporosis. In two double-blind, randomized, placebo-controlled phase I studies, postmenopausal female subjects received odanacatib (ODN), an orally active, potent, and selective CatK inhibitor, once weekly for 3 weeks or once daily for 21 days. Bone turnover biomarkers, safety monitoring, and plasma ODN concentrations were assessed. These studies showed ODN to be well tolerated. Pharmacokinetic (PK) analysis revealed a long half-life (t(1/2); 66-93 h) consistent with once-weekly dosing. Pronounced reductions in C-terminal telopeptide of type I collagen (approximately 62%) and N-terminal telopeptide of type I collagen normalized to creatinine (NTx/Cr) (approximately 62%) at trough (C(168 h)) were seen following weekly administration. Robust reductions in CTx (up to 81%) and NTx/Cr (up to 81%) were seen following daily administration. ODN exhibits robust and sustained suppression of bone resorption biomarkers (CTx and NTx/Cr) at weekly doses > or = 25 mg and daily doses > or = 2.5 mg.
Stoch
S A
SA
Merck Research Laboratories, Rahway, New Jersey, USA. aubrey_stoch@merck.com
Zajic
S
S
Stone
J
J
Miller
D L
DL
Van Dyck
K
K
Gutierrez
M J
MJ
De Decker
M
M
Liu
L
L
Liu
Q
Q
Scott
B B
BB
Panebianco
D
D
Jin
B
B
Duong
L T
LT
Gottesdiener
K
K
Wagner
J A
JA
D000284:Administration, Oral; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D001862:Bone Resorption / Q000097:blood / Q000188:drug therapy*; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D024042:Collagen Type I; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D010446:Peptide Fragments / Q000097:blood*; D010455:Peptides; D011347:Procollagen / Q000097:blood*; D016896:Treatment Outcome
D015415:Biomarkers; D001713:Biphenyl Compounds; D024042:Collagen Type I; D010446:Peptide Fragments; D010455:Peptides; D011347:Procollagen; C052929:collagen type I trimeric cross-linked peptide; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C527128:odanacatib