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Cited by 66Bone health and osteoporosis researchBone Metabolism and DiseasesBone health and treatments

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

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Stone, Julie A., McCrea, Jacqueline B., Witter, Rose, Zajic, Stefan, Stoch, S. Aubrey·2019·British Journal of Clinical Pharmacology
DOI 10.1111/bcp.13869PMC PMC6533439
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Abstract

Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in‐patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 μM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half‐life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C‐telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross‐linked carboxy‐terminal telopeptide of type 1 collagen (approximately 55%). The 50‐mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO‐5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formation‐sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build‐up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.

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  • Odanacatib prevents pathological bone loss while preserving bone formation but failed in clinical phase III trials due to increased risk of stroke.

    “odanacatib, was shown to prevent pathological bone loss while preserving bone formation but failed in clinical phase III trials due to increased risk of stroke [72]”

    From Osteoclasts and Microgravity (2020) · cites this paper as [72]

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Authors
Stone, J. A., McCrea, J. B., Witter, R., Zajic, S., & Stoch, S. A.
Affiliations
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author
Stoch, S. Aubrey
ORCID
Venue
British Journal of Clinical Pharmacology
Publisher
Wiley
Published
2019-03-18
Volume
85
Issue
6
Pages
1072-1083
ISSN
  • 0306-5251 (ISSN-L)
  • 1365-2125
DOI
10.1111/bcp.13869
PMC
PMC6533439
OpenAlex
W2913353766
Cited by
66
References
0
Citations by year
2026: 11 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 11 · 2019: 4 · 2018: 1
FWCI
1.72
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • British Journal of Clinical Pharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Oncology › Bone health and treatments
Keywords
odanacatib, cathepsin K inhibitors, osteoporosis, bone resorption, pharmacokinetics, target engagement, bone turnover markers, deoxypyridinoline, bone mineral density, fracture risk reduction, drug safety, adverse events, drug-drug interactions
MeSH terms
Animals, Biphenyl Compounds, Bone and Bones, Female, Humans, Male, Osteoporosis, Signal Transduction, Cysteine Proteinase Inhibitors, Bone Remodeling, Treatment Outcome, Bone Density Conservation Agents, Cathepsin K, Translational Research, Biomedical

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