title: Applicability of in vitro-in vivo translation of cathepsin K inhibition from animal species to human with the use of free-drug hypothesis.
abstract: The correlation of in vitro inhibition of cathepsin K (CatK) activity and in vivo suppression of collagen I biomarkers was examined with three selective CatK inhibitors to explore the potential translatability from animal species to human. These inhibitors exhibited good in vitro potencies toward recombinant CatK enzymes across species, with IC50values ranging from 0.20 to 6.1 nM. In vivo studies were conducted in animal species following multiple-day dosing of the CatK inhibitors to achieve steady-state plasma drug concentration-time profiles. Measurement of urinary bone resorption biomarkers (cross-linked N-terminal telopeptide and helical peptide of type I collagen) revealed drug concentration-dependent suppression of biomarkers, with EC50values estimated to be 12 to 160 nM. Marked improvement in the correlation between in vitro and in vivo CatK activities was observed with the application of unbound (free) fraction in plasma, consistent with the conditions stipulated by the free-drug hypothesis. These results indicate that the in vitro-in vivo translation of CatK inhibition observed in animal species can translate to humans when the unbound fraction of the inhibitor is considered. Interestingly, residual levels of urinary bone resorption marker were detected as the suppression reached saturation (at an average of 82% inhibition), an apparent phenomenon observed regardless of the species, biomarker, or compound examined. Since cathepsin enzymes other than CatK were reported to catalyze cleavage of collagen I, it is hypothesized that CatK-mediated degradation of collagen I in bone represents ~82% of overall collagen I turnover in the body.
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, MSD, West Point, PA, 19486, USA. bennett_ma@merck.com.
authors.forename: Bennett
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, MSD, West Point, PA, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, MSD, West Point, PA, USA.
authors.forename: Danielle H
authors.initials: DH
authors.lastname: Euler
authors.affiliation: Department of Bone Biology, MSD, West Point, PA, USA.
authors.forename: Tara E
authors.initials: TE
authors.lastname: Cusick
authors.affiliation: Department of Bone Biology, MSD, West Point, PA, USA.
authors.forename: Gregg
authors.initials: G
authors.lastname: Wesolowski
authors.affiliation: Department of Bone Biology, MSD, West Point, PA, USA.
authors.forename: Helmut
authors.initials: H
authors.lastname: Glantschnig
authors.affiliation: Department of Bone Biology, MSD, West Point, PA, USA.
authors.forename: Le T
authors.initials: LT
authors.lastname: Duong
authors.affiliation: Department of Pharmacology, MSD, West Point, PA, USA.
authors.forename: Yangsi
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Department of Pharmacology, MSD, West Point, PA, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Carroll
authors.affiliation: Department of Pharmacology, MSD, West Point, PA, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Lubbers
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000652:urine; D001713:Biphenyl Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D001798:Blood Proteins / Q000378:metabolism; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000097:blood*; D024042:Collagen Type I / Q000652:urine; D015853:Cysteine Proteinase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D004285:Dogs; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000652:urine; D011485:Protein Binding; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D011817:Rabbits; D013450:Sulfones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000652:urine; D055815:Young Adult
chemical_list: C532852:5,5-dichloro-N-(1-cyanocyclopropyl)-2-(4-(4-(methylsulfonyl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyraazol-3-yl)cyclohexanecarboxamide; D015415:Biomarkers; D001713:Biphenyl Compounds; D001798:Blood Proteins; D024042:Collagen Type I; D015853:Cysteine Proteinase Inhibitors; C552196:MK 0674; D010455:Peptides; D011720:Pyrazoles; D013450:Sulfones; C052929:collagen type I trimeric cross-linked peptide; D056657:Cathepsin K; C527128:odanacatib
keywords: Bone resorption; Cathepsin K; Free-drug hypothesis; In vitro-in vivo correlation