Applicability of in vitro-in vivo translation of cathepsin K inhibition from animal species to human with the use of free-drug hypothesis

Naunyn Schmiedebergs Arch Pharmacol. 2017 Apr;390(4):435-441. doi: 10.1007/s00210-017-1356-5. Epub 2017 Feb 20.

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 IC50 values 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 EC50 values 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.

Keywords: Bone resorption; Cathepsin K; Free-drug hypothesis; In vitro-in vivo correlation.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Biomarkers / urine
  • Biphenyl Compounds / blood
  • Biphenyl Compounds / pharmacokinetics
  • Biphenyl Compounds / pharmacology
  • Biphenyl Compounds / urine
  • Blood Proteins / metabolism
  • Cathepsin K / antagonists & inhibitors
  • Cathepsin K / blood*
  • Collagen Type I / urine
  • Cysteine Proteinase Inhibitors / blood*
  • Cysteine Proteinase Inhibitors / pharmacokinetics
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cysteine Proteinase Inhibitors / urine
  • Dogs
  • Female
  • Humans
  • Macaca mulatta
  • Male
  • Middle Aged
  • Peptides / urine
  • Protein Binding
  • Pyrazoles / blood
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology
  • Pyrazoles / urine
  • Rabbits
  • Sulfones / blood
  • Sulfones / pharmacokinetics
  • Sulfones / pharmacology
  • Sulfones / urine
  • Young Adult

Substances

  • 5,5-dichloro-N-(1-cyanocyclopropyl)-2-(4-(4-(methylsulfonyl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyraazol-3-yl)cyclohexanecarboxamide
  • Biomarkers
  • Biphenyl Compounds
  • Blood Proteins
  • Collagen Type I
  • Cysteine Proteinase Inhibitors
  • MK 0674
  • Peptides
  • Pyrazoles
  • Sulfones
  • collagen type I trimeric cross-linked peptide
  • Cathepsin K
  • odanacatib