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Suppression of cathepsin K biomarker in synovial fluid as a free-drug–driven process

Cathepsin K (CatK) inhibitors exhibited chondroprotective and pain-reducing effects in animal models, however, improvements were relatively modest at dose levels achieving maximal suppression of CatK biomarkers in urine. In this report, a previously characterized CatK inhibitor (MK-1256) is utilized...

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Autores principales: Ma, Bennett, Wesolowski, Gregg, Luo, Bin, Lifsted, Traci, Wessner, Keith, Adamson, Gary, Glantschnig, Helmut, Lubbers, Laura S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327326/
https://www.ncbi.nlm.nih.gov/pubmed/30671145
http://dx.doi.org/10.1177/1849454418821819
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author Ma, Bennett
Wesolowski, Gregg
Luo, Bin
Lifsted, Traci
Wessner, Keith
Adamson, Gary
Glantschnig, Helmut
Lubbers, Laura S
author_facet Ma, Bennett
Wesolowski, Gregg
Luo, Bin
Lifsted, Traci
Wessner, Keith
Adamson, Gary
Glantschnig, Helmut
Lubbers, Laura S
author_sort Ma, Bennett
collection PubMed
description Cathepsin K (CatK) inhibitors exhibited chondroprotective and pain-reducing effects in animal models, however, improvements were relatively modest at dose levels achieving maximal suppression of CatK biomarkers in urine. In this report, a previously characterized CatK inhibitor (MK-1256) is utilized to explore the potential of reduced target engagement and/or suboptimal exposure (free drug) as limiting factors to the pharmacological potential of CatK inhibitors in the knee joint. Following oral administration of MK-1256 at a dose level achieving maximal inhibition of urinary biomarker (helical peptide) in dogs, full suppression of the biomarker in synovial fluid was observed. Subsequent tissue distribution studies conducted in dogs and rabbits revealed that MK-1256 levels in synovial fluid and cartilage were consistent with the free-drug hypothesis. Reasonable projection (within twofold) of drug levels in these tissues can be made based on plasma drug concentration with adjustments for binding factors. These results indicate that the previously observed efficacies in the animal models were not limited by compound distribution or target engagement in the knee tissues.
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spelling pubmed-63273262019-01-22 Suppression of cathepsin K biomarker in synovial fluid as a free-drug–driven process Ma, Bennett Wesolowski, Gregg Luo, Bin Lifsted, Traci Wessner, Keith Adamson, Gary Glantschnig, Helmut Lubbers, Laura S J Circ Biomark Research Article Cathepsin K (CatK) inhibitors exhibited chondroprotective and pain-reducing effects in animal models, however, improvements were relatively modest at dose levels achieving maximal suppression of CatK biomarkers in urine. In this report, a previously characterized CatK inhibitor (MK-1256) is utilized to explore the potential of reduced target engagement and/or suboptimal exposure (free drug) as limiting factors to the pharmacological potential of CatK inhibitors in the knee joint. Following oral administration of MK-1256 at a dose level achieving maximal inhibition of urinary biomarker (helical peptide) in dogs, full suppression of the biomarker in synovial fluid was observed. Subsequent tissue distribution studies conducted in dogs and rabbits revealed that MK-1256 levels in synovial fluid and cartilage were consistent with the free-drug hypothesis. Reasonable projection (within twofold) of drug levels in these tissues can be made based on plasma drug concentration with adjustments for binding factors. These results indicate that the previously observed efficacies in the animal models were not limited by compound distribution or target engagement in the knee tissues. SAGE Publications 2019-01-07 /pmc/articles/PMC6327326/ /pubmed/30671145 http://dx.doi.org/10.1177/1849454418821819 Text en © The Author(s) 2019 http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Research Article
Ma, Bennett
Wesolowski, Gregg
Luo, Bin
Lifsted, Traci
Wessner, Keith
Adamson, Gary
Glantschnig, Helmut
Lubbers, Laura S
Suppression of cathepsin K biomarker in synovial fluid as a free-drug–driven process
title Suppression of cathepsin K biomarker in synovial fluid as a free-drug–driven process
title_full Suppression of cathepsin K biomarker in synovial fluid as a free-drug–driven process
title_fullStr Suppression of cathepsin K biomarker in synovial fluid as a free-drug–driven process
title_full_unstemmed Suppression of cathepsin K biomarker in synovial fluid as a free-drug–driven process
title_short Suppression of cathepsin K biomarker in synovial fluid as a free-drug–driven process
title_sort suppression of cathepsin k biomarker in synovial fluid as a free-drug–driven process
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327326/
https://www.ncbi.nlm.nih.gov/pubmed/30671145
http://dx.doi.org/10.1177/1849454418821819
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