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

Bennett Ma; Gregg Wesolowski; Bin Luo; Traci Lifsted; Keith Wessner; Gary Adamson; Helmut Glantschnig; Laura S Lubbers

doi:10.33393/jcb.2019.2097

Authors

Bennett Ma Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., West Point, PA, USA
Gregg Wesolowski Department of Bone Biology, Merck & Co., West Point, PA, USA
Bin Luo Department of Pharmacology, Merck & Co., West Point, PA, USA
Traci Lifsted Department of Pharmacology, Merck & Co., West Point, PA, USA
Keith Wessner Department of Pharmacology, Merck & Co., West Point, PA, USA
Gary Adamson Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., West Point, PA, USA
Helmut Glantschnig Department of Bone Biology, Merck & Co., West Point, PA, USA
Laura S Lubbers Department of Pharmacology, Merck & Co., West Point, PA, USA

DOI:

https://doi.org/10.33393/jcb.2019.2097

Keywords:

Cathepsin K, MK-1256, osteoarthritis, synovial fluid, cartilage

Abstract

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.