A phase 1 pooled PK/PD analysis of bone resorption biomarkers for odanacatib, a Cathepsin K inhibitor
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ORIGINAL PAPER
A phase 1 pooled PK/PD analysis of bone resorption biomarkers for odanacatib, a Cathepsin K inhibitor Stefan Zajic1,2 • S. Aubrey Stoch1 • Jacqueline B. McCrea1 • Rose Witter1 • Ghassan N. Fayad1 Monika Martinho1 • Julie A. Stone1,3
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Received: 24 February 2020 / Accepted: 26 June 2020 Ó Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract To develop a framework for evaluating the resorption effects of Cathepsin K (CatK) inhibitors and to inform dose regimen selection, a pharmacokinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N = 249) were fit reasonably to a population inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarker response) were significant covariates for biomarker response. Simulations of typical osteoporosis patients (by age, sex and weight) indicated minimal differences between sexes in concentration-uNTx/ Cr relationship. There was no evidence that regimen (daily vs. weekly dosing) influenced the PK/PD relationship of resorption inhibition for odanacatib. PK/PD models based on data from odanacatib (ODN) Phase 1 studies demonstrated that uNTx/Cr was an appropriate bone resorption biomarker for assessment of the effects of a CatK inhibitor. The models also identified the determinants of response in the PK/PD relationship for ODN (body weight on E0 and age on Emax). Keywords Odanacatib Cathepsin K PK/PD Phase 1 Modeling
Background Odanacatib (ODN), an oral selective oral inhibitor of cathepsin K (CatK), was an investigational agent previously in development for the treatment of osteoporosis [1]. In the long-term odanacatib fracture trial, odanacatib 50 mg significantly reduced the risk of osteoporotic fractures in women with postmenopausal osteoporosis compared to placebo, but this was associated with an observed increase in the risk of stroke and further clinical development was stopped. The clinical and translational pharmacology of odanacatib has been summarized recently [2]. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09699-9) contains supplementary material, which is available to authorized users. & Julie A. Stone [email protected] 1
Merck & Co. Inc., Kenilworth, NJ, USA
2
GSK, Collegeville, PA, USA
3
Merck & Co. Inc., UG4D-48, 351 North Sumneytown Pike, P.O. Box 1000, North Wales, PA 19454-2505, USA
Odanacatib has low clearance (approximately 13 mL/min) with an apparent terminal half-life of approximately 80 h, making once-weekly dosing possible. 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. Osteoporosis is characterized by low bone mass and accompanying microarchitectural deterioration that result in skeletal fragi
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