Merck & Co., Inc., Kenilworth, NJ, USA.
Br J Clin Pharmacol. 2019 Jun;85(6):1072-1083. doi: 10.1111/bcp.13869. Epub 2019 Mar 18.
Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 μM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that 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. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formation-sparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.
组织蛋白酶 K（CatK）是一种丰富存在于破骨细胞中的半胱氨酸蛋白酶，定位于这些细胞的溶酶体和吸收陷窝中。CatK 是负责降解骨胶原的主要酶。odanacatib 是一种选择性、可逆的 CatK 抑制剂，效力在纳摩尔范围内。odanacatib 的药代动力学已得到广泛研究，在年轻健康男性、绝经后女性和老年男性中相似，并且在整个 1 期开发和住院研究中具有定性相似性。在每周一次 50mg 治疗 3 周后，0 至 168 小时的几何平均曲线下面积为 41.1μM·h，168 小时的浓度为 126nM，调和平均表观终末半衰期为 84.8 小时。由于溶解度限制吸收，odanacatib 的暴露量呈低于剂量比例的增加。据估计，吸收剂量的约 70% 通过代谢消除，20%以胆汁或粪便中的未改变药物排泄，10%以尿液中的未改变药物排泄。全身清除率较低（约 13mL/min）。odanacatib 可降低骨基质蛋白的降解，并降低骨吸收的效率，通过 1 型胶原 C-端肽（约 60%）、1 型胶原氨基端交联端肽/肌酐比（约 50%）和总尿脱氧吡啶啉/Cr（约 30%）的血清中骨胶原的稳健下降，同时血清中 1 型胶原交联羧基末端肽（约 55%）增加，从而证实了目标结合。在 3 期评估的 50mg 每周剂量方案在整个治疗期间实现了对骨吸收的几乎最大抑制。odanacatib 广泛的临床计划，以及其他 CatK 抑制剂（balicatib 和 ONO-5334）的更有限的临床经验，为 CatK 抑制的临床药理学以及 CatK 在骨转换和矿物质稳态中的潜在作用提供了重要的见解。关键发现包括该机制能够：（i）持续降低吸收标志物，增加骨密度，并证明降低骨折风险；（ii）与相对形成保留作用相关，从而在没有伴随的骨形成有意义降低的情况下实现持续的吸收减少；（iii）导致破骨细胞数量以及其他破骨细胞活性（包括 CatK 酶的积累）增加，这可能导致治疗停止后吸收的短暂增加和治疗剂量下的潜在非单调反应。
