组织蛋白酶K抑制剂ONO-5334在绝经后骨质疏松症II期试验中的抗吸收作用及其与骨密度增加的关系。
Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis.
作者信息
Tanaka Makoto, Hashimoto Yoshitaka, Hasegawa Chihiro, Deacon Steve, Eastell Richard
机构信息
Research Promotion, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Osaka, 618-8585, Japan.
Translational Medicine Center, Ono Pharmaceutical Co., Ltd, Shimamoto, Osaka, Japan.
出版信息
BMC Musculoskelet Disord. 2017 Jun 19;18(1):267. doi: 10.1186/s12891-017-1625-y.
BACKGROUND
ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain.
METHODS
Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship. sCTX was selected because it has a high signal-to-noise ratio compared to other telopeptides. A negative sigmoidal shape for the PK/PD relationship between plasma ONO-5334 and sCTX levels was obtained in our previous study.
RESULTS
The simulated sCTX inhibition reached >99% of the maximal inhibitory effect (Emax) at 0.5 h in all treatment groups, and decreased to <80% Emax at 8 and 12 h at 50 mg BID and 100 mg QD, respectively. However, sCTX inhibition at 300 mg QD was maintained at ≥82% Emax over 24 h. The mean sCTX inhibition rates for 24 h at 100 mg QD, 300 mg QD and 50 mg BID were 63, 95 and 80% Emax, respectively. There was a positive linear relationship by treatment group between mean sCTX inhibition over 24 h and observed BMD gain in the phase II study.
CONCLUSION
The dose response for BMD with ONO-5334 at 100 and 300 mg QD and higher BMD gain at 50 mg BID vs. 100 mg QD can be explained by sCTX inhibition over 24 h. The simulation gave the antiresorptive effect of ONO-5334 over 24 h and allowed prediction of BMD gain due to ONO-5334.
TRIAL REGISTRATION
The registration number in The European Union Clinical Trials Register is 2007-002417-39 . The date of registration was August 31, 2007.
背景
ONO-5334是一种组织蛋白酶K抑制剂，在一项针对绝经后骨质疏松症患者的II期研究中可使骨矿物质密度（BMD）增加。尽管在研究期间仅能在早晨监测到抗吸收作用，但通过模拟可评估24小时内的抗吸收作用，并评估其与BMD增加之间的关系。
方法
利用I期研究中多次给药的血浆ONO-5334药代动力学（PK）数据以及PK-药效学（PK/PD）关系对应的sCTX抑制情况，模拟了ONO-5334剂量为每日1次100mg（QD）、每日1次300mg（QD）和每日2次50mg（BID）时对血清I型胶原C末端肽（sCTX）水平的抑制作用。选择sCTX是因为与其他末端肽相比，它具有较高的信噪比。在我们之前的研究中，血浆ONO-5334与sCTX水平之间的PK/PD关系呈负S形。
结果
在所有治疗组中，模拟的sCTX抑制在0.5小时时达到最大抑制作用（Emax）的>99%，在50mg BID和100mg QD组中，分别在8小时和12小时时降至<80% Emax。然而，300mg QD组的sCTX抑制在24小时内维持在≥82% Emax。100mg QD、300mg QD和50mg BID组24小时的平均sCTX抑制率分别为63%、95%和80% Emax。在II期研究中，按治疗组划分，24小时内平均sCTX抑制与观察到的BMD增加之间存在正线性关系。
结论
ONO-5334每日100mg和300mg时BMD的剂量反应以及每日2次50mg对比每日1次100mg时更高的BMD增加，可通过24小时内的sCTX抑制来解释。该模拟给出了ONO-5334在24小时内的抗吸收作用，并能够预测ONO-5334导致的BMD增加。
试验注册
欧盟临床试验注册中心的注册号为2007-002417-39。注册日期为2007年8月31日。
Zotero 插件