默克的骨转新药：组织蛋白酶K抑制剂Odanacatib

我妈用艾本已经一年半了，是使用一年就不能再用了吗，这个药现在有吗

唑莱磷酸，据说打了一年，不用再打，我老爸的主治医生也是这样说的，

期待好药多出啊。老马这是在给大家掘金。

Odanacatib, a Selective Cathepsin K inhibitor to Treat Osteoporosis: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics - Results from Single Oral Dose Studies in Healthy Volunteers;
Bortel L, Lasseter KC, Pramanik B, Cilissen C, Liu Q, Liu L, Scott BB, Panebianco D, Ding Y, Gottesdiener K, Wagner JA; British Journal of Clinical Pharmacology (Sep 2012)
AIM: To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), of odanacatib (ODN), a novel cathepsin K inhibitor, in humans. METHODS: Two double-blind, randomized placebo-controlled single oral-dose studies were performed with ODN (2-600mg) in 44 healthy volunteers (36 men and 8 postmenopausal women). RESULTS: Adverse experiences (AE) with single-doses of ODN were transient and considered to be mild to moderate with the exception of one AE of gastroenteritis which was considered severe. The most frequent AE reported was headache. After absorption of ODN (with initial peak concentrations 4-6 hours postdose) plasma concentrations exhibited a largely monophasic decline with an apparent terminal half-life (t(1/2) ) of ∼40-80 hours. AUC(0-24hr) , C(24hr) and C(max,overall) increased in a less than dose-proportional manner from 2-600mg. Administration of ODN with a high fat meal led to ∼100% increases in AUC(0-24hr) , C(max,day1) , C(max,overall) , and C(24hr) relative to fasted, while administration with a low fat meal led to a ∼30% increases in those parameters (C(max,day1) and C(max,overall) were calculated in order to characterize multiple concentration peaks that were observed in many subjects). Reduction of biomarkers of bone resorption, the C- and N- telopeptides of cross-links of type I collagen, termed CTx and NTx respectively, was noted at 24h for doses ≥5mg and at 168hr 76 postdose for ≥10mg. In postmenopausal women administered 50mg ODN, reductions in 77 serum CTx (sCTx) of -66% and urinary NTx/Cr (uNTx/Cr) of -51% relative to placebo were observed at 24hr. At 168hr, reductions in sCTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline (placebo comparisons not made due to insufficient sample size). PK/PD modeling was used to characterize the ODN concentration-uNTx/Cr relationship, with a modeled EC(50) value of 43.8 nM and approximately 80% maximal uNTx/Cr reduction. CONCLUSION: ODN was well tolerated and has a PK and PD profile suitable for once weekly dosing.
http://www.docguide.com/odanacat ... -pharmacokinetics-a
odanacatib (ODN)的半衰期为40-80小时，服药后4-6小时到达血药浓度峰值，与空腹服用药物比较，与高脂肪食物同时服用时，生物利用度提高100%，与低脂肪食物同时服用时，生物利用度提高30%。

Potential role of odanacatib in the treatment of osteoporosis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410681/
Potential role of odanacatib in the treatment of osteoporosis.pdf (277.42 KB, 下载次数: 73)

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这烦请哪位高人翻译下吧～～～

这药什么时候才可以有啊？

Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 26, No 15S (May 20 Supplement), 2008: 1023
© 2008 American Society of Clinical Oncology

Abstract

Effect of cathepsin k inhibition on suppression of bone resorption in women with breast cancer and established bone metastases in a 4-week, double-blind, randomized controlled trial
A. B. Jensen, N. Olmeo, C. Wynne, G. Ramirez, A. Lebrecht, A. Mehta, W. He, Y. Song, Y. Berd and A. Lombardi
Aarhus University Hospital, Aarhus, Denmark; Azienda Ospedaliera di Sassari, Sassari, Italy; Christchurch Clinical Studies Trust, Christchurch, New Zealand; Javeriana University, Bogota, Colombia; Johannes Gutenberg-Universität Mainz, Mainz, Germany; Merck Research Laboratories, Rahway, NJ

1023

Background: In breast cancer patients with metastatic bone disease (MBD), osteolysis releases factors that sustain tumor cell survival and proliferation. Cathepsin (Cat) K inhibition suppresses osteolysis in preclinical models of MBD. The current study assessed the safety and efficacy of odanacatib, a selective Cat K inhibitor, in reducing markers of bone remodeling in women with breast cancer and MBD. Methods: This double-blind study randomized women with breast cancer and MBD to oral odanacatib 5 mg daily for 4 weeks or IV zoledronic acid (ZA) 4 mg given once at study initiation. Bone remodeling was assessed by measuring urinary N-telopeptide of type I collagen corrected for creatinine (uNTx; primary objective, pmol BCE/µmol creatinine); urinary deoxypyridinoline corrected for creatinine (uDPD, pmol/µmol creatinine), and bone formation (serum bone-specific alkaline phosphatase [sBSAP, ng/mL]). Inhibition of Cat K activity was determined by serum crosslinked C-terminal peptide of type I collagen (s1CTP, µg/L). Adverse events (AE) were monitored throughout the 4-week study and up to 14 days after last dose. Results: 43 patients (mean age 60 yrs) received odanacatib (n=29) or ZA (n=14); 40 patients completed 4 weeks. 12 (41%) and 17 (59%) patients on odanacatib and 6 (43%) and 7 (50%) patients on ZA received chemotherapy or hormone therapy, respectively. Results for markers of bone remodeling and Cat K activity are tabulated (Table). The most common AEs were nausea, vomiting, headache, and bone pain, which were generally not attributed to study drug. Conclusions: In women with breast cancer and MBD, the Cat K inhibitor odanacatib suppressed markers of bone resorption after 4 weeks of treatment. Mean uNTx and uDPD were decreased in both treatment groups. The increase in s1CTP suggests specific inhibition of Cat K. In this study, odanacatib was generally safe and well tolerated.

警报：Odanacatib药物试验提前结束。什么可能出问题？

Odanacatib, 默克公司很快将要发布的骨质疏松症药物（虽然它是一定要有一个吸引人的名字， 来冲击市场）。当默克公司的福善美(Fosamax), 一种骨质疏松症药物, 专利权于2008年到期后，默克公司利润受到了很大的打击, 正在摩拳擦掌另一个有利可图的，申请专利的骨质疏松症的药物。

为了使它变得“更好”......在过去的一周中，由于“有利的利益与风险配置”， 已及“在某些选定的区域仍然有安全问题。” 独立数据监控委员会已停止III期临床试验.  没有人知道那些“安全问题”，但我很有信心，我可以预言，至少有一些这其中的原因。

老一套，老一套...

Odanacatib阻止组织蛋白酶K的酶，这种酶在参与破骨细胞和骨吸收。换句话说，组织蛋白酶K分解骨组织。人体的骨骼自修复过程，是维持和提高骨质密度正常的骨骼重塑的必要条件。人体的骨骼自修复过程陷入僵局就会导致骨吸收，会导致骨老，骨头脆，更容易发生骨折。

双磷酸盐类药物如阿仑膦酸钠，默克公司的Fosamax，以及如Boniva的，Actonel的Reclast的药物的仿制也抑止骨吸收。 Prolia的（狄诺塞麦）去激活破骨细胞，来抑止骨吸收。

预测

基于对Odanacatib的作用机制，这是很容易预测，“安全问题”可能是相同的 - 或者甚至比FOSAMAX更糟 -。但当然，这将极有可能不会被败露，就象FOSAMAX, 直到很久以后，这些” 安全问题”才暴露.

阿仑膦酸钠(Alendronate)试验是在第一次持续时间相对较短。美国和国际三期试验与安慰剂进行只有三个years.，在骨折干预试验（FIT），研究对象与阿仑膦酸钠(Alendronate)治疗三到四年，一个50岁，骨折干预试验随访长期延伸试验（FLEX），它表明：

    “......对于很多女性来说停止阿仑膦酸钠长达5年并没有出现显着增加骨折”

其他长期研究的FLEX试验，包括III期延长10年的研究，没有观察到不寻常的一面effects. 福善美(FOSAMAX)1996年批准的。请记住，这一年以来，数以百万计的骨质疏松症患者服用的药物，在不知不觉中充当豚鼠。同时，福善美(FOSAMAX)销售额为2007年已达到约三十亿dollars.

2011年9月正式宣布双磷酸盐类药物的安全担忧，药物的颚骨坏死和非典型股骨骨折。一个月后, 又新发现的食管癌的风险增加。这时FOSAMAX已上市15年.


长话短说...

很明显，最初的药物试验是短期的原因是：大制药公司，随着监管机构的收容，相互串通，允许非常不良的副作用被发现之前,取得最大的利润。一旦获得批准，医生难免会开药给患者，有效地引发了巨大的利润，这些巨大的利润与他们可能需要赔赏给未来受伤的患者相形见绌。

事实上，未来看起来相当明亮Odanacatib,在“福布斯”杂志公布，摩根大通非常看好新药，预测

    “......2014年推出为Odanacatib与销售，到2017年达到约10亿美元。”

不幸的是，一个黯淡的未来等待着那些谁将会成为下一个受害者.  

By Vivian Goldschmidt, MA

Saveourbones.com/alert-odancatib