The Cathepsin K Inhibitor Odanacatib Suppresses Bone Resorption in Women With Breast Cancer and Established Bone Metastases: Results of a 4-Week, Double-Blind, Randomized, Controlled Trial
The Cathepsin K Inhibitor Odanacatib Suppresses Bone Resorption in Women With Breast Cancer and Established Bone Metastases: Results of a 4-Week, Double-Blind, Randomized, Controlled Trial
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DOI：
10.3816/cbc.2010.n.059
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发表时间：
2010-12-01
影响因子：
3.1
通讯作者：
Lombardi, Antonio
中科院分区：
文献类型：
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作者：
Jensen, Anders Bonde;Wynne, Christopher;Lombardi, Antonio
背景：转移性骨病(MBD)是乳腺癌患者常见的并发症，发病率较高。这项研究评估了选择性Cat K抑制剂odanacatib在降低乳腺癌和MBD妇女骨吸收标志物方面的药代动力学、有效性和安全性。患者和方法：乳腺癌合并MBD的女性患者被随机分为2：1(双盲)，在研究开始时每日口服5 mg奥那替布或静注唑来膦酸4 mg。采集血浆样品进行药代动力学分析。骨吸收通过测定尿中I型胶原的N-端肽(uNTx；主要目标是pmolBCE/mMol肌酐)来评估。在整个为期4周的研究期间和最后一次服药后的14天内监测不良事件(AEs)。结果：43例患者(平均年龄60岁)接受奥那西布(n=29)或ZA(n=14)治疗，40例患者完成4周的治疗。UNTx在第4周的平均百分比变化为-77%(95%CI，-82至-71；odanacatib)和-73%(95%CI，-80至-62；ZA)。奥达那替布的平均血药浓度(标准差)为511.7(202.9)nM，范围为63.7-844.8 nM。最常见的不良反应是恶心、呕吐、头痛和骨痛，这些通常不被归因于研究药物。结论：在乳腺癌和MBD患者治疗4周后，odanacatib抑制uNTx的作用与ZA相似。奥那卡替布总体上是安全的，耐受性良好。这些结果表明，抑制Cat K是治疗MBD的一种潜在的重要的新的治疗方法。
Background: Metastatic bone disease (MBD) is a frequent complication in patients with breast cancer and is associated with significant morbidity. This study assessed the pharmacokinetics, efficacy, and safety of odanacatib, a selective Cat K inhibitor, in reducing markers of bone resorption in women with breast cancer and MBD. Patients and Methods: Women with breast cancer and MBD were randomized 2:1 (double-blind) to oral odanacatib 5 mg daily for 4 weeks or intravenous zoledronic acid (ZA) 4 mg given once at study initiation. Plasma samples were collected for pharmacokinetic analysis. Bone resorption was assessed by measuring urinary N-telopeptide of type I collagen corrected for creatinine (uNTx; primary objective, pmol BCE/mu mol creatinine). Adverse events (AEs) were monitored throughout the 4-week study and up to 14 days after last dose. Results: A total of 43 patients (mean age, 60 years) received odanacatib (n = 29) or ZA (n = 14); 40 patients completed 4 weeks of treatment. The mean percent change in uNTx values at week 4 was -77% (95% CI, -82 to -71; odanacatib) and -73% (95% CI, -80 to -62; ZA). Mean (standard deviation) plasma concentration of odanacatib was 511.7 (202.9) nM; the range was 63.7-844.8 nM. The most common AEs were nausea, vomiting, headache, and bone pain, which were generally not attributed to study drug. Conclusion: Odanacatib suppressed uNTx similarly to ZA after 4 weeks of treatment in women with breast cancer and MBD. Odanacatib was generally safe and well tolerated. These results suggest that Cat K inhibition is a potentially important, novel therapeutic approach for treating MBD.