哌伯塞克雷布

<正>由美国辉瑞公司研发的治疗乳腺癌药物哌伯塞克雷布(palbociclib,商品名为Ibrance)于2015年2月3日获美国FDA批准上市。哌伯塞克雷布是FDA批准的首个细胞周期蛋白依赖性激酶4/6(CDK4/6)抑制剂,该药为胶囊剂,作为内分泌治疗的初始方案,与来曲唑联合使用治疗雌激素受体阳性/人表皮生长因子受体-2阴性(ER+/HER2)绝经后的晚期乳腺癌[1]。哌伯塞克雷布的中     

乐伐替尼

<正>乐伐替尼(lenvatinib)是由日本卫材(Eisai)公司开发的一种用于治疗放射性碘难治性分化型甲状腺癌(RRDTC)的药物,于2015年2月13日获美国FDA批准上市,商品名为Lenvima[1]。乐伐替尼在日本、美国、欧盟均被授予孤儿药认定。乐伐替尼中文化学名称:4-[3-氯-4-(N-环丙基脲基)苯氧基]-7-甲氧基喹啉-6-甲酰胺甲磺酸盐;英文化学名     

Lenvatinib for the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) accounts for 2–3% of all solid tumors. Expression of the receptor for the vascular endothelial growth factor (VEGF) is one of the most common features of RCC.

Areas covered: Lenvatinib is a novel multi-kinase inhibitor that has been studied in several solid tumors. It has shown promising results in the treatment of RCC, especially when combined with everolimus, In this review, we summarize the available data of lenvatinib for the treatment of advanced/metastatic renal cell carcinoma.

Expert opinion: Lenvatinib in combination with everolimus has provided encouraging results in both clinical and laboratory investigations showing that blocking angiogenesis and the mTOR signalling pathway could be a remarkable approach for treating RCC. As an additive to this type of approach it would be interesting in future clinical settings testing also the combination of lenvatinib and everolimus with immune-therapy.     

高效液相色谱法测定帕博西林的有关物质

目的：建立测定帕博西林的有关物质方法。方法：采用高效液相色谱法。色谱柱为Dikma Inspire-C18,流动相为0.1%TFA水溶液-0.1%TFA乙腈溶液（梯度）,流速为1.0ml&#183;min-1,检测波长为260nm,进样量为10μl,柱温为30℃。结果：主成分和各杂质分离度良好,主成分和杂质1～6线性关系良好,检测限分别为30ng&#183; ml-1、38ng&#183; ml-1、36ng&#183; ml-1、35.5ng&#183; ml-1、29ng&#183; ml-1、31.5ng&#183; ml-1、33ng&#183; ml-1,平均回收率在90%～110%,RSD 均小于5.0%。结论：建立的方法简便、快速、准确,灵敏度高,适用于帕博西林的有关物质测定。     

Lenvatinib combined with nivolumab in advanced hepatocellular carcinoma-real-world experience

Investigational New Drugs - Lenvatinib, a multi-tyrosine kinase inhibitor that inhibits vascular endothelial growth factor and fibroblast growth factor receptors pathway, activated the immune...     

甲磺酸仑伐替尼胶囊在中国健康受试者中的生物等效性研究

摘 要 目的：研究国产甲磺酸仑伐替尼胶囊在中国健康受试者中的药代动力学特征,评价国产受试制剂（T）与原研参比制剂（R,商品名：乐卫玛■）的生物等效性。方法：采用空腹/餐后、随机、开放、两周期、两序列、双交叉试验设计。空腹试验和餐后试验分别入组28例健康受试者,男女兼有。入组的受试者随机分配至T-R或R-T给药序列组,每周期单次空腹或餐后口服甲磺酸仑伐替尼胶囊受试制剂或参比制剂4 mg/粒。采用高效液相色谱-串联质谱法（HPLC-MS/MS）测定0 ~ 120 h不同采集点的血浆中仑伐替尼浓度。采用Phoenix WinNonlin 8.2软件计算药代动力学参数（Cmax、tmax、AUC0 - t、AUC0 - ∞、t1/2）,并对主要参数进行生物等效性评价。结果：健康受试者空腹单次口服给药后,受试制剂及参比制剂的Cmax、AUC0 - t、AUC0 - ∞的算数平均值分别为70.55和69.89 ng·mL-1、801.3和792.6 h·ng·mL-1、823.6和814.6 h·ng·mL-1,几何均值比值及90%CI分别为103.17%（96.52% ~ 110.28%）、101.15%（98.09% ~ 104.30%）和101.10%（98.12% ~ 104.18%）;健康受试者餐后单次口服给药后,受试制剂及参比制剂的Cmax、AUC0 - t、AUC0 - ∞算数平均值分别为44.82和49.21 ng·mL-1、738.1和747.5 h·ng·mL-1、765.1和777.1 h·ng·mL-1,几何均值比值及90%CI分别为90.41%（83.92% ~ 97.42%）、98.81%（96.16% ~ 101.53%）和98.50%（95.94% ~ 101.13%）。不良事件程度轻度,未出现严重不良事件和非预期不良反应。结论：国产甲磺酸仑伐替尼胶囊与参比制剂甲磺酸仑伐替尼胶囊（乐卫玛■）于空腹或餐后状态下给药后,在中国健康受试者体内两制剂生物等效。     

聚乙二醇（帕布昔利布、SB-743921）联体的化学合成

目的合成聚乙二醇双抗癌药偶联体并进行结构表征。方法以小分子抗癌药帕布昔利布为原料药,以可生物降解的GLG肽链作为连接链,经过酰胺化反应,去Boc保护反应等反应,得到Fmoc-E(GLG-PCB)(OH);再以类似方法得到H2N-GLG-SB743921后,使其与Fmoc-E(GLGPCB)(OH)进行反应,得到E(GLG-SB743921)(GLG-PCB),再与Boc-Gly-OH进行反应,分离纯化后得到G-E(GLG-SB743921)(GLG-PCB),将其与PEG-10K在N,N-二甲基甲酰胺作溶剂的条件下,低速、避光在室温下搅拌反应一周,经分离纯化得到目标产物PEG-10K-G-E(GLGSB743921)(GLG-PCB)。结果与结论首次合成了聚乙二醇偶联双抗癌药PEG-10K-G-E(GLG-SB743921)(GLG-PCB),重要中间体和目标产物的结构经1H-NMR、MS谱确证,均为未见文献报道的新化合物。利用该方法可合成聚乙二醇偶联双抗癌药,为高分子偶联抗癌药提供新的合成路线。     

首个CDK4/6抑制剂帕博西尼的药理和临床综述

本文介绍了帕博西尼和来曲唑联合用于治疗绝经后妇女对雌激素受体（ER）阳性,对人表皮生长因子受体2（HER2）阴性的晚期乳腺癌,作为转移性疾病的初始内分泌为基础的治疗的药理、药动学、临床研究和安全性信息。这些信息主要参考了国外有关的帕博西尼的注册和临床资料。临床试验表明帕博西尼和来曲唑联合应用能使患者的无进展生存期（PFS）明显提高。     

基于平行人工膜渗透模型预测抗癌药甲磺酸仑伐替尼胶囊生物等效性

目的 采用平行人工膜渗透模型,预测自产甲磺酸仑伐替尼胶囊与参比制剂的体内生物等效性。方法 通过推测甲磺酸仑伐替尼的BCS分类,基于平行人工膜渗透模型,搭建甲磺酸仑伐替尼胶囊体外溶出-渗透速率测试模型,实时监测甲磺酸仑伐替尼胶囊和参比制剂在空腹条件模拟液以及餐后条件模拟液下的溶出度和渗透量,计算药物通过膜的通量、渗透总量。结果 在模拟空腹和餐后条件下,处方A的渗透速率和渗透量的几何均值比90%置信区间均在80.00%~125.00%范围内,处方B未落在此区间。结论 本研究方法可以预测甲磺酸仑伐替尼胶囊与参比制剂生物等效性,并具备一定的体内外相关性。     

高效液相色谱法同时测定帕博西尼胶囊中5种有关物质

目的采用高效液相色谱法,建立一种帕博西尼胶囊有关物质的检测方法。方法色谱柱为Ultimate XB C18(250 mm×4. 6 mm,5μm);流动相A:体积分数0. 1%三氟乙酸-水溶液,流动相B:乙腈-水-三氟乙酸(体积比70∶30∶0. 1)溶液,进行梯度洗脱;检测波长:290 nm;进样体积:10μL;流速:1. 0 m L·min~(-1);柱温:35℃;运行时间:50 min。结果杂质WB001-A、WB001-B、WB001-E、WB001-F、WB001~(-1)和帕博西尼的定量限分别为27. 0、63. 0、42. 0、26. 0、27. 0、18. 0μg·L~(-1),线性范围分别为0. 09～0. 59 mg·L~(-1)、0. 11～0. 71 mg·L~(-1)、0. 07～0. 47 mg·L~(-1)、0. 09～0. 58 mg·L~(-1)、0. 09～0. 60 mg·L~(-1)和0. 09～0. 61 mg·L~(-1),平均回收率分别为96. 79%、101. 18%、97. 23%、100. 75%和103. 56%。结论本方法可准确检测帕博西尼胶囊的有关物质。     

The potential role of PD0332991 (Palbociclib) in the treatment of multiple myeloma

Introduction: Multiple myeloma (MM) remains an incurable malignancy indicating a need for continued investigation of novel therapies. Recent studies have highlighted the role of cyclin-dependent kinases (CDK) in the pathogenesis of MM. PD0332991 (Palbociclib) is an orally bioavailable, highly selective inhibitor of the CDK4/6-cyclin complex and downstream retinoblastoma protein (Rb) activation pathway that induces cell cycle arrest in the G1 phase.

Areas covered: In this review, the authors summarize the role of the CDK4/6 signaling pathway in MM. They also summarize the development of PD0332991 as a specific inhibitor of CDK4/6, and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM.

Expert opinion: While PD0332991 is essentially cytostatic, inducing prolonged G1 arrest, it enhances the cytotoxic effect of other agents effective in MM, including bortezomib and lenalidomide, as confirmed in early phase clinical trials. However, with a plethora of other drugs of different classes being tested in MM, further development of PD0332991 will depend on defining the most efficacious combination with least toxicity. An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM. The next few years are likely to better define the place of PD0332991 in the treatment of MM.     

Lenvatinib for use in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy

Introduction: In patients with mRCC options for second line therapies, following progression on anti-angiogenic agents, that demonstrate a survival advantage in clinical trials have been limited. Recently a number of agents have demonstrated efficacy in this setting. Here in we profile one such therapy, the combination of lenvatinib and everolimus, and discuss the expanded options for therapy available in this setting.

Areas covered: In this review, we discuss current algorithms for treatment of mRCC in both the first-line and second-line setting. We discuss the recent addition of cabozantinib and nivolumab, in the second line setting, to the market. Lenvatinib’s pharmacology, clinical efficacy and toxicity profile is discussed. A comprehensive literature review was performed using PUBMED.

Expert commentary: The current treatment algorithms for mRCC will likely see significant change in the coming years. The addition of immunotherapy to our treatment options in mRCC is of particular importance. Future trials examining the use of immunotherapy, both as monotherapy and in combination with VEGF targeted therapy, will likely be a dominant influence in the therapeutic landscape of mRCC. Progress in terms of the rapid expansion of available active therapies in mRCC needs to be balanced with current deficiencies in terms of predictive biomarkers.     

Palbociclib and beyond for the treatment of HR + HER2- metastatic breast cancer: an Asian-Pacific perspective and practical management guide on the use of CDK4/6 inhibitors

Abstract

Breast cancer is the most frequent cancer amongst women worldwide including in Asia where the incidence rate is rapidly increasing. Even with treatment, around 30% of patients with early breast cancer progress to metastatic disease, with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer the most common phenotype. First-line endocrine therapy targeting the estrogen receptor signaling pathway provides a median progression-free survival or time to progression of 6–15?months in HR?+?HER2- metastatic breast cancer. Recently, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, combined with endocrine therapy, have achieved more than two years median progression-free survival in HR?+?HER2- metastatic breast cancer. However, the characteristics of the Asian breast cancer population differ from those of Western populations and need to be considered when selecting a suitable treatment. Breast cancer is diagnosed at a younger age in Asian populations and late stage at presentation is generally more common in low-/middle-income countries than high-income countries. Consequently, the proportion of premenopausal women with metastatic breast cancer is higher in Asian compared with Western populations. While CDK4/6 inhibitors have been approved in the USA (FDA) since 2015, experience with them in Asia is more limited. We review the experience with the CDK4/6 inhibitor palbociclib in Asian patients with HR?+?HER2- metastatic breast cancer and provide guidance on the use of palbociclib in these patients.     

Degraded and undegraded carrageenans and experimental gastric and duodenal ulceration

The prevention of histamine-induced gastric and duodenal ulceration in the guinea-pig has been examined using a series of undegraded and degraded carrageenans. Undegraded carrageenans were active at lower doses than degraded carrageenans. The high viscosity of the undegraded carrageenans in solution prevented their use in larger doses. Degradation of carrageenan without serious loss of sulphate, gives a product which allows the dose to be increased to an extent that its effect more than offsets the slight loss in activity caused by the degradation. No single feature of carrageenan structure can be related to anti-ulcer activity although degradation, and hence reduction of molecular size, generally reduces activity. Sulphate contents over 30% have little apparent effect on activity; κ-carrageenans were not consistently different in anti-ulcer activity from Λ-carrageenans. This contrasts with the antipeptic activity of carrageenans where κ-carrageenans are less active than their Λ-counter-parts. As with antipeptic activity, the degree of anti-ulcer activity is probably determined by a combination of structural features which includes molecular size and polyanionic properties.