Vinblastine Sulfate

点击上方的 行舟Drug ▲ 添加关注 摘 要：基于生物药剂学分类系统（BCS）的生物等效性豁免旨在减少对体内生物等效性研究的需求，即可以提供一种体内生物等效性的替代方法。基于BCS分类的生物等效性豁免需提供药物的溶解性、渗透性和体外溶出数据。主要论述药物溶解性、渗透性和体外溶出度测定的方法，希望建立药物相关特性的标准化、规范化测定流程，以保证企业在申报生物等效性豁免时，所提供的数据是准确、可靠的。 关键词：生物等效性豁免；溶解性；渗透性；溶出度 基于生物药剂学分类系统（BCS）的生物豁免旨在减少对体内生物等效性研究的需求，可以减少不必要的生物等效性研究，加速高质量药品的研发。世界卫生组织（World Health Organization，WHO）、欧 洲 药 品 管 理 局（European Medicines Agency， EMA）、美国食品药品监督管理局（U.S. Food and Drug Administration，FDA）等药品监管机构分别出台了基于BCS的生物等效性豁免指导原则，中国国家药品监督管理局（NPMA）2016 年5 月发布了《人体生物等效性试验豁免指导原则》，适用于仿制药质量和疗效一致性评价中普通口服常释制剂申请生物等效性豁免。 根据要求，药物申报企业在申请生物等效性豁免时，需首先提供相应资料或数据证明所申报的药物属于BCS I 或Ⅲ类，即提供药物的溶解性和渗透性数据，此外还应提供药物快速溶出的数据支持。 按照《化学药品仿制药口服固体制剂质量和疗效一致性评价申报资料要求》中所提及的BCS的文献数据查询来源，可以查询WHO 发布的BCS 数据库（2005 年），NICHD 和FDA 研究归纳的BCS 数据库（2011 年），tsrlinc 网站的BCS 等［2］。但是，在我国仿制药一致性评价研究中，存在着药物BCS分类不明，或BCS 分类文献报道不一致的情况，一方面是由于针对仅在我国上市的药物BCS研究数据缺乏，如黄连素片、复方甘草片、奋乃静片等品种在上述数据库中均无法查到，另一方面是由于不同来源的BCS 分类数据所参考的药物规格、剂型及判断标准等不统一造成的［3］，如盐酸环丙沙星片，在tsrlinc 网站上查询为Ⅲ类，但是在WHO 发布的BCS 分类表中为I/Ⅲ类，阿莫西林胶囊/颗粒按照WHO 发布的BCS分类表为I 类，tsrlinc网站上查询为Ⅳ类。 因此，对于无确定BCS 分类数据的药物，企业在申请生物利用度豁免时，需根据《人体生物等效性试验豁免技术指导原则》提供测定的溶解性和渗透性数据。尽管相关指导原则中对于实验进行了相关规范，但是对于具体的实验溶液的配制、pH值是否调节的细节问题等未做明确规定，本文旨在建立统一的药物溶解性、渗透性实验方法，增加数据的可靠性和统一性。 1 药物溶解性评价方法 根据BCS 对溶解性的分类，即制剂的最大剂量所对应的药物是否能在体积不大于250 mL、pH 值在1.0～6.8 的水溶性介质中完全溶解，能完全溶解即为高溶解性药物，反之则为低溶解性药物［4］。因此，药物的溶解性跟最大使用剂量和溶解度有关，建立测定药物溶解度的方法有助于合理地对药物溶解性进行评价。测定药物在（37±1）℃温度下，pH 值在1.0～6.8 水溶性介质中的平衡溶解度，并绘制原料药pH-溶解性曲线。该曲线上的pH值选择应该有充足的点，如pH 1.0，4.0 或4.5，6.8 的介质。此外，如果药物的解离常数（pKa）在pH 1.0～6.8，还应评估药物在pKa、pKa＋1、pKa－1的pH介质中的溶解度。 测定溶解度时每个pH值条件至少要平行测定3 次，必要时还需多次重复测定。不同pH值的水性介质的配法可以参考《普通口服固体制剂溶出曲线测定与比较指导原则》附录中不同pH 值溶出介质的制备方法，如果特定的缓冲溶液会对药物的理化性质产生影响，也可以使用其他介质。 在原料药加入到介质后和溶解度实验结束时，应测定溶液的pH 值，已确定溶解度的测定是在指定pH值条件下进行，必要时进行pH调节。 药物在不同pH介质中的溶解度测定方法应该是经过验证的，如药物在介质中不稳定，此方法应能区分药物和降解产物。如原料药的降解是缓冲液成分或者pH 值引起的，则需提交胃肠道稳定性 研究部分的稳定性数据。如药物在溶解度测定过程中不稳定（降解＞10%），则所测得的溶解度数据不能用于生物等效性豁免。 根据测得的在pH 1.0～6.8 范围内水性介质中药物溶解的最高剂量，即最低溶解度来确定药物的溶解性分类。若药物的最高剂量在pH值1.0～6.8、均能够完全溶解在不大于250 mL的水溶性介质中，即可认为该药物是高溶解性的。 除了传统的摇瓶法，也可以使用酸碱滴定法及其他方法测定药物溶解度，但应证明所用方法的合理性，并且有方法学数据的支持。 在提供溶解性数据的同时，还应提供药物的基本信息：原料药的化学结构、相对分子质量、性质（酸、碱、两性或中性）和pKa；以及分析方法和缓冲溶液组成的测定方法的描述；溶解性结果应提供药物在不同pH溶液中的平衡溶解度以及溶解最大规格需要的介质体积［1］。 2 药物的渗透性分类评价 BCS I 和Ⅲ类药物均为高溶解性药物，但是渗透性不同，看似只要进行溶解性和溶出度研究就可以进行生物等效性豁免申请，与渗透性高低关系不大，但是根据《人体生物等效性试验豁免指导原则》，BCS I 和Ⅲ类药物在申请生物等效性豁免时，所提交的资料是不同，如：BCS Ⅲ类药物要求仿制制剂必须与参比制剂含有相同的辅料组成，各组成用量相似，而BCS I 类药物无此要求。因此对于药物的渗透性研究依然很有必要。 药物渗透性评价应该是基于人体药动学研究的 吸 收 程 度 ，如 绝 对 生 物 利 用 度（absolute bioavailability）或质量平衡（mass balance）。一般认为，当绝对生物利用度不小于85%；或不小于85%的药物以原型药物或以原型药物及代谢物（吸收后产生的代谢物）总和的形式从尿液中排出，即可认为药物为高渗透性药物［4］。由于部分药物可能在胃肠道中未被吸收，因此粪便中的原型药物一般不能归属于被吸收范围内［1，5］。 药物渗透性数据允许使用原研说明书、审评报告等资料中的人体药动学数据证明药物渗透性。一般来说，药物的绝对生物利用度及尿液中原型药物排泄率比较容易从说明书及审评文件中获得。 在采用绝对生物利用度或质量平衡进行渗透性研究时，应注意以下问题：根据研究的可变性，评估受试者例数，保证吸收度数据的可靠性；关注药物在胃肠道中的稳定性，可以研究药物在人体内取出的胃液和肠液中的稳定性，也可以考察药物在合适的动物模型胃肠液或者模拟液体中的稳定性。 除绝对生物利用度或质量平衡等人体吸收数据外，可以采用肠道灌注法、离体肠道灌流法或者合适的单层上皮细胞的渗透性测定等方法进行渗透性测定。但是，当上述单一的渗透性检测不足以充分说明药物的渗透性时，建议采用两种不同的分析方法。当两种不同实验类型的研究数据对于药物渗透性分类有矛盾时，应用人体数据进行准确判断。 需要注意的是，被动转运药物的渗透性研究可以使用动物或人类单层培养上皮细胞模型进行。若药物是膜转运蛋白（如p-糖蛋白）底物，容易造成渗透性分级错误。这是因为动物、离体人或动物肠道、单层人工培养上皮细胞模型中和药物外排相关的转运蛋白可能缺失，或者其表达程度和人体相比较低。判断药物是否为被动转运的依据：药物在人体内呈线性药动，剂量和浓度-时间曲线下面积表现出线性关系；采用动物模型进行体内或原位渗透性测定时，测定值与灌注液的初始药物浓度无关；使用已被证明能表达已知转运蛋白的细胞模型进行渗透性测定时，测得的渗透性数值与转运方向无关。可以采用地高辛、长春碱、罗丹明123等选定的模型药物或浓度不饱和外排系统的化学品，表征出已知转运蛋白的表达，证明药物在基底外侧至顶端方向的转运速率高于顶端至基底外侧方向［5-8］。 此外，在选择肠道灌注法、离体肠道灌流法或者合适的单层上皮细胞模型进行渗透性测定时，应当有明确的表征指标对模型的可用性进行判断，同时有充分的数据证明测得的渗透性数值和药物在人体内吸收的程度的顺序关系。如采用经验证的Caco-2 细胞模型进行渗透性评价时，一般通过比较实验前后跨膜电阻（TEER）的测量值和/或其他合适的指标，确认细胞单层完整性（即是否形成紧密连接）。在进行实验时，应使用零、低（＜50%，如法莫替丁、依那普利等）、中（50%～84%，如二甲双胍、雷尼替丁等）和高（≥85%，如茶碱、美托洛尔等）渗透性模型药物，通过建立实验渗透率与人体药物吸收程度之间的排序相关性，证明Caco-2 细胞测定方法的适用性［1，5-7］。 在提供渗透性数据时，还应提供测定方法的描述，包括分析方法和缓冲溶液的组成；人体药动学研究（PK），包括设计方案和PK数据对应的方法；对于直接渗透性研究方法，需要说明所用方法的适用性，包括研究方案的描述，受试者、动物和上皮细胞系的选择标准，供体液里的药物浓度，分析方法的描述，计算吸收程度或渗透性的方法等信息；对于采用动物模型或单层细胞模型测得的数据，还应提供选择的模型药物的清单，说明研究方法适用性的人体内的吸收度数据，每个模型药物的渗透率值，每个模型药物的渗透性分类等。 3 结语 多个药品监管机构出台了基于BCS 的生物等效性豁免指导原则，BCS I 和Ⅲ类口服制剂，在满足快速释放，且在符合其他要求（如不含有影响药物吸收的辅料等）的前提下，可以进行生物等效性豁免，这将大大降低企业在一致性评价和仿制药研制中的资金和时间投入。在申请生物等效性豁免时，需提交药物的BCS 分类依据，包括溶解性和渗透性，尽管指导原则中允许引用原研说明书及审评文件中的数据，但是部分品种，由于仅在我国上市等原因，无法获取可靠的分类数据，因此需企业完成相关研究。本文希望对在药物溶解性、渗透性评价中的方法进行合理规范，为企业进行相关研究提供参考。 文章信息源于CDE，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。 学如逆水行舟，不进则退； 心似平原走马，易放难收。 行舟Drug 每日更新 欢迎订阅+ 医药大数据|行业动态|政策解读

Phase 1/2 data showed a median overall survival ("mOS") of 21.3 months versus a synthetic control of 6.7 months, an increase in T-cell activation, and favorable safety profile for patients receiving INT230-6 alone INVINCIBLE-3 Study is recruiting and expected to enroll 333 patients with leiomyosarcoma, liposarcoma and undeferential pleomorphic sarcoma; authorizations for the INVINCIBLE-3 Study have been received in the U.S., Canada, Europe and Australia SHELTON, Conn., Nov. 18, 2024 /PRNewswire/ -- Intensity Therapeutics, Inc. (Nasdaq: INTS), ("Intensity" or "the Company") a late-stage clinical biotechnology company focused on the discovery and development of proprietary, novel immune-based intratumoral cancer therapies designed to kill tumors and increase immune system recognition of cancers, today announced that Christian F. Meyer M.D., Ph.D., Assistant Professor of Oncology and lead medical oncologist for adult sarcoma patients at Johns Hopkins University's Sidney Kimmel Cancer Center, presented final safety and efficacy data from the Company's Phase 1/2 clinical trial of INT230-6 that was used as a monotherapy in patients with relapsed, refractory, and metastatic sarcomas, along with an overview of the Company's ongoing INVINCIBLE-3 Study design (NCT06263231). Dr. Meyer shared the information during an oral podium presentation in a late-breaking session at the 2024 Connective Tissue Oncology Society ("CTOS") on November 16, 2024, at 9 AM PST. The abstract's lead author was Albiruni Razak, MB BCh, BM BCh, Clinician Investigator, Princess Margaret Cancer Centre at the University Hospital Network in Toronto, Ontario, Canada. Both Drs. Razak and Meyer, enrolled patients in the Phase 1/2 clinical trial. This year's annual CTOS conference was held in San Diego from November 13 to 16, 2024 at the Grand Hyatt. "The data in the Phase 1/2 study has shown that INT230-6 causes cell death leading to tumor necrosis, improved cancer recognition by immune cells, and an ignition of a systemic anti-cancer immune response that results in T-cells entering the tumor microenvironment and has shown a favorable safety profile in soft tissue sarcomas," said Dr. Razak. "Systemically delivered chemotherapies have severe side effects, including cardiotoxicity, and most sarcoma subtypes have only a minimal response to immunotherapies. In addition, most sarcoma patients remain on current therapies for only a few months prior to progression, death or excessive toxicity. Demonstrating statistically significant improvement in median overall survival for the INT230-6 treatment arm compared to the standard of care arm in the INVINCIBLE-3 Study would be a major step forward in treating patients with these deadly soft tissue sarcomas." Phase 1/2 Study (Sarcoma Subset Data: 15 Patients): Demographics: Median (min, max) lines for prior drug therapies: 3 (1.00, 7.00) Mean (SD) age: 62.8 (8.1) years and ranged from 41.9 to 76.1 years ECOG performance status at screening was 0, 1 and 2 for 2 (13.3%), 12 (80.0%), and 1 (6.7%) subjects respectively The sarcoma diagnoses of the Phase 2 patients included liposarcoma, pleomorphic sarcoma, leiomyosarcoma, chondrosarcoma, osteosarcoma (chondroid syringoma), myofibroblastic, osteosarcoma, Kaposi sarcoma and chordoma Efficacy: The mOS in the mixed sarcoma population: 21.3 months for INT230-6 The mOS had not been reached with 21.4 months of median follow-up for patients who received a cumulative INT230-6 dose volume that was greater than 40% of their total tumor burden INT230-6 extended overall survival in refractory sarcoma subjects by nearly 15 months as monotherapy when compared to a synthetic control group based on the Royal Marsden Hospital scoring method Sarcoma population's overall disease control rate (DCR): 93.3% (95% CI: 68.1, 99.8) at 2 months Median duration of response (DOR): 4.0 months (95% CI: 1.7, NA) and 11.3 months (95% CI: 2.8, NA) for subjects who received a cumulative dose of ≥ 40% of the total incoming total tumor burden INT230-6 demonstrated an increase in T-cells within the tumors 27% of patients had uninjected tumors shrink (abscopal effects), though tumors less than 1 cm were uninjected, untracked and unreported by investigators, so the true abscopal percentage is unknown; further radiomics work is on-going Safety INT230-6 demonstrated a favorable safety profile and was well-tolerated 3 subjects (20%) had one or more drug regimen-related Grade ≥ 3 Treatment Emergent Adverse Events (TEAE); all were grade 3 (there were no grade 4 or 5 TEAEs) INVINCIBLE-3 Study Overview The INVINCIBLE-3 Study is designed to evaluate INT230-6 administered intratumorally by an interventional radiologist or an equivalently trained physician using image guidance compared to systemically dosed standard of care ("SOC") chemotherapy. The study endpoints are overall survival and safety, along with an exploratory quality of life (QoL) assessment using the EORTC-30 survey. This is a global randomized Phase 3 study comparing the efficacy and safety of INT230-6 intratumoral (IT) injection with any of three standard of care therapies (pazopanib, trabectedin, or eribulin) in approximately 333 adult participants with locally recurrent, inoperable, or metastatic soft tissue sarcoma ("STS") patients who had disease progression prior to study enrollment following standard therapies, which must have included an anthracycline-based regimen unless contraindicated. Participants may also have received a maximum of one additional regimen. Randomization will occur after screening and eligibility confirmation. As this is a survival study, there is no crossover allowed between SOC and INT230-6. Disease progression will be determined by the World Health Organization (WHO) criteria. Participants will be prospectively stratified into 1 of 3 histologically defined STS strata: leiomyosarcoma liposarcoma (dedifferentiated, myxoid, round cell and pleomorphic) undifferentiated pleomorphic sarcoma The comparator agents used are all U.S., Europe, Canadian and Australian-approved agents for sarcomas: pazopanib tablets, trabectedin, and eribulin mesylate. Authorizations for the INVINCIBLE-3 Study have been obtained from the U.S. FDA, Health Canada, the European Medicines Agency, and Australia's Therapeutic Goods Administration. Sites will be opened in 8 countries and the study is presently recruiting participants in the U.S., Canada, and Europe. "The safety and efficacy data of our lead drug candidate, INT230-6, generated for sarcomas was quite encouraging. Many insights were gained from the over 200 patients treated before initiating the INVINCIBLE-3 study and applied to the ongoing study. Our approach uses sophisticated interventional radiology technologies to guide needles into tumors to inject our novel cytotoxic drug, which is highly absorbed by tumors, and showed a potential meaningful impact on lengthening metastatic sarcoma patient lives, reducing toxicities and improving quality of life compared to current treatments in our first clinical trial," said Lewis H. Bender, Intensity's President and Chief Executive Officer. "Our unique chemistry enables water-based products to diffuse throughout tumors and into cancer cells, causing immunologic cell death." About INT230-6 INT230-6, Intensity's lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity's proprietary DfuseRx℠ technology platform. The drug is comprised of two proven, potent anti-cancer agents, cisplatin and vinblastine sulfate, and a penetration enhancer molecule (SHAO) that helps disperse potent cytotoxic drugs throughout tumors for diffusion into cancer cells. These agents remain in the tumor, resulting in a favorable safety profile. In addition to local disease control and direct tumor killing, INT230-6 causes a release of a bolus of neoantigens specific to the malignancy, leading to immune system engagement and systemic anti-tumor effects. Importantly, these effects are mediated without immunosuppression, which often occurs with systemic chemotherapy. About Intensity Therapeutics Intensity is a late-stage clinical biotechnology company whose novel engineered chemistry enables aqueous cytotoxic-containing drug formulations to mix and saturate a tumor's dense, high-fat, pressurized environment following direct intratumoral injection. As a result of the saturation, Intensity's clinical trials have demonstrated the ability of INT230-6 to kill tumors and elicit an adaptive immune response within days of injection, representing a new approach to cancer cell death that holds the potential to shift the treatment paradigm and turn many deadly cancers into chronic diseases even for malignancies that do not respond to conventional immunotherapy. Intensity has completed two clinical studies and enrolled over 200 patients using INT230-6: a Phase 1/2 dose escalation study in metastatic cancers including sarcomas (NCT03058289), and a Phase 2 randomized control clinical trial in locally advanced breast cancer (the "INVINCIBLE-2 Study") (NCT04781725) in women without undergoing chemotherapy prior to their surgery. The Company initiated a Phase 3 trial in soft tissue sarcoma (the "INVINCIBLE-3 Study") (NCT06263231), testing INT230-6 as second or third-line monotherapy compared to the standard of care ("SOC") with overall survival as an endpoint. Intensity also initiated a Phase 2 study in collaboration with The Swiss Group for Clinical Cancer Research, SAKK (the "INVINCIBLE-4 Study") (NCT06358573) as part of a Phase 2/3 program evaluating INT230-6 followed by the SOC immunochemotherapy and the SOC alone for patients with presurgical triple-negative breast cancer. Pathological complete response ("pCR") is the endpoint. For more information about Intensity, including publications, papers, and posters about its novel approach to cancer therapeutics, visit . Forward-Looking Statements Certain statements in this press release may constitute "forward-looking statements" within the meaning of the United States Private Securities Litigation Reform Act of 1995, as amended to date. These statements include, but are not limited to, statements relating to the Company's expected future plans, cash runway, development activities, projected milestones, business activities or results. When or if used in this communication, the words "may," "could," "should," "anticipate," "believe," "estimate," "expect," "intend," "plan," "predict" and similar expressions and their variants, as they relate to the Company or its management, may identify forward-looking statements. The forward-looking statements contained in this press release are based on management's current expectations and projections about future events. Nevertheless, actual results or events could differ materially from the plans, intentions, and expectations disclosed in, or implied by, the forward-looking statements. These risks and uncertainties, many of which are beyond our control, include: the initiation, timing, progress and results of future preclinical studies and clinical trials and research and development programs; the need to raise additional funding before the Company can expect to generate any revenues from product sales; plans to develop and commercialize product candidates; the timing or likelihood of regulatory filings and approvals; the ability of the Company's research to generate and advance additional product candidates; the implementation of the Company's business model, strategic plans for the Company's business, product candidates and technology; commercialization, marketing and manufacturing capabilities and strategy; the rate and degree of market acceptance and clinical utility of the Company's system; the Company's competitive position; the Company's intellectual property position; developments and projections relating to the Company's competitors and its industry; the Company's ability to maintain and establish collaborations or obtain additional funding; expectations related to the use of cash and cash equivalents and investments; estimates regarding expenses, future revenue, capital requirements and needs for additional financing; and other risks described in the section entitled "Risk Factors" in the Company's SEC filings, which can be obtained on the SEC website at . Readers are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date on which they are made and reflect management's current estimates, projections, expectations and beliefs. The Company does not plan to update any such forward-looking statements and expressly disclaims any duty to update the information contained in this press release except as required by law. Investor Relations Contact: Justin Kulik [email protected] CORE IR (516) 222-2560 Media Contact: Jules Abraham CORE IR [email protected] SOURCE Intensity Therapeutics Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED