Comparative study to evaluate efficacy and safety of topical alcaftadine 0.25% versus topical olopatadine 0.2% eye drops in patients with allergic conjunctivits in a tertiary care teaching hospital, Haldwani - NIL

开始日期2024-03-25

申办/合作机构-

CTRI/2022/07/043825

/ Not yet recruiting临床1期

Single dose comparative bioavailability study of ALDP 001 (nasal Spray, 0.5%) and â??LASTACAFTÂ®â?? (alcaftadine ophthalmic solution) 0.25% in healthy adult human subjects under fasting conditions.

开始日期2022-08-26

申办/合作机构

Alkem Laboratories Ltd.

CTRI/2018/10/016170

/ Not yet recruiting临床4期IIT

A Randomized,Open label ,Parallel comparative study of efficacy,safety and tolerability of ophthalmic solutions of Alcaftadine 0.25% and Olopatadine 0.1% in patients with Allergic conjunctivitis in a tertiary care center

开始日期2018-10-29

申办/合作机构-

100 项与阿卡他定相关的临床结果

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100 项与阿卡他定相关的转化医学

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100 项与阿卡他定相关的专利（医药）

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项与阿卡他定相关的文献（医药）

2024-12-01·Sustainable Chemistry and Pharmacy

An integrated paradigm between green analytical chemistry and quality-by-design for robust analysis of alcaftadine and ketorolac tromethamine in aqueous humor via sustainable chromatographic methods

作者: Wadie, Mina ; Rezk, Mamdouh R. ; Hussein, Ola G.

The field of pharmaceutical industry has witnessed the launch of a new co-formulated eye drop, composed of alcaftadine and ketorolac tromethamine, for alleviating allergic conjunctivitis.Such new formulation evokes the need for a sensitive, robust and fast anal. method capable of their quantification in their dosage form, in aqueous humor for pharmaco-kinetics studies as well as in presence of plausible degradation products.In this work, two validated stability-indicating chromatog. methods were developed for alcaftadine and ketorolac assaying with good adherence to values of green anal. chem.Drugs stabilities were tested under various stress conditions where drugs showed liability for oxidative degradation only.For the first chromatog. method, an integrated merger between anal. quality-by-design and green anal. chem. was implemented via a UPLC method coupled with photo-diode array detector.A short C₁₈ anal. column of 100 mm was utilized with mobile phase of ethanol: aqueous solution pH 4.0 containing 0.1% triethylamine (40: 60, by volume).Second method was thin layer chromatog. one using HPTLC silica plates as a stationary phase and a developing system of dichloromethane: ethanol (5:4, by volume).Both methods achieved to selectively quantify the studied drugs with high accuracy and precision without any interference from degradation products or related excipients in eye drops.The methods were also successfully exploited for ALF and KTC assaying in rabbit aqueous humor, with no need for prior extraction procedures, for further pharmacokinetic studies.Finally, usage of green solvents gives us the advantage of applying various evaluation tools to conclude method greenness.

2024-06-01·Advanced science (Weinheim, Baden-Wurttemberg, Germany)

Cutaneous Calcium/Calmodulin‐Dependent Protein Kinase II‐γ–Positive Sympathetic Nerves Secreting Norepinephrine Dictate Psoriasis

Article

作者: Wang, Yirui ; Zhen, Qi ; Li, Zhuo ; Mao, Yiwen ; Sun, Liangdan ; Bai, Yuanming ; Yu, Yafen ; Li, Bao ; Fan, Wencheng ; Chen, Weiwei ; Hu, Hongbo

Abstract:

Cutaneous sympathetic nerve is a crucial part of neuropsychiatric factors contributing to skin immune response, but its role in the psoriasis pathogenesis remains unclear. It is found that cutaneous calcium/calmodulin‐dependent protein kinase II‐γ (CAMK2γ), expressed mainly in sympathetic nerves, is activated by stress and imiquimod in mouse skin. Camk2g‐deficient mice exhibits attenuated imiquimod‐induced psoriasis‐like manifestations and skin inflammation. CaMK2γ regulates dermal γδT‐cell interleukin‐17 production in imiquimod‐treated mice, dependent on norepinephrine production following cutaneous sympathetic nerve activation. Adrenoceptor β1, the primary skin norepinephrine receptor, colocalises with γδT cells. CaMK2γ aggravates psoriasiform inflammation via sympathetic nerve–norepinephrine–γδT cell–adrenoceptor β1–nuclear factor‐κB and –p38 axis activation. Application of alcaftadine, a small‐molecule CaMK2γ inhibitor, relieves imiquimod‐induced psoriasis‐like manifestations in mice. This study reveals the mechanisms of sympathetic‐nervous‐system regulation of γδT‐cell interleukin‐17 secretion, and provides insight into neuropsychiatric factors dictating psoriasis pathogenesis and new potential targets for clinical psoriasis treatment.

2024-04-01·MICROCHEMICAL JOURNAL

Suppression of photo-induced electron transfer of alcaftadine for its photoluminescence detection in aqueous humor

作者: Mostafa, Islam M. ; Elsayed, Mohamed Ahmed ; Omar, Mahmoud A. ; Mohamed, Abobakr A.

A green, facile and selective fluorimetric approach was described for estimating alcaftadine (ALC) in its pure form, eye drop formulation, and artificial aqueous humor for the first time.The developed approach depends on the suppression of the photoinduced electron transfer (PET) impact of the lone pair of the N-atom of the piperidine ring of ALC.PET suppression was attained by using 0.3 M acetic acid as an efficient protonating agent.By virtue of this phenomenon, ALC was quantified from 50 to 400 ng mL-1 with a very low detection and quantitation limit of 2.22 and 6.72 ng mL-1, resp.Addnl., the presented method was employed for estimating the target drug in artificial aqueous humor and observably there is no significant interference from the aqueous humor matrix.

项与阿卡他定相关的新闻（医药）

2024-11-28

·精准药物

共价药物体外时间依赖性抑制（TDI）数据分析和解读

前言共价药物（Covalent drug）是指在结构中包含反应性的官能团，能与靶蛋白形成共价键，实现与靶蛋白长期结合，从而提供独特的药效学特征。从偶然发现到目标性设计，共价药物在多个疾病领域蓬勃发展，尤其是抗肿瘤领域。自KRAS靶点在癌症中的作用被发现以来，近30年间研究者使用传统药物发现方法一直没有突破这一靶点的不可成药性，而共价抑制剂Sotorasib（Lumakras）和Adagrasib（Krazati）打破了KRAS“不可成药靶点”的魔咒。近年来，多款共价药物成功上市，包括针对EGFR、BTK、KRAS等靶点的抑制剂。细胞色素P450酶（以下简称CYP酶）是体内参与药物代谢最广泛的I相代谢酶，主要位于肝脏，参与约75%的小分子药物代谢。药物对CYP酶的抑制会引起联用药物的暴露量增加或活性代谢产物暴露量减少，造成潜在毒性或影响疗效。抑制评价分为可逆性抑制（Reversible inhibition）和时间依赖性抑制（Time-dependent inhibition, TDI）评价，其中TDI会造成更为严重的药物相互作用（Drug interaction, DDI）。药物本身或其代谢后生成的反应性中间体与CYP酶的共价结合是TDI发生的机理之一，那么共价药物是否一定会发生TDI呢？共价药物的TDI风险比非共价抑制剂更高吗？如何评估TDI风险和解读TDI数据呢？本文分析了29个已上市的共价药物对CYP酶的TDI研究结果，并对体外TDI风险评估的方法和数据解读提供相关建议。上市共价药物对CYP450酶的抑制结果分析据报道，自1947年以来共117种共价药物获批[1]，已上市的共价药物主要涉及抗感染（青霉素、磷霉素）、抗病毒（奈马特韦）和抗肿瘤（奥西替尼、达克替尼）等治疗领域。本文检索了自2000年以来上市的共价药物对CYP酶的体外TDI结果，共整理出29个共价药物的数据，详见文末附表1。其中19个共价药物对至少一种CYP酶表现出TDI，约占65.5%。TDI在7种常见CYP酶的分布汇总如图1，有15个药物对CYP3A存在TDI，约占79%；其次是2C8，5个共价药物对其存在TDI，约占26%；对1A2和2B6存在TDI的共价药物都为3个，占比约16%；有1个共价药物对2C19存在TDI，占比约5%。19个共价药物对2C9和2D6不存在TDI或目前未见报道。图1. 自2000年之后上市的具有TDI的共价药物在常见CYP酶的分布情况一项体外[22]研究评估了14个蛋白激酶抑制剂对CYP2C8和CYP3A的TDI，结果表明经过与NADPH预孵育以后，11个激酶抑制剂对CYP3A的抑制效果增强，3个对CYP2C8的抑制效果增强，（如图2）。其中有8个已被文献报道为CYP3A的TDI抑制剂，另外3个在随后的研究中证实抑制CYP3A的IC50偏移率大于2倍。这14个药物并非共价药物，由此看来，非共价药物尤其是蛋白激酶抑制剂的TDI风险依然不容忽视。对于共价药物和非共价药物，TDI都是需要重点关注的内容。图2. 蛋白激酶抑制剂与NADPH预孵育30min后抑制阿莫地喹N-去乙基化（CYP2C8）和咪达唑仑1'-羟化（CYP3A）的结果。BOSU, bosutinib; BOSU iso, bosutinib isomer 1; CRIZ, crizotinib; DASA, dasatinib; ERLO, erlotinib; GEFI, gefitinib; LEST, lestaurtinib; NILO, nilotinib; PAZO, pazopanib; SARA, saracatinib; SORA, sorafenib; SUNI, sunitinib. [22] 体外TDI风险评估的方法建议监管机构和制药公司已经认识到评估TDI风险的重要性，人用药品技术要求国际协调理事会（ICH）发布的指导原则M12《Drug Interaction Studies》[23]于今年5月21日最终采纳。结合指南推荐，体外评估药物TDI风险的方法总结如下： “ 1 酶活性损失百分比、假一级速率常数kobs和IC50偏移早期药物发现阶段，需要高通量、快速筛选确定CYP酶的TDI潜力，可以通过单一化合物浓度下含和不含NADPH预孵育后损失百分比（%Activity loss），CYP酶活性降低（kobs）或多浓度的化合物含和不含NADPH预孵育后IC50值的偏移(IC50 shift)来判断化合物是否有TDI潜力。 “ 2 TDI抑制的动力学常数测定（kinact、KI）评估CYP酶TDI的重要动力学常数包括最大失活速率常数（kinact）、导致半数最大失活的抑制剂浓度（KI）。采用不同浓度的化合物（至少6个）与酶源（即肝微粒体、肝细胞、重组酶系统）及NADPH进行第1次孵育（至少6个时间点），也称失活孵育；在特定的孵育时间后，将失活孵育混合物加入含有CYP同工酶探针底物的二次孵育当中，反应一定时间后，终止反应，并测量探针底物的代谢产物生成。计算失活后相对于没有抑制剂时所测得的活性的剩余百分比，剩余百分比与失活孵育的时间进行线性拟合作图，得到一系列一级衰减曲线，如图3a，直线斜率的负值即为一个浓度点的表观抑制速率（kobs）。用不同浓度下的表观抑制速率与化合物的浓度进行非线性拟合即可计算得到kinact和KI，如图3b。图3. Verapamil的体外TDI动力学常数测定（kinact和KI）测量kinact和KI的体外实验方法通常不适合早期药物发现项目中的高通量筛选。但从药物发现的角度，较大的kinact值和较小的KI值通常会增加CYP酶失活导致DDI的可能性。因此在临床前药物发现中，也可以通过kinact/KI比值衡量化合物CYP酶失活的效率，对同系列化合物进行排序。案例分享与TDI数据的解读建议 Ritlecitinib是一种共价JAK3酪氨酸激酶抑制剂，主要用于治疗脱发症，尤其是斑秃和非节段型白癜风（NSV）。其共价抑制机制主要通过与JAK3催化域中的半胱氨酸残基（Cys-909）发生不可逆的共价结合来实现。这一残基在其他JAK家族成员中被丝氨酸残基所取代，这使得Ritlecitinib对JAK3具有高度的选择性[24, 25]。 Ritlecitinib在体外肝微粒体TDI评价体系中，被评估为CYP1A2和CYP3A的TDI抑制剂。其中，Ritlecitinib对CYP1A2（以咖啡因底物）代谢活性抑制常数分别是KI为327 μmol/L，kinact为0.0917 min-1。由于在测试的浓度范围内（3-200 μmol/L）未达到抑制饱和，因此无法确定对CYP3A（以咪达唑仑底物）代谢活性的KI或kinact，但kinact/KI估计为0.871 mL/min/μmol[20]。在斑秃患者中，每日一次口服50 mg的Ritlecitinib后最大稳态游离药物浓度（Cmax,u）估计值1.1 μmol/L[20]，结合上述体外TDI参数，根据ICH M12指导原则[23]的基本方法初步评价TDI风险如表1。计算得到Ritlecitinib对CYP1A2的表观一级失活速率常数(Kobs)为0.001517 min-1。Kdeg是酶的表观一级降解速率常数，引用自指导原则，计算（kobs+kdeg）/kdeg的值为6.06，大于1.25，说明需关注Ritlecitinib潜在临床抑制风险。表1. 基本模型预测Ritlecitinib对CYP1A2的TDI风险注：kobs=(kinact*5*Cmax,u)/(KI+5*Cmax,u)，此处计算所使用数据引用自文献[20] 该药物开展了相应的临床DDI研究。Liu[26]等人在健康志愿者中开展的临床研究中发现，咖啡因（CYP1A2底物）与Ritlecitinib联合使用时，咖啡因的AUC和Cmax分别增加了约165%和10%，表明Ritlecitinib是CYP1A2的中等抑制剂，可以增加CYP1A2底物的暴露量。Ritlecitinib与CYP酶底物合用的临床DDI研究结果汇总如表2，Ritlecitinib与咪达唑仑（CYP3A底物）合用导致咪达唑仑的AUC和Cmax分别增加了约169%和81%，而其与Efavirenz（CYP2B6底物）和Tolbutamide（CYP2C底物）合用后，底物的暴露量变化不具有临床意义[27]。在Ritlecitinib药品说明书中，提示与CYP3A和CYP1A2的底物合用时，可能增加不良反应风险，需考虑额外的监测或调整剂量。表2. Ritlecitinib临床与CYP酶底物合用引起的暴露量变化 c: 合用Ritlecitinib相比于单独给药的Cmax和AUCinf的比值。 d: 报告了Efavirenz的AUC0-72。以上结果整理自药品说明书。 TDI数据解读建议药物研发早期可通过单一浓度下的酶活性降低(酶活性损失率%Activity loss或假一级速率常数kobs或多浓度点下IC50偏移(≥1.5)，检测化合物的TDI潜力；如药物具有TDI潜力，可通过体外研究获得TDI的动力学参数kinact、KI，结合人体PK数据，应用模型排除或预测临床TDI风险。结语本文整理的数据表明65%以上的共价药物表现出对CYP酶的TDI，而文献显示非共价药物如蛋白激酶抑制剂的TDI风险同样不容忽视，因此，不论是否为共价药物，均建议在研发早期考察TDI风险。 TDI引起的临床不良反应往往是极其严重的，如米贝拉地尔的撤市，其作为CYP3A的强TDI抑制剂，与其他3A的底物合用会引起严重的毒性反应，严重时导致死亡。对于存在TDI风险的药物，必要时通过体外实验获取抑制动力学参数kinact和KI，结合临床PK数据进行临床DDI风险的评估，如果体外数据和模型无法排除临床抑制风险，则应使用敏感探针底物进行临床DDI研究。药明康德DMPK已经建立了一套专门针对共价药物的药代动力学研究体系，其中包括早期的高通量筛选、共价药物多样化的体内外代谢模型与方法、丰富的体外ADME试验类型、以及14C标记化合物的合成和相应的ADME技术平台，可以支持客户加速共价药物的研发和申报。附表1. 29个共价药物对CYP酶的TDI结果汇总（下滑查看更多） a: 结果引用自药品说明书。 b: 由于测试浓度（3-200 μM）下抑制未被饱和，无法计算准确KI和kinact值。参考文献： [1] Journal of Medicinal Chemistry 2022 65 (8),5886-5901 DOI: 10.1021/acs.jmedchem.1c02134 [2] Suchy D, Łabuzek K, Stadnicki A, Okopień B. Ezetimibe--a new approach in hypercholesterolemia management. Pharmacol Rep. 2011;63(6):1335-48. doi: 10.1016/s1734-1140(11)70698-3. PMID: 22358082. [3] Investigation of drug-drug interaction potential of bortezomib in vivo in female Sprague-Dawley rats and in vitro in human liver microsomes；Drug Metab Dispos. 2006 Apr;34(4):702-8. [4] M. F Moghaddam, et al. Drug Metabolism Letters, 2014, 8, 19-30. [5] NDA 22-134: https://www.fda.gov/files/drugs/published/22134-Alcaftadine-ClinPharm-PREA.pdf [6] Chapron B, Risler L, Phillips B, Collins C, Thummel K, Shen D. Reversible, time-dependent inhibition of CYP3A-mediated metabolism of midazolam and tacrolimus by telaprevir in human liver microsomes. J Pharm Pharm Sci. 2015;18(1):101-11. doi: 10.18433/j3288c. PMID: 25877445. [7] Wang, Z., Yang, J., Kirk, C., Fang, Y., Alsina, M., Badros, A., Infante, J. R. (2012). Clinical Pharmacokinetics, Metabolism, and Drug-Drug Interaction of Carfilzomib. Drug Metabolism and Disposition, 41(1), 230–237. doi:10.1124/dmd.112.047662 [8] Jordi Aubets et,al; No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P‐glycoprotein (P‐gp) drug transporter;Pharmacol Res Perspect. 2019 Dec; 7(6): e00540. [9] NDA 206829: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206829orig1s000clinpharmr.pdf [10] DMD Fast Forward. Published on March 10, 2014 as DOI: 10.1124/dmd.113.055335 [11] Evaluation of the Drug–Drug Interaction Potential of Acalabrutinib and Its Active Metabolite, ACP‐5862, Using a Physiologically‐Based Pharmacokinetic Modeling Approach; CPT Pharmacometrics Syst Pharmacol. 2019 Jul; 8(7): 489–499. [12] NDA 209776: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209776Orig1s000PharmR.pdf [13] Report on the Deliberation Results: https://www.pmda.go.jp/files/000240418.pdf [14] Zhang H, Ou YC, Su D, Wang F, Wang L, Sahasranaman S, Tang Z. In vitro investigations into the roles of CYP450 enzymes and drug transporters in the drug interactions of zanubrutinib, a covalent Bruton's tyrosine kinase inhibitor. Pharmacol Res Perspect. 2021 Dec;9(6):e00870. doi: 10.1002/prp2.870. PMID: 34664792; PMCID: PMC8524670. [15] Report on the Deliberation Results: https://www.pmda.go.jp/files/000237315.pdf [16] NDA 214665: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214665Orig1s000MultidisciplineR.pdf [17] NDA 215301: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/215310Orig1s000MultidisciplineR.pdf [18] KRAZATI 200 mg film-coated tablets: ANNEX I [19] Heather Eng et al, Disposition of Nirmatrelvir, an Orally Bioavailable Inhibitor of SARS-CoV-2 3C-Like Protease, across Animals and Humans; Drug Metab Dispos. 2022 May;50(5):576-590. [20] Litfulo review report; https://www.pmda.go.jp/files/000266925.pdf [21] https://www.ema.europa.eu/en/documents/rmp-summary/skyclarys-epar-risk-management-plan_en.pdf [22] Drug Metab Dispos 42:1202–1209, July 2014, http://dx.doi.org.libproxy1.nus.edu.sg/10.1124/dmd.114.057695 [23] ICH M12《Drug Interaction Studies》 [24] Xu H, Jesson MI, Seneviratne UI, et al. PF-06651600, a dual JAK3/TEC family kinase inhibitor. ACS Chem Biol. 2019;14(6):1235–42. [25] Telliez JB, Dowty ME, Wang L, et al. Discovery of a JAK3- selective inhibitor: functional diferentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem Biol. 2016;11(12):3442–51. [26] Liu J, Solan R, Wolk R, et all. Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants. Br J Clin Pharmacol. 2023;89:2208–2215. [27] Pfzer Inc. LITFULO™ (ritlecitinib) capsules, for oral use: US prescribing information. 2023. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2023/215830s000lbl.pdf. Accessed 26 Jul 2023. （下滑查看更多）作者：吴文萍，马虹莹，马利萍，周莹，金晶编辑：姜利芳，钱卉娟，陈根富设计：倪德伟，张莹莹声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

上市批准一致性评价医药出海

2024-01-09

·SYNAPSE

Deciphering H1 receptor antagonists and Keeping Up with Their Recent Developments

The H1 receptor, also known as the histamine H1 receptor, plays a crucial role in the human body. It is primarily found in smooth muscle cells, endothelial cells, and nerve cells. Activation of the H1 receptor by histamine leads to various physiological responses, including vasodilation, increased vascular permeability, bronchoconstriction, and stimulation of sensory nerve endings. These responses are involved in allergic reactions, inflammation, and immune responses. Antagonists of the H1 receptor, commonly known as antihistamines, are widely used to treat allergies, hay fever, and other conditions associated with excessive histamine release. Understanding the role of the H1 receptor is essential for developing effective treatments for allergic and inflammatory disorders. The analysis of the target H1 receptor reveals a competitive landscape with multiple companies actively developing drugs. GSK Plc, Sanofi, Pfizer Inc., Bayer AG, and Novartis AG are among the companies with the highest number of approved drugs or drugs in advanced stages of development. The indications with the most approved drugs include Common Cold, Rhinitis, Allergic, Urticaria, Pruritus, and Hypersensitivity. Small molecule drugs are the most rapidly progressing drug type, indicating intense competition in this area. China, the United States, and Japan are the countries with the highest number of approved drugs, with China showing significant progress in the development of drugs targeting the H1 receptor. Overall, the target H1 receptor presents opportunities for further research and development, particularly in indications with high unmet medical needs. How do they work?H1 receptor antagonists, also known as H1 blockers or antihistamines, are a class of drugs that block the action of histamine at the H1 receptor. Histamine is a chemical released by the body during an allergic reaction, causing symptoms such as itching, sneezing, runny nose, and watery eyes. H1 receptor antagonists work by binding to the H1 receptors on cells, preventing histamine from binding and exerting its effects. From a biomedical perspective, H1 receptor antagonists are commonly used to treat allergic conditions, such as hay fever (allergic rhinitis), hives (urticaria), and allergic conjunctivitis. They help alleviate symptoms by reducing the effects of histamine, thereby relieving itching, sneezing, and other allergic reactions. There are different generations of H1 receptor antagonists, each with varying degrees of sedative effects. First-generation antihistamines, such as diphenhydramine and chlorpheniramine, can cause drowsiness and are often used for their sedative properties in addition to their antihistamine effects. Second-generation antihistamines, such as cetirizine, loratadine, and fexofenadine, are less likely to cause sedation and are preferred for daytime use. In summary, H1 receptor antagonists are drugs that block the action of histamine at the H1 receptor, providing relief from allergic symptoms. They are commonly used in the treatment of various allergic conditions and come in different generations with varying sedative effects. List of H1 receptor AntagonistsThe currently marketed H1 receptor antagonists include: Olopatadine Hydrochloride/Mometasone Furoate MonohydrateChlorpheniramine Maleate/Codeine PhosphateDiphenhydramine Hydrochloride/Naproxen SodiumRecombinant interferon alfa-2b/LoratadineRupatadine FumarateAzelastine/mometasoneEbastine/Pseudoephedrine HydrochlorideAzelastine Hydrochloride/Fluticasone PropionateChlorpheniramine Maleate/Hydrocodone Bitartrate/Pseudoephedrine HydrochlorideAlcaftadineFor more information, please click on the image below. What are H1 receptor antagonists used for?H1 receptor antagonists are widely used to treat allergies, hay fever, and other conditions associated with excessive histamine release. For more information, please click on the image below to log in and search. How to obtain the latest development progress of H1 receptor antagonists?In the Synapse database, you can keep abreast of the latest research and development advances of H1 receptor antagonists anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

2023-11-18

·药智网

康缘药业，如何拿下50亿抗癫痫市场？

近日，康缘药业的吡仑帕奈片获国家药监局批准，拿下了我国首款获批上市的吡仑帕奈仿制药“头衔”。原研吡仑帕奈出自日本卫材，是一种高度选择性、非竞争性的AMPA型谷氨酸受体拮抗剂，通过靶向突触后AMPA受体-谷氨酸的活动，减少与癫痫发作相关神经元的过度兴奋，于2012年7月获美国FDA批准上市。据弗若斯特沙利文预测，2025年我国抗癫痫药物市场将达48亿，康缘药业如何一步步拿下？01小小一片仿制药，是迎合市场更是国产药担当癫痫是最常见神经疾病之一，其中，部分发作性和全身发作性癫痫患者分别占60%和40%，极度影响了正常生活。据弗若斯特沙利文数据显示，我国2016年的癫痫持续状态患者为54.4万人，2020年增至75.3万人，预计到2024年将突破100万人。国内急迫的临床用药需求，让日本卫材的吡仑帕奈一路开挂，2019年9月通过优先审批程序在国内获批，用于12岁及以上癫痫患者部分发作性癫痫（伴或不伴继发性全身性癫痫）的辅助治疗，吡仑帕奈一经获批，就被纳入2020年《国家医保目录》。2021年7月，吡仑帕奈又获国家药监局批准用于成人和4岁及以上儿童癫痫部分性发作（伴或不伴有继发全面性发作）的治疗；2023年5月，日本卫材的吡仑帕奈口服混悬液在国内获。2023年3月发布的《临床诊疗指南·癫痫病分册（2023修订版）》，将吡仑帕奈作为新诊断局灶性发作患者的一线用药，市场炙热程度再次猛增。据药智数据企业版——医院销售数据显示，吡仑帕奈在国内上市以来呈持续放量态势，除2021年因纳入《国家医保目录》后1295.37%的销售额增长外，2022年仍翻倍达188.73%，2023年上半年又达7106.02万元，已占2022全年销售额的81.23%。图1 2020年至2023年吡仑帕奈销售额图片来源：药智数据据弗若斯特沙利文预测，我国抗癫痫药物市场到2025年将达48亿元，进口药的一家独大，和患者更高性价比的用药需求，让吡仑帕奈被纳入了国家《第二批鼓励仿制药品目录》，其中包括吡仑帕奈片剂和口服混悬剂。图2 第二批鼓励仿制药品目录图片来源：国家卫健委官网康缘药业的吡仑帕奈片获批上市，一举打破了进口药的市场垄断，且还有一大波仿制药“走”在即将获批的路上。据药智数据显示，除青峰药业的上市申请未被批准外，万高药业、远大德天、海纳制药/帝益药业和泰恩康制药的吡仑帕奈片都已处于上市申请评审中。图3 吡仑帕奈片在研进展图片来源：药智数据仿制药研发相比创新药，难度要小不少，但让笔者不禁佩服且又疑惑的是，作为一直深耕中药领域的康缘药业，是怎样走出了一段打破进口药垄断的历程。02居安思危，药企生存发展的必须状态康缘药业是中药行业名副其实的王牌药企之一，2021年和2022年连续两年有3款中药新药获批，分别为银翘清热片、散寒化湿颗粒和苓桂术甘颗粒，成为2021年以来中药新药获批数量最多的药企，其中，苓桂术甘颗粒实现了中药3.1类新药从无到有的跨越。据2022年报显示，截至2023年2月，康缘药业共获有205个药品生产批件，其中46个药品为中药独家品种，4个中药为保护品种。支撑康缘药业业绩的主要产品也均为中药，分别是治疗呼吸领域的热毒宁注射液、金振口服液、杏贝止咳颗粒；治疗心脑领域的银杏二萜内酯葡胺注射液、天舒胶囊；治疗骨伤科领域的复方南星止痛膏、腰痹通胶囊；以及治疗妇科领域的桂枝茯苓胶囊、散结镇痛胶囊。其中，热毒宁注射液、金振口服液和银杏二萜内酯葡胺注射液又是康缘药业最核心产品，2022年，3款药品的销售额均占总营收的10%以上。然而，核心产品市场销量可观，但增长动力明显放缓。尽管康缘药业的业绩还算稳定，仅在疫情元年，与大多数药企一样，出现过营收和净利润的双下滑，但之后迅速回暖。这让善于居安思危的康缘药业有了不丢中药主业、积极布局化药和生物药的发展思路。图4 康缘药业业绩情况图片来源：招商证券因仿制药研发难度较小，自然成了康缘药业实现入局化药的“试金石”，2020年以来，除吡仑帕奈片外，还获批了注射用兰索拉唑、吸入用异丙托溴铵溶液、米诺地尔搽剂等多款仿制药，此外，还通过了苯磺酸氨氯地平片和马来酸依那普利片的仿制药一致性评价。值得一提的是，康缘药业是首家通过米诺地尔搽剂一致性评价的药企，此次吡仑帕奈片的获批，是康缘药业立足中药，“转战”化药/生物药最有意义的阶段性胜利。03专挑首仿下手，创新药管线雏形亦现康缘药业的仿制药之路，走的有点与众不同，有种“专挑”首仿下手的味道。据其2023半年报显示，在仿制药项目中，除了吡仑帕奈片外，博舒替尼片、盐酸多佐胺/多佐噻吗滴眼液、阿卡他定片、盐酸维拉佐酮片、盐酸罗卡色林片、苹果酸卡博替尼胶囊、替比培南酯、琥珀酸舒马普坦萘普生钠片等，均未在国内上市。图5 康缘药业开发支出图片来源：康缘药业2023半年报其中，不乏重磅药物，博舒替尼由辉瑞原研，最早在2012年9获美国FDA批准用于治疗慢性粒细胞白血病，2022年全球销售额达40.09亿元；苹果酸卡博替尼由Exelixis原研，最早在2012年11月获美国FDA批准用于治疗甲状腺癌，现已获批治疗晚期肾细胞癌、肝细胞癌、甲状腺髓样癌、转移性结直肠癌、肾细胞癌等多个癌种，2022年全球销售额达133.25亿元。仿制药虽然研发难度相对较低，但康缘药业却给自己选择了一条最难走的路，这也为其再向创新药发展磨快了“刀”，2023年上半年，将2款化药创新药推至临床阶段，分别为KY0135和KY1702。KY0135是一种小分子Porcupine抑制剂，用于晚期实体瘤；KY1702是一款EGFR/HER2高效双重抑制剂，用于EGFR基因敏感突变的晚期非小细胞肺癌的治疗。此外，据康缘药业2022年报显示，还有3款创新药早已推至临床阶段，其中，2款化药创新药KY0467和氟诺哌齐片，分别用于治疗小儿手足口病和阿尔茨海默症，已进展至2期临床；生物创新药KYS202002A用于治疗多发性骨髓瘤的临床试验已进展至1期，值得一提的是，2023年6月，KYS202002A又获美国FDA批准开展治疗复发和难治性多发性骨髓瘤临床试验，2023年8月，用于治疗成人系统性红斑狼疮的拓展适应症临床试验再获国家药监局批准。较好的业绩及充足的现金储备，也将为康缘药业创新药管线保驾护航，截至2023年6月，康缘药业拥有现金及现金等价物余额为19.77亿元。04小结很喜欢《士兵突击》中的“吴哲”一角，天之骄子,却有着平常心，不图安逸，在有能力的年龄干着喜欢且更有意义的事，康缘药业更像是药企中的“吴哲”，中药实力强不骄，业绩稳定不自封，在“成长”的路上勇于自我加担。参考来源：药智数据康缘药业公告、半年报及年报声明：本内容为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 八斤转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

上市批准优先审批放射疗法临床研究

100 项与阿卡他定相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06552	阿卡他定	S01GX11	DB06766

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
变应性结膜炎	美国	AbbVie, Inc.	2010-07-28
瘙痒	美国	AbbVie, Inc.	2010-07-28

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
常年过敏性结膜炎	临床3期	日本	Allergan UC	2014-03-01
季节性过敏性结膜炎	临床3期	美国	Vistakon Pharmaceuticals LLC	2006-08-01
急性结膜炎	临床3期	美国	Vistakon Pharmaceuticals LLC	2005-10-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ARVO2016	N/A	过敏	111	Lastacaft	膚繭憲構範窪簾顧窪糧(淵夢廠齋鹽構襯簾範窪) = 製鑰醖憲範膚蓋糧製憲膚選壓鏇齋壓衊鏇鹽鬱 (鬱鏇鹽築鑰壓鏇積遞積 )	-	2016-05-01
				Pataday	膚繭憲構範窪簾顧窪糧(淵夢廠齋鹽構襯簾範窪) = 觸選構鏇鹹鹽艱選窪蓋膚選壓鏇齋壓衊鏇鹽鬱 (鬱鏇鹽築鑰壓鏇積遞積 )
NCT02161146 (CTgov)	临床3期	变应性结膜炎	240	AGN-229666 (AGN-229666)	簾夢夢蓋夢壓製範鏇衊(鏇鬱糧餘遞獵壓艱襯鏇) = 獵壓鏇製築夢襯範糧獵糧顧膚餘構網鏇築鑰膚 (獵憲襯範醖糧鹹積範膚, 0.523) 更多	-	2016-03-07
				Vehicle to AGN-229666 (Vehicle)	簾夢夢蓋夢壓製範鏇衊(鏇鬱糧餘遞獵壓艱襯鏇) = 鹽鬱製艱夢繭簾遞糧觸糧顧膚餘構網鏇築鑰膚 (獵憲襯範醖糧鹹積範膚, 0.904) 更多
NCT02082262 (CTgov)	临床3期	常年过敏性结膜炎	140	AGN-229666	顧構餘鏇網鬱選餘鑰範(憲衊顧願艱鑰齋製齋繭) = 積製鏇夢鑰艱壓淵夢鏇構選觸鬱積壓築廠壓鹹 (網獵艱夢糧餘鑰遞壓簾, 0.49) 更多	-	2015-10-08
NCT01470118 \| NCT01732757 (Pubmed \| Adv Ther)	临床4期	变应性结膜炎	284	Alcaftadine 0.25%	糧鏇蓋獵襯遞鑰艱鹽願(艱觸選淵膚顧選膚簾遞) = 壓鏇鏇鏇觸願鏇艱衊膚簾範鏇夢繭鏇顧獵夢積 (廠齋齋蓋窪顧積觸選窪 )	积极	2014-10-01
				Olopatadine 0.2%	糧鏇蓋獵襯遞鑰艱鹽願(艱觸選淵膚顧選膚簾遞) = 築膚選艱積醖網衊築襯簾範鏇夢繭鏇顧獵夢積 (廠齋齋蓋窪顧積觸選窪 )
NCT01754766 (CTgov)	临床2期	变应性结膜炎	90	AGN-229666 (AGN-229666 Dose A)	餘繭窪壓選鏇艱醖廠遞(製衊觸夢蓋膚範餘餘構) = 糧壓齋廠積廠襯獵顧選顧鹹膚糧憲鏇蓋糧壓製 (積醖淵夢鹹夢範鑰鹹選, 0.5123) 更多	-	2014-02-04
				AGN-229666 (AGN-229666 Dose B)	餘繭窪壓選鏇艱醖廠遞(製衊觸夢蓋膚範餘餘構) = 衊製衊憲築製願衊獵觸顧鹹膚糧憲鏇蓋糧壓製 (積醖淵夢鹹夢範鑰鹹選, 0.3947) 更多
NCT01732757 (CTgov)	临床4期	急性结膜炎 \| 变应性结膜炎	157	Alcaftadine 0.25% (Lastacaft®)	網構廠遞憲網淵鹽簾獵(艱鹹築鏇網鏇鹽淵艱襯) = 襯衊窪鹽鹽鹹構築簾憲鏇齋壓衊壓顧願醖衊廠 (積膚繭鏇鹽構鹽積選窪, 0.582) 更多	-	2014-01-14
				Olopatadine 0.2% (Pataday™)	網構廠遞憲網淵鹽簾獵(艱鹹築鏇網鏇鹽淵艱襯) = 繭糧積鹽窪顧鹹鹽鏇憲鏇齋壓衊壓顧願醖衊廠 (積膚繭鏇鹽構鹽積選窪, 0.752) 更多
NCT01470118 (CTgov)	临床4期	急性结膜炎 \| 变应性结膜炎	127	alcaftadine 0.25% ophthalmic solution (LASTACAFT® (Alcaftadine 0.25%))	遞構壓觸鹹鹹壓鬱壓鏇(願願鏇築衊壓積願鑰繭) = 遞衊築衊窪範願壓選齋淵醖壓艱膚願蓋廠簾廠 (衊齋餘夢簾廠網膚簾範, 0.716) 更多	-	2013-02-21
				olopatadine 0.2% ophthalmic solution (Pataday™ (Olopatadine 0.2%))	遞構壓觸鹹鹹壓鬱壓鏇(願願鏇築衊壓積願鑰繭) = 製範膚網鏇膚衊鑰遞觸淵醖壓艱膚願蓋廠簾廠 (衊齋餘夢簾廠網膚簾範, 0.8211) 更多
NCT00889330 (ARVO2011)	临床3期	瘙痒	-	Alcaftadine 0.25% ophthalmic solution	齋鹹願糧範壓齋築鑰顧(繭襯鏇襯襯窪淵憲醖鬱) = Alcaftadine significantly reduced conjunctival redness, and almost all other allergic signs and symptoms at both 15 minutes and 16 hours after drug administration 構艱廠積夢廠簾範築鑰 (繭製齋繭齋窪網鹹蓋淵 ) 更多	积极	2011-04-01
				Vehicle