Tolbutamide

Small interfering RNA (siRNA) drugs, as a novel class of therapeutics based on the RNA interference (RNAi) mechanism, have achieved significant advancements in the biotechnology field in recent years. According to Maximize Market Research, the siRNA therapeutics market is projected to grow substantially from $12.7 billion in 2023 to $39.2 billion by 2029, with a remarkable compound annual growth rate (CAGR) of 25.3%. This growth is primarily driven by the widespread application of siRNA drugs in treating various diseases and the continuous advancements in delivery technologies. North America is currently the largest contributor to the siRNA drug market, particularly the United States, which had a market size of $902 million in 2023 and is expected to reach $5.221 billion by 2030, with a CAGR of 25.58%. The European market is also notable, with a size of $506 million in 2023, anticipated to grow to $4.541 billion by 2030, representing a CAGR of 34.51%. RNA interference mechanism via siRNA pathway1Delivery Methods for siRNA DrugsAs an emerging therapeutic approach, siRNA drugs offer high specificity and efficacy but face numerous challenges in practical application, especially regarding the efficient and safe delivery to target cells. Currently, the primary delivery systems include lipid nanoparticles (LNPs) and N-acetylgalactosamine (GalNAc) conjugation technology. LNPs enable siRNA delivery to various tissues, while GalNAc conjugation facilitates liver-specific delivery. With the advancement of nanotechnology and biomaterials science, more efficient delivery systems, such as polymer-based nanoparticles, exosomes, and viral vectors, are expected to be developed. These innovative technologies will further enhance the delivery efficiency and safety of siRNA therapeutics. Structure and Composition of Lipid Nanoparticles (LNPs)LNPs are multi-component lipid formulations designed to encapsulate siRNA, protecting it from degradation in the bloodstream and facilitating its transmembrane delivery into target cells. This delivery system demonstrates exceptional performance in enhancing the stability and targeting ability of siRNA and has been applied in several siRNA therapeutics, such as Patisiran. Ionizable lipids are among the most critical components of LNPs, exhibiting distinct charge characteristics under different pH conditions. Under acidic conditions (e.g., within endosomes), ionizable lipids carry a positive charge, promoting the formation of complexes with negatively charged siRNA. Under physiological pH, ionizable lipids are mostly neutral, helping to minimize immune responses and cytotoxicity. The molecular structure of ionizable lipids includes a charged head group, linker segments, and hydrophobic tails. The charge density and lipophilicity of the head group are crucial for LNP performance. For instance, the head groups of ALC-0315 and SM-102 contain terminal hydroxyl groups that reduce hydration effects, enhancing hydrogen bonding interactions with siRNA and improving transfection efficiency. Nucleotides derived nanoparticles2Cholesterol enhances the structural stability and rigidity of LNPs, helping to prevent siRNA leakage. The cholesterol content in LNPs typically ranges from 20% to 50%, and optimizing its proportion can improve LNP stability and delivery efficiency. Helper lipids, often neutral or cationic lipids, contribute to forming a stable lipid bilayer structure. Commonly used helper lipids include 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), which help maintain the structural integrity and stability of LNPs. Polyethylene glycol (PEG)-modified lipids increase the solubility and stability of LNPs, reducing recognition and clearance by the immune system and prolonging circulation time in the bloodstream. The hydrophilic shell provided by PEG-modified lipids forms a "stealth" barrier that prevents rapid clearance by the mononuclear phagocyte system (MPS), enhancing LNP bioavailability and delivery efficiency. The mechanism of action of LNPs in the application of siRNA drugsDuring LNP preparation, siRNA forms complexes with ionizable lipids via electrostatic interactions and is encapsulated within the lipid bilayer, effectively protecting the siRNA from degradation by nucleases in the plasma. PEG modification on the LNP surface extends circulation time and reduces immune recognition. LNPs deliver siRNA to specific cells or tissues via passive or active targeting mechanisms. Active targeting typically involves ligands such as GalNAc that bind specifically to receptors on target cell surfaces. Once LNPs are internalized by endocytosis, the acidic environment within endosomes activates ionizable lipids to disrupt the endosomal membrane, releasing siRNA into the cytoplasm. The siRNA then assembles with proteins like Argonaute-2 to form the RNA-induced silencing complex (RISC), which silences specific genes by cleaving or inhibiting the translation of target mRNA, achieving therapeutic effects. Cell type-specific aptamer-functionalized nanocarriers for targeted therapy2Despite significant advancements in LNP-mediated siRNA delivery, challenges remain, including improving delivery efficiency, reducing side effects, and achieving broader tissue targeting. Future research will focus on enhancing LNP stability and targeting specificity through the design and screening of new lipid components, such as ionizable lipids with higher pH sensitivity and lower toxicity, and biocompatible substitutes for helper lipids and cholesterol. Surface modifications with antibodies, peptides, or small molecule ligands could enable more precise cell or tissue-specific binding, minimizing off-target effects and improving safety and efficiency. The integration of diverse delivery technologies, such as microneedles or oral formulations, could broaden application scenarios, including inhalable or oral LNP systems for respiratory or gastrointestinal diseases. Additionally, advances in gene sequencing and bioinformatics could facilitate the design of personalized siRNA sequences and delivery strategies tailored to individual patient differences, driving the development of precision medicine. Selected examples of conjugate, linear, and branched type architectures for siRNA delivery2The Mechanism of GalNAc in siRNA Drug DeliveryGalNAc (N-acetylgalactosamine) is a naturally occurring sugar molecule with high affinity for the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes. ASGPR, which is highly expressed on liver cells and functions as an endocytic receptor, facilitates the transport of bound ligands into the cell. The strong binding affinity between GalNAc and ASGPR allows for specific targeting of hepatocytes, enabling efficient siRNA delivery. Although ASGPR is also expressed in certain other cell types, its expression level is significantly lower outside the liver, ensuring that GalNAc primarily targets hepatocytes and minimizes non-specific uptake by non-target cells. By chemical modification, GalNAc can be covalently attached to the 3' end of siRNA, forming a GalNAc-siRNA conjugate. This conjugate remains stable in circulation, resisting degradation, which ensures the siRNA reaches its target cells effectively. The covalent attachment process involves multiple steps, typically employing a linker that connects the GalNAc molecule to the siRNA's 3' end. The design of the linker is critical—it must ensure stable attachment while also allowing the siRNA to be released under intracellular conditions. Common linkers include disulfide bonds and ester bonds, which are designed to cleave in the cell’s reductive or acidic environments, thereby releasing the siRNA. Delivery of GalNAc-siRNA conjugates into hepatocytes3To enhance delivery efficiency, multiple GalNAc molecules are often attached to the 3' end of the sense strand of siRNA, creating a multivalent conjugate. Multivalent conjugates improve binding affinity to ASGPR and increase cellular uptake efficiency. Studies have shown that trivalent GalNAc conjugates offer the highest delivery efficiency and are widely used in practice. This multivalent design not only enhances siRNA delivery but also reduces the required dose, minimizing potential side effects. When GalNAc-siRNA conjugates enter the bloodstream, the GalNAc moiety binds specifically to ASGPR receptors on the surface of hepatocytes. Through clathrin-mediated endocytosis, the conjugates are internalized into cells, forming endosomes. As the endosomal environment acidifies, the decreasing pH triggers the cleavage or hydrolysis of the linker, such as disulfide or ester bonds, under reductive or acidic conditions, releasing the siRNA. To enhance siRNA escape from endosomes into the cytoplasm, researchers have developed various strategies, including incorporating cationic lipids or peptides to destabilize the endosomal membrane and optimizing the physicochemical properties of the conjugate, such as its size and shape. These methods collectively improve the endosomal escape efficiency, increase the bioavailability of siRNA in the cytoplasm, and significantly enhance the overall delivery efficiency of GalNAc-siRNA conjugates. GalNac-siRNA conjugate mediated gene silencing1GalNAc conjugation technology achieves efficient siRNA delivery through specific hepatocyte targeting, effective cellular uptake and endosomal escape, and precise gene-silencing mechanisms. This technology has been applied to multiple drugs, demonstrating significant potential. Future research will further optimize GalNAc conjugate design to enhance delivery efficiency, reduce side effects, and expand its application to more disease areas. Application of Polymer Nanoparticles (PNPs) in siRNA Drug DeliveryPNPs are an efficient siRNA delivery system that forms stable nano-complexes by binding with siRNA, protecting it from degradation. They enable precise delivery to specific cells or tissues via mechanisms including blood circulation, targeted delivery, cellular uptake, and gene silencing. Common polymers include cationic polymers (e.g., PEI), biodegradable polymers (e.g., PLGA), and dendrimers (e.g., PAMAM). Fabrication methods include self-assembly, emulsion-solvent evaporation, and microfluidics. PNPs have shown great potential in treating cancer, cardiovascular diseases, and viral infections. However, challenges remain, including delivery efficiency, cytotoxicity, and immune responses. Future research will focus on optimizing polymer structures, surface modifications, and multimodal delivery techniques to improve their safety and efficacy. ConclusionsiRNA-based drugs leverage RNA interference mechanisms, offering high specificity and efficacy in treating various diseases. However, achieving efficient and safe siRNA delivery to target cells remains a major challenge. While delivery systems such as LNPs, GalNAc conjugates, and PNPs have significantly improved siRNA stability and targeting, continuous optimization is necessary to further enhance delivery efficiency, reduce side effects, and expand the range of targetable tissues. Future research will aim to develop safer and more effective siRNA delivery methods, promoting broader clinical application of these innovative therapies. To explore market dynamics and the competitive landscape in ASO, click on Patsnap Synapse. For deeper insights into bio sequences and modifications, click on Patsnap Bio. Refrence 1.Dong Y, Siegwart DJ, Anderson DG. Strategies, design, and chemistry in siRNA delivery systems. Adv Drug Deliv Rev. 2019 Apr;144:133-147. doi: 10.1016/j.addr.2019.05.004. Epub 2019 May 15. PMID: 31102606; PMCID: PMC6745264.2.Zhou J, Rossi J. Aptamers as targeted therapeutics: current potential and challenges. Nat Rev Drug Discov. 2017 Mar;16(3):181-202. doi: 10.1038/nrd.2016.199. Epub 2016 Nov 3. Erratum in: Nat Rev Drug Discov. 2017 Jun;16(6):440. doi: 10.1038/nrd.2017.86. PMID: 27807347; PMCID: PMC5700751.3.Springer AD, Dowdy SF. GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics. Nucleic Acid Ther. 2018 Jun;28(3):109-118. doi: 10.1089/nat.2018.0736. Epub 2018 May 24. PMID: 29792572; PMCID: PMC5994659.

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. 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[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↓