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Article(id=1193523095899173173, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1193523095437799732, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0797, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1723996800000, receivedDateStr=2024-08-19, revisedDate=1725897600000, revisedDateStr=2024-09-10, acceptedDate=null, acceptedDateStr=null, onlineDate=1762487680648, onlineDateStr=2025-11-07, pubDate=1739289600000, pubDateStr=2025-02-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762487680648, onlineIssueDateStr=2025-11-07, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762487680648, creator=13701087609, updateTime=1762487680648, updator=13701087609, issue=Issue{id=1193523095437799732, tenantId=1146029695717560320, journalId=1189982191388893191, year='2025', volume='60', issue='2', pageStart='245', pageEnd='532', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1762487680538, creator=13701087609, updateTime=1764224912893, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200809576107987438, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1193523095437799732, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200809576107987439, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1193523095437799732, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=245, endPage=259, ext={EN=ArticleExt(id=1193523096134054198, articleId=1193523095899173173, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Brief analysis on the fixed dose composition, columnId=1190335349059588909, journalTitle=Acta Pharmaceutica Sinica, columnName=Professionals Forum, runingTitle=null, highlight=null, articleAbstract=

New drugs approved by authorities are classified into two categories: new molecular entities (NME) and fixed dose combination (FDC) formulations, both of which are documented by scientific experiments and clinical trials. Complex diseases frequently possess multifactorial causes, and drugs that only focus on a single target may not achieve satisfactory results; moreover, it is difficult to achieve full optimization of the pharmacodynamics, pharmacokinetics, safety, and patient compliance for a drug. Therefore, combinatorial remedies with two (or more) drugs at a fixed dose may provide patients with better treatment options. Based upon understanding the various molecular regulation of pathological processes and principles of drug action, clinicians and pharmacologists are able to design new FDC to achieve optimum efficiency in clinical practice. In this sense the significance of FDC is no less than NME, because it is closer to clinical practice and directly meets the needs of patients. This article briefly analyzes the development of FDC from the microscopic characteristics of pathology and the molecular mechanism of drug action with influential examples.

, correspAuthors=Zong-ru GUO, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2025 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Zong-ru GUO), CN=ArticleExt(id=1193524018125959777, articleId=1193523095899173173, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=简析固定剂量复方药物的研制, columnId=1190335349206389552, journalTitle=药学学报, columnName=专家论坛, runingTitle=null, highlight=null, articleAbstract=

药监部门审定的新药分两类, 一是新分子实体(new molecular entities, NME), 另一是固定剂量复方(fixed dose combination, FDC) 制剂, 二者都是经科学实验和临床验证确定下来的安全有效的治疗手段。复杂难治疾病具有多因素病因, 只针对单一靶标施以治疗的药物未必达到满意效果; 而且一个药物的药效、药代、安全和患者依从达到全优化也是勉为其难, 因而用两个(或更多) 药物以固定的剂量组成复方药物可为患者提供更优良的治疗手段。临床和药理学家在洞悉病理过程的各个环节和分子调控的基础上, 在临床实践中把控药物的作用机制和药效/药代/物化配伍等环节的优化, 创造出FDC, 其意义不亚于NME, 因为FDC更贴近于临床, 直接满足患者的需求。本文以有影响的实例, 从病理的微观特征与药物作用的分子机制入手, 对研制FDC作简要的分析。

, correspAuthors=郭宗儒, authorNote=null, correspAuthorsNote=
*郭宗儒, E-mail:
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Discovery of a cyclic boronic acid β-lactamase inhibitor (RPX7009) with utility vs class A serine carbapenemases [J] J Med Chem, 2015, 58: 3682-3692., articleTitle=null, refAbstract=null), Reference(id=1194709803885896588, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193523095899173173, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=null, journalName=null, refType=null, unstructuredReference=Castanheira M, Rhomberg PR, Flamm RK, et al. Effect of the beta-lactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase-producing Enterobacteriaceae [J]. Antimicrob Agents Chemother, 2016, 60: 5454-5458., articleTitle=null, refAbstract=null), Reference(id=1194709803961394061, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193523095899173173, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=null, journalName=null, refType=null, unstructuredReference=Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19 [J]. Science, 2021, 374: 1586-1593., articleTitle=null, refAbstract=null), Reference(id=1194709804028502926, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193523095899173173, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[33], rfOrder=32, authorNames=null, journalName=null, refType=null, unstructuredReference=Sevrioukova IF, Poulos TL. Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir [J]. 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FDCName (dosage form)CompositionTargetIndicationSale/＄ billion
1Biktarvy (Tab)BictegravirHIV-1 integraseHIV infection11.84
EmtricitabineReverse transcriptase
Enofovir alafenamideReverse transcriptase
2Trikafta (Tab)ElexacaftorCFT regulatorCystic fibrosis8.94
Tezacaftor
Ivacaftor
3Entresto (Tab)SacubitrilNeprilysin inhibitorHeart failure6.04
ValsartanAT1 inhibitor
4Trelegy Ellipta (Inhale)UmeclidiniumLAMACOPD2.38
VilanterolLABA
FuticasoneGlucocorticoid receptor
5Symbicort (Inhale)BudesonideGlucocorticoid receptorCOPD2.36
Formoterolβ2-Adrenergic receptorAsthma
6Genvoya (Tab)ElvitegravirHIV-1 integraseHIV infection2.06
CobicistatCYP3A4/5/7 inh
EmtricitabineReverse transcriptase
Tenofovir alafenamideReverse transcriptase
7Descovy (Tab)EmtricitabineReverse transcriptaseHIV infection1.99
Tenofovir alafenamideReverse transcriptase
8Dovato (Tab)DolutegravirHIV-1 integraseHIV infection1.96
LamivudineReverse transcriptase
9Tafinlar + Mekinist (Tab)DabrafenibBRAFV600ENSCLC1.92
TrametinibMEK
10Prezista (Tab)DarunavirHIV proteaseHIV infection1.85
CobicistatCYP3A4/5/7 inh
11Trajenta (Tab)LinagliptinDPP-4 inhType 2 diabetes1.81
MetforminPRKAB1 agonist
12Epclusa (Tab)SofosbuvirRdRPHCV1.54
VelpatasvirNS5A polymerase
13Mavyret (Tab)GlecaprevirNS3/4A protease inhHCV1.43
PibrentasvirHCV NS5A inh
14Odefsey (Tab)EmtricitabineReverse transcriptaseHIV infection1.35
RilpivirineReverse transcriptase
Tenofovir alafenamideReverse transcriptase
15Janumet (Tab)CitagliptinDPP-4Type 2 diabetes1.18
MetforminPRKAB1 agonist
16Sulperazon (Inj)CefoperazonePBBsBacterial infections0.76
Sulbactamβ-Lactamase
17YAZ (Tab)DrospirenoneAR/MR antag, PRagonistContraceptive0.73
Ethinyl estradiolSuppressing gonadotrophic hormone
18JulucaDolutegravirHIV-1 integraseHIV infection0.71
RilpivirineReverse transcriptase
19ExfolgeAmlodipineCa2+ channel antagHypotensor0.71
ValsartanAT1R inh
20Augmentin (Tab)AmoxillinePBBsBacterial infections0.68
Clavulanateβ-Lactamase
21Briztri (Inhal)BudesonideGlucocorticoid receptorCOPD0.668
GlycopyrrolateAnticholinergic
FormoterolLABA
22Diovan (Tab)ValsartanAT1R inhHypotensor0.61
HydrochlorotiazideThiazide-sensitive sodium-chloride cotransporter
23Lonsurf (Tab)TrifluridineDNA polymeraseColorectal or gastric cancer0.53
TipiracilThymidine phosphorylase
24Symtuza (Tab)DarunavirHIV proteaseHIV infection0.53
EmtricitabineReverse transcriptase
Tenofovir alafenamideEmtricitabine
CobicistatCYP3A4/5/7 inh
25Atozet (Tab)AtorvastatinHMG CoE A reductaseReduce cholesterol0.52
EzetimibeNiemann Pick C1 like 1
26Zavicefta (Inj)CeftazidimePBBsBacterial infections0.52
Avibactamβ-Lactamase
27Duodopa (intestinal gel)LevodopaD1 receptor agonistParkinson Dis0.47
CarbidopaAromatic amino acid decarboxylase inhibitor
28Lokelma (Susp)Sodium zirconium cyclosilicateHyperkalemia0.41
29OrkambiLumacaftorCFTR correctorCystic fibrosis0.33
IvacaftorCFTR potentiator
30PaxlovidNirmatrelvir3C-like protease (3CLPRO)COVID-19-
RitonavirCYP3A4 Inh
), ArticleFig(id=1194709800450761579, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1193523095899173173, language=CN, label=Table 1, caption=

Fixed dose combination (FDC) formulations of top 200 drug sales in 2023

, figureFileSmall=null, figureFileBig=null, tableContent=
FDCName (dosage form)CompositionTargetIndicationSale/＄ billion
1Biktarvy (Tab)BictegravirHIV-1 integraseHIV infection11.84
EmtricitabineReverse transcriptase
Enofovir alafenamideReverse transcriptase
2Trikafta (Tab)ElexacaftorCFT regulatorCystic fibrosis8.94
Tezacaftor
Ivacaftor
3Entresto (Tab)SacubitrilNeprilysin inhibitorHeart failure6.04
ValsartanAT1 inhibitor
4Trelegy Ellipta (Inhale)UmeclidiniumLAMACOPD2.38
VilanterolLABA
FuticasoneGlucocorticoid receptor
5Symbicort (Inhale)BudesonideGlucocorticoid receptorCOPD2.36
Formoterolβ2-Adrenergic receptorAsthma
6Genvoya (Tab)ElvitegravirHIV-1 integraseHIV infection2.06
CobicistatCYP3A4/5/7 inh
EmtricitabineReverse transcriptase
Tenofovir alafenamideReverse transcriptase
7Descovy (Tab)EmtricitabineReverse transcriptaseHIV infection1.99
Tenofovir alafenamideReverse transcriptase
8Dovato (Tab)DolutegravirHIV-1 integraseHIV infection1.96
LamivudineReverse transcriptase
9Tafinlar + Mekinist (Tab)DabrafenibBRAFV600ENSCLC1.92
TrametinibMEK
10Prezista (Tab)DarunavirHIV proteaseHIV infection1.85
CobicistatCYP3A4/5/7 inh
11Trajenta (Tab)LinagliptinDPP-4 inhType 2 diabetes1.81
MetforminPRKAB1 agonist
12Epclusa (Tab)SofosbuvirRdRPHCV1.54
VelpatasvirNS5A polymerase
13Mavyret (Tab)GlecaprevirNS3/4A protease inhHCV1.43
PibrentasvirHCV NS5A inh
14Odefsey (Tab)EmtricitabineReverse transcriptaseHIV infection1.35
RilpivirineReverse transcriptase
Tenofovir alafenamideReverse transcriptase
15Janumet (Tab)CitagliptinDPP-4Type 2 diabetes1.18
MetforminPRKAB1 agonist
16Sulperazon (Inj)CefoperazonePBBsBacterial infections0.76
Sulbactamβ-Lactamase
17YAZ (Tab)DrospirenoneAR/MR antag, PRagonistContraceptive0.73
Ethinyl estradiolSuppressing gonadotrophic hormone
18JulucaDolutegravirHIV-1 integraseHIV infection0.71
RilpivirineReverse transcriptase
19ExfolgeAmlodipineCa2+ channel antagHypotensor0.71
ValsartanAT1R inh
20Augmentin (Tab)AmoxillinePBBsBacterial infections0.68
Clavulanateβ-Lactamase
21Briztri (Inhal)BudesonideGlucocorticoid receptorCOPD0.668
GlycopyrrolateAnticholinergic
FormoterolLABA
22Diovan (Tab)ValsartanAT1R inhHypotensor0.61
HydrochlorotiazideThiazide-sensitive sodium-chloride cotransporter
23Lonsurf (Tab)TrifluridineDNA polymeraseColorectal or gastric cancer0.53
TipiracilThymidine phosphorylase
24Symtuza (Tab)DarunavirHIV proteaseHIV infection0.53
EmtricitabineReverse transcriptase
Tenofovir alafenamideEmtricitabine
CobicistatCYP3A4/5/7 inh
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EzetimibeNiemann Pick C1 like 1
26Zavicefta (Inj)CeftazidimePBBsBacterial infections0.52
Avibactamβ-Lactamase
27Duodopa (intestinal gel)LevodopaD1 receptor agonistParkinson Dis0.47
CarbidopaAromatic amino acid decarboxylase inhibitor
28Lokelma (Susp)Sodium zirconium cyclosilicateHyperkalemia0.41
29OrkambiLumacaftorCFTR correctorCystic fibrosis0.33
IvacaftorCFTR potentiator
30PaxlovidNirmatrelvir3C-like protease (3CLPRO)COVID-19-
RitonavirCYP3A4 Inh
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简析固定剂量复方药物的研制
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郭宗儒 *
药学学报 | 专家论坛 2025,60(2): 245-259
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药学学报 | 专家论坛 2025, 60(2): 245-259
简析固定剂量复方药物的研制
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郭宗儒*
作者信息
  • 中国医学科学院、北京协和医学院药物研究所, 北京 100050

通讯作者:

*郭宗儒, E-mail:
Brief analysis on the fixed dose composition
Zong-ru GUO*
Affiliations
  • Institute of Materia Medica, Chinese Academy of Medcal Sciences and Peking Union Medical College, Beijing 100050, China
出版时间: 2025-02-12 doi: 10.16438/j.0513-4870.2024-0797
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摘要
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药监部门审定的新药分两类, 一是新分子实体(new molecular entities, NME), 另一是固定剂量复方(fixed dose combination, FDC) 制剂, 二者都是经科学实验和临床验证确定下来的安全有效的治疗手段。复杂难治疾病具有多因素病因, 只针对单一靶标施以治疗的药物未必达到满意效果; 而且一个药物的药效、药代、安全和患者依从达到全优化也是勉为其难, 因而用两个(或更多) 药物以固定的剂量组成复方药物可为患者提供更优良的治疗手段。临床和药理学家在洞悉病理过程的各个环节和分子调控的基础上, 在临床实践中把控药物的作用机制和药效/药代/物化配伍等环节的优化, 创造出FDC, 其意义不亚于NME, 因为FDC更贴近于临床, 直接满足患者的需求。本文以有影响的实例, 从病理的微观特征与药物作用的分子机制入手, 对研制FDC作简要的分析。

固定剂量复方制剂  /  药效学  /  药动学  /  患者依从性

New drugs approved by authorities are classified into two categories: new molecular entities (NME) and fixed dose combination (FDC) formulations, both of which are documented by scientific experiments and clinical trials. Complex diseases frequently possess multifactorial causes, and drugs that only focus on a single target may not achieve satisfactory results; moreover, it is difficult to achieve full optimization of the pharmacodynamics, pharmacokinetics, safety, and patient compliance for a drug. Therefore, combinatorial remedies with two (or more) drugs at a fixed dose may provide patients with better treatment options. Based upon understanding the various molecular regulation of pathological processes and principles of drug action, clinicians and pharmacologists are able to design new FDC to achieve optimum efficiency in clinical practice. In this sense the significance of FDC is no less than NME, because it is closer to clinical practice and directly meets the needs of patients. This article briefly analyzes the development of FDC from the microscopic characteristics of pathology and the molecular mechanism of drug action with influential examples.

fixed dose composition  /  pharmacodynamics  /  pharmacokinetics  /  patient compliance
郭宗儒. 简析固定剂量复方药物的研制. 药学学报, 2025 , 60 (2) : 245 -259 . DOI: 10.16438/j.0513-4870.2024-0797
Zong-ru GUO. Brief analysis on the fixed dose composition[J]. Acta Pharmaceutica Sinica, 2025 , 60 (2) : 245 -259 . DOI: 10.16438/j.0513-4870.2024-0797
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新药创制在于满足患者和临床的需求, 为此, 不拘一格地涌现出不同形式的疗法, 例如细胞疗法、生物大分子和小核酸、生物大分子与小分子结合物(ADC, 缀合蛋白等), 新分子实体(new molecular entities, NME) 还发明了例如蛋白靶向降解嵌合体(PROTAC)、分子胶(molecular glue) 和共价键药物等新的结构类型, 提供患者以更多的治疗选择。
然而复杂难治性疾病往往是多因素引发的病理状态, 例如高血压、糖尿病和某些感染性疾病, 基于靶标为中心创制的新药, 虽然经过一系列的概念验证(proof-in-conception) 得以批准上市, 但NME单一药物疗法未必能获得满意疗效, 更何况病原体的基因变异逃逸治疗而降效或失效。此外, 尽管NME经多轮优化和临床验证而上市, 但让一个化学结构容纳药效/药代/安全性等全部呈最优化状态, 也是勉为其难。因而, 为了满足临床患者的需求, 临床和药理学家通过研究和实践治疗, 对一些疾病形成联合用药的治疗原则, 针对两(或多)个因素干预疾病过程, 可以获得强于单药的治疗效果。经过反复的循证医学(evidence-based medicine) 发展成为固定剂量复方(fixed-dose combination, FDC) 的治疗药物。FDC是与NME并列的新药, 创新的内容虽然不同, 作为新药都须经过国家药监部门审核, 用临床充分的数据表明FDC是优化的药物组合而被批准。就满足临床与患者的需求而言, FDC与NME有同样重要的意义。固定剂量复方药物在某种意义上类似于NME中的双(多) 功能分子, FDC靶向于疾病的两(多) 个病理环节, 有明确的作用机制。
1 既往FDC的简要回眸
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固定剂量的复方制剂早在上世纪中叶就已存在, 这是临床学家在实践中发展成的治疗策略, 发展至今更完善化和制度化了, 纳入为国家法定药物。
1.1 丙磺舒药代助力青霉素的抗菌作用
20世纪50年代丙磺舒(probenecid) 治疗痛风病, 是由于抑制肾近曲小管对尿酸的重吸收, 从而增加尿液中尿酸排泄量, 降低了血清尿酸水平, 因而用来治疗痛风病。丙磺舒还竞争性地抑制肾小管对各种弱有机酸的分泌, 例如青霉素等含酸性基团的药物, 由于难以尿液排泄, 导致酸性药物在血浆中滞留, 浓度增加。作用机制是抑制了体内广泛分布的有机阴离子转运蛋白(organic anion transporters, OAT), OAT的功能是与内/外源性有机阴离子形成轭合物(conjugate), 对药物与毒物排泄起重要作用[1]。如今较少用丙磺舒作为延长血药浓度的手段, 也没有固定剂量的复方制剂, 但可作为一些需维持长期高浓度“西林”和“头孢”类药物血浓度辅助治疗, 如亚急性感染性心内膜炎和淋病等。
1.2 碳酸氢钠促进磺胺溶解
当今基本退出抗菌舞台的磺胺药, 在20世纪50/60年代是抗感染主打药物。磺胺类药物极性较强, 但水溶性低, 在酸性环境中容易析出结晶, 以至堵塞尿道甚至引发肾病。即使新一代的磺胺分子如磺胺甲噁唑也因磺酰基和异噁唑的双边拉电子效应使-NH-呈弱酸性而析晶。为此, 磺胺治疗同时服用碳酸氢钠, 尿液的微碱性有利于磺胺的溶解。然而未曾有二合一的FDC片剂, 可能是片重过大不易服用的缘故。
1.3 治疗普通感冒的复方阿司匹林片(APC)
20世纪50/60年代的APC是最常用的普通感冒治疗药, APC片剂含3种药: 抗炎止痛的阿司匹林(0.22 g)、解热药非那西丁(0.15 g) 和缓解头痛的咖啡因(35 mg), 组成的非处方药, 应用效果显著。但后来发现有潜在的毒性, 是因为非那西丁在体内去乙酰和去乙基的代谢产物, 氧化生成亚胺醌的致癌作用, 长期服用引起肾癌和膀胱癌, APC已被禁用。
现今治疗感冒的FDC是氨酚烷胺片, 每片含对乙酰氨基酚250 mg、盐酸金刚烷胺100 mg、人工牛黄10 mg、咖啡因15 mg和马来酸氯苯那敏2 mg。弃用了APC中解热止痛不明显的阿司匹林, 用乙酰氨基酚替换非那西丁, 增添了抗感冒药金刚烷胺和抗过敏药氯苯那敏。
2 固定剂量复方制剂的特征
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许多疾病治疗的过程中需要应用FDC, 尤其在控制感染性疾病、肿瘤、高血压、心血管病、糖尿病和高血脂症方面, FDC的效果比单药明显。联合使用的每个药物对整体治疗效果都是有确定的贡献, 表现在疗效上的协同或叠加作用, 或改善了治疗药的药代动力学性质例如半衰期延长, 服用剂量或频次减少, 以及消除或降低不良反应等, 这些不仅有临床数据的支持, 而且患者表现对FDC的依从性。为了达到以上(某方面) 的要求, 设计的FDC处方中的每个药物应有明确的作用机制支持, 有明确的靶标或作用环节。
在药物经济学方面FDC比同时使用几种药品更为方便合理, 简化了药品流通环节, 提高了患者用药的依从性。
3 全球销量较大的固定剂量复方制剂
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2023年全球在小分子药物、肽类药物、生物药物单药以及FDC制剂的销售量前200名中, 有29款是FDC制剂, 占比14.5%, 大都集中在抗感染、高血压、糖尿病和心血管疾病的治疗领域[2]。表 1列出了这些FDC的名称、组成和适应症, 此外还列出了2023年批准上市的抗COVID-19药物帕罗韦德(Paxlovid), 曾于2021年12月新冠高发期FDA批准为紧急授权申请, 2022年销量逾百亿美元。
表 1中的数据是来自全球的统计, 虽然有营销方面的因素, 但治疗效果有可信性。30个FDC制剂中, 15款是抗感染药物(抗病毒12, 抗菌3), 心血管类药物5款(含降脂和降高血钾症), 降糖药3款, 慢性阻塞性肺疾病药物3款, 抗癌药2款等, 反映出对感染性疾病的发病和治疗机制的认识有坚实的基础。下面对代表性复方制剂作简要的讨论。
4 简析代表性FDC的组方和特征
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4.1 阻断HIV-1增殖的三联复方片剂Biktarvy
HIV-1病毒引发艾滋病, 破坏人体免疫系统。病毒在人体细胞内的复制过程有5个步骤: 吸附和融合、逆转录、整合、转录和翻译、装配和释放。简述如下: ①吸附和融合: HIV病毒外膜有两种糖蛋白gp120和gp41。入侵后gp120与人体细胞表面受体CD4结合, 构象改变后再与辅助宿主受体CCR5/CXCR4等结合, 构象进一步改变, 使得病毒gp41暴露, 导致病毒包膜和宿主细胞膜融合, 病毒核衣壳穿入细胞, 然后病毒核酸及复制所需的逆转录酶、整合酶、蛋白酶等进入人体细胞。②逆转录: HIV是单链RNA病毒, 进入人体细胞后以单链RNA为模板, 在逆转录酶作用下合成DNA; 再以单链DNA为模板, 在DNA聚合酶的作用下合成双链DNA。③整合: 包含2个步骤, a. HIV-DNA 3′端的处理。双链DNA在整合酶作用下分别被切掉3′端的2个核苷酸, 形成整合前复合体(PIC); b. 转移反应。PIC进入细胞核后, 整合酶继续对3′端切割, 同时对人体细胞染色体的DNA做一个交错切口, 为HIV-DNA的嵌入“打开”间隙, 最后整合酶将HIV DNA嵌入到宿主DNA中, 两片DNA连接在一起。这种整合的双链DNA即为前病毒。④转录和翻译: 前病毒被活化作自身转录, 病毒DNA为模板转录合成RNA, 一部分RNA加帽加尾成为病毒的自身基因组; 另一部分RNA则拼接成为病毒mRNA, 在细胞核蛋白体上翻译成多聚前体蛋白, 后者在蛋白酶作用下被剪接成小分子蛋白质, 即病毒所需的结构蛋白和功能蛋白。⑤装配和释放: RNA与Gag蛋白结合装配成核壳体, 通过芽生方式从胞质膜释放时获得病毒体的胞膜, 形成成熟的病毒颗粒。
这5个环节都可进行药物干预, 研制出针对不同靶标的抑制剂。
2018年在美国上市并于2020年在中国批准上市的比克恩丙诺片(Biktarvy, 必妥维) 是由一个整合酶链转移抑制剂和两个逆转录酶抑制剂组成的三联复方单片制剂, 每片比克恩丙诺片含比克替拉韦(1, bictegravir) 50 mg、恩曲他滨(2, emtricitabine) 200 mg、丙酚替诺福韦(3, tenofovir alafenamide) 25 mg。
比克替拉韦(1) 是整合酶链转移第二代抑制剂[3], 由于HIV-1编码酶发生了Gln148His和Gly140Ser的变异使第一代抑制剂拉替拉韦(raltegravir) 不能阻断病毒复制, 而1阻止HIV-1整合到宿DNA和HIV-1前蛋白的转化。1的体外活性EC50 = 5.0 nmol·L-1, 生物利用度F > 70%, 半衰期t1/2 = 18 h. 图 1是比克替拉韦与变异的整合酶复合物晶体结构图, 结合特征仍然保持了与镁离子的最佳配位[4]。恩曲他滨和丙酚替诺福韦都是逆转录酶抑制剂, 分别为胞嘧啶核苷和腺嘌呤核苷酸类似物, 二者在体内三磷酸化后参入到HIV-1的核酸结构中。3的结构已预构了一磷酸基, 但同时带来两个负电荷, 分别用苯酚和丙氨酸异丙酯掩盖负电荷, 故而是个前药, 可口服吸收, 在体内脱去保护基再经两次磷酸化而起效[5]。
临床试验表明, 基于整合酶抑制剂的复方单片制剂必妥维(Biktarvy) 能够更快地降低病毒载量, 安全性高, 与其他药物的相互作用较少, 而且单一片剂方便吞服。2023年销售额达到118亿美元。
4.2 治疗慢阻肺的三联吸入剂
4.2.1 慢性阻塞性肺病及其治疗环节
慢性阻塞性肺病(chronic obstructive pulmonary disease, COPD) 简称慢阻肺, 是一种以气流阻塞为特征的慢性支气管炎和(或) 肺气肿, 可进一步发展为肺心病和呼吸衰竭, 为常见慢性疾病, 致残率和病死率很高。临床治疗慢阻肺常用支气管扩张剂, 主要是抗胆碱能药物和β2受体激动剂, 通过吸入方式用药, 因为这样起效快, 全身不良反应小。
慢阻肺患者的迷走神经张力较高, 张力越高, 支气管基础口径越窄, 通气越受阻。此外, 各种刺激均能传递到迷走神经末梢, 反射性地引起支气管痉挛。抗胆碱能药物可抑制迷走神经, 从而控制支气管痉挛的发生。
4.2.2 长效胆碱能受体阻断剂
毒蕈碱样胆碱能受体阻断剂常用作慢阻肺治疗药, 乌美溴铵(4, umeclidinium bromide) 作为长效毒蕈碱样受体阻断剂(LAMA), 2013年以单药吸入粉雾剂上市, 治疗慢阻肺[6, 7]。
4.2.3 长效β2-肾上腺素能激动剂
长效β2-肾上腺素能激动剂(LABA) 是另一类治疗慢阻肺的有效药物。维兰特罗(5, vilanterol) 是选择性LABA。其作用机制是激活细胞内腺苷酸环化酶, 催化三磷酸腺苷(ATP) 转化为环状-3′, 5′-一磷酸腺苷(cAMP)。cAMP的增加松弛支气管平滑肌并抑制肺肥大细胞释放超敏反应介质。服用后作用持续24 h, 单用每日一吸治疗COPD和哮喘[8]。维兰特罗与乌美溴铵制成的二联FDC, 称作Anoro Ellipta (乌美溴铵/维兰特罗62.5 µg/25 µg) 于2013年上市, 同时吸入LAMA和LABA治疗慢性阻塞性肺疾病的效果强于单一用药[9]。后继研制的COPD的FDC是三联吸入剂。
4.2.4 抗炎作用的糖皮质激素
炎症是哮喘发病机制的重要因素。糖皮质激素广泛作用于多种炎症细胞类型(例如肥大细胞、嗜酸性粒细胞、中性粒细胞、巨噬细胞、淋巴细胞)和介质(例如组胺、类花生酸、白三烯、细胞因子)。体外/内模型证明糠酸氟替卡松(6, fluticasone furoate) 的作用包括激活糖皮质激素反应元件, 抑制促炎转录因子(如NFκB) 以及抑制抗原诱导的致敏大鼠肺嗜酸性粒细胞增多症。
6作为人工合成的糖皮质类激素诱导抗炎因子的合成, 导致快速、强效而非特异性的抗炎作用, 对各种炎症都有治疗效果, 而且6通过诱导针对炎症而合成的蛋白质可抑制白细胞炎症蛋白酶的生成, 阻止炎症的发生。此外, 6还抑制炎性因子的合成和诱导炎性细胞的凋亡而起到抗炎作用。6是强效的糖皮质类激素, 对受体的结合亲和力是地塞米松的30倍、丙酸氟替卡松的1.7倍[10]。
4.2.5 3种不同组合的FDC
GSK对以上3个药物以不同的组合研制了3种治疗慢阻肺的吸入粉雾剂: Breo Ellipta是维兰特罗/糠酸氟替卡松固定剂量二联粉雾剂, 剂量25/100 μg, 经特定的吸入装置定量吸入干粉。每日一吸。同年又上市了二联的Anoro Ellipta, 为维兰特罗/乌美溴铵固定剂量为25/62.5 μg, 也是每日一吸。再后又于2017年上市的三合一的FDC制剂, 通用名为氟替美维吸入粉雾剂(商品名Trelegy Ellipta), 维兰特罗/乌美溴铵/糠酸氟替卡松固定剂量为25/62.5/100 μg, 通过GSK公司独有的易纳器(Ellipta®) 干粉吸入装置每日一吸用药。其改善患者的生活质量和肺功能明显, 降低慢阻肺患者急性加重显著优于二联FDC[11]。表 2列出了以上3种FDC制剂的组成、剂量和上市时间。
4.3 治疗心衰的Entresto
既往治疗心力衰竭药物是用血管紧张素转化酶抑制剂“普利”类或血管紧张素Ⅱ受体拮抗剂“沙坦”类药物, 是抑制肾素-血管紧张素-醛固酮系统(RAS) 的策略。
体内还有另一个心脏神经内分泌系统, 即脑啡肽酶-利钠肽酶-心房钠肽(ANF) 降解系统, ANF具有利尿和舒张血管效应, 调整血压、体液容量和电解质平衡的功能。ANF与RAS功能是两个独立系统, Entresto是由沙库巴曲(7, sacubitril) 和缬沙坦(8, valsartan) 组成的FDC制剂, 分别作用于这两个系统的蛋白。7是保护ANF的脑啡肽酶抑制剂。
心房钠肽(9) 是心肌细胞产生的28肽, 分泌到外周血中, 半衰期很短(内分泌激素都很短, 调节功能的要求), 是被脑啡肽酶或称中性内切酶(neprilysin, NEP) 水解所致, 所以抑制NEP得以使内源性ANF肽维持在一定的水平, 保护心脏血管。诺华公司研制的沙库巴曲是NEP强效抑制剂, 作为前药, 在制成FDC时加入的NaOH成为钠盐而起效[12]。
缬沙坦也是诺华公司研制的, 作为AT1受体拮抗剂治疗高血压和心力衰竭, 上市于1996年。基于7和8的体内外活性的相近(相对分子质量也相近, 但靶标不同), 以等摩尔量制成FDC制剂, 每片含有沙库巴曲49 mg, 缬沙坦51 mg, 于2015年上市。该FDC生成超分子结构, 但仍保持各自的功能。Entresto治疗心力衰竭效果与标准疗法比较, 显著地降低心衰患者的死亡率, 被认为是近40年来心衰治疗药的重大突破[13], 2023年全球销售额达到60亿美元, 2024上半年销售37.7亿美元。
Entresto是共晶复合物, X射线衍射分析提示, 每个共晶体由6个沙库巴曲负离子, 6个缬沙坦负离子, 18个钠离子(用的氢氧化钠量不是化学计量) 和15个水分子构成, 分子式为C288H330N36Na18O48·15H2O, 相对分子质量为5 748.03, 为白色六边形片状结晶性粉末, 熔点138 ℃。复合物在固态和pH 5~7的水溶液是稳定的。
作为超分子的钠复合物, 18个钠离子与来自沙库巴曲和缬沙坦的12个羧基和18个羰基的氧原子, 以及15个水分子中的13个氧原子形成配位结构, 如图 2所示。超分子还由于形成氢键网络而稳定化。缬沙坦的四唑环没有与钠形成离子键, 而是与沙库巴曲的酰氨NH形成氢键[14]。
沙库巴曲作为新分子实体, 是以复合制剂被批准面市的, 两个主成分的药理作用各司其职, 功能却呈互补性, 使得Entresto在治疗心衰患者成为划时代的突破。在剂量设计和分子结构上也很有特色: 两个成分的治疗剂量恰好是等摩尔量; 与钠离子形成配位键结合以及分子内和分子间的氢键网络, 构成了稳定的超分子结合的共晶结构, 并非简单的物理混合物[15]。
4.4 治疗艾滋病的四联药物Genvoya
吉利德公司于2015年上市的治疗HIV-1感染的FDC药品Genvoya是由4个药物组成: 埃替格韦(10, elvitegravir)、可比司他(11, cobicistat)、恩曲他滨(2, emtricitabine) 和丙酚替诺福韦(3, tenofovir alafenamide)。
埃替格韦是HIV-1整合酶链转移抑制剂, 是病毒复制所必需的酶系。抑制整合酶可阻止HIV-1 DNA整合到宿主DNA中, 从而阻断HIV-1前病毒的形成和病毒传播。埃替格韦是继首创药雷特格韦(默克公司) 之后FDA于2012年批准吉利德公司的整合酶抑制剂, 日服一次。在体内被CYP3A氧化代谢(继之葡醛酸苷化) 而失活, 所以与CYP3A抑制剂合用, 可延长作用时间[16]。
第2个组分也是由吉利德公司研制的, 于2014年批准上市, 作为细胞色素P450 3A抑制剂, 本身没有抗HIV活性(这与利托那韦不同), 但与埃替格韦联用, 能使后者在较低剂量下达到较高血药浓度, 从而提高了对病毒的抑制作用并减少了不良反应[17]。
第3和4个组分恩曲他滨(2) 和丙酚替诺福韦(3) 都是HIV逆转录酶抑制剂, 需在体内活化抑制病毒DNA的反转录化, 已于4.1节中叙述。
Genvoya所含有的整合酶抑制剂埃替福韦是新结构类型的“福韦”, 在体内血液中的药物水平低于HIV-1复制的细胞内水平, 这种选择性分布显著降低了不良反应[18]。
4.5 治疗肺癌两个环节的复方药
4.5.1 MAPK信号通路
哺乳动物细胞信号系统中有个丝裂原活化蛋白激酶(MAPK) 通路, 其中RAF驱动基因是关键因子。在静息细胞中, RAF处于胞浆中。当生长因子与细胞表面受体酪氨酸激酶(receptor tyrosine kinases, RTKs) 结合时(EGFR是最早发现的RTK), 受体-配体相互作用促进细胞内部RTK二聚化、活化和自体磷酸化, 活化的RTK促进Ras上GTP与GDP交换, RAS-GTP可以直接与RAF蛋白结合, 将RAF从细胞质中迁移募集到细胞膜上, 使RAF成为一种活性激酶。随后, 活化的RAF对其下游底物(即MEK和ERK) 进行一系列磷酸化反应, 启动经典MAPK途径的活化, 调节细胞生长和增殖、分化、存活和迁移(图 3)。
非小细胞肺癌(NSCLC) 约占肺癌的85%。在NSCLC中BRAF基因突变率为1.5%~3.5%; BRAF V600X约占所有BRAF突变的50%, 其中最常见的突变类型是V600E。BRAF突变是晚期NSCLC的少见驱动基因, BRAF V600X突变患者的预后差, 总生存期较短, 目前化疗和免疫治疗的临床获益并不理想。
4.5.2 非小细胞肺癌与突变的BRAF和MEK
RAF有A/B/C3种亚型, 其中最容易发生突变的是BRAF, 导致MAPK下游细胞信号转导通路的持续激活, 促使细胞生长、增殖, 介导肿瘤发生, 尤其在NSCLC常见V600E的变异。若能精确地抑制BRAF蛋白活性, 可阻断肿瘤细胞的生长和分裂, 应是治疗的一个环节。MAPK下游通路的MEK1/2激酶也是NSCLC的重要因子, 若同时有药物抑制MEK1/2的活性, 这种双靶组合抑制MAPK的两个节点, 可提高治疗效果和降低不良反应。
4.5.3 达拉非尼和曲美替尼
达拉非尼(12, dabrafenib) 是GSK公司研制的BRAFV600E/K/D选择性抑制剂, 活性强于野生型一个数量级, 说明非极性的Val600残基突变成Glu/Lys/Asp等极性氨基酸残基与12更有利于结合。图 4a是达拉非尼与BRAFV600复合物晶体结构图, 定位于ATP结合域中的12, 氨基嘧啶与Cys532形成氢键网络, 叔丁基进入疏水腔, 磺酰胺与Asp594和Phe595的肽骨架形成氢键, 二氟苯基与Phe595发生π-π堆积作用(图 4a中未显示突变位点的结合域)。12以治疗黑色素瘤于2013年上市, 成为继维罗非尼(vemurafenib) 批准的第2个治疗转移性黑色素瘤的小分子药物, 后继的适应症是非小细胞肺癌[19]。
本二联FDC的另一个药物是曲美替尼(13, trametinib), GSK公司研制并与2013年上市口服治疗黑色素瘤。13是MAPK信号通路上MEK1和MEK2的强效抑制剂, 体外活性IC50均为2 nmol·L-1, 而且还可激活癌细胞自噬和诱导凋亡。其作用机制是可逆性地结合未磷酸化的MEK变构位点, 阻断催化作用。图 4b是13与MEK1复合物单晶结构图, 稠合环的吡啶酮既与Ser212发生氢键结合, 也与Phe209的苯环形成π-π堆积。嘧啶的酮基与Lys97和Asp 208发生氢键结合[20, 21]。
在非小细胞肺癌患者中, 大约30%具有可靶向治疗的基因突变, 经临床使用, 达拉非尼和曲美芬尼联合治疗晚期NSCLC有效, 2017年美国FDA批准了该FDC治疗BRAFV600E突变的转移性非小细胞肺癌, 总有效率超过60%, 疾病缓解时间长达12.6个月。
4.6 抑内攘外的降脂药
4.6.1 抑制体内生成的胆固醇
体内高水平血脂有潜在的心血管疾病的危险, 血中高水平的脂质低密度蛋白胆固醇(LDL-C) 是引发动脉粥样硬化和心血管疾病的因素。人体内的胆固醇大约70%是自身de novo合成的, 膳食摄取占30%。本节讨论的FDC是由两个药物组成, 分别是抑制体内胆固醇的合成和阻断机体对膳食来源的胆固醇吸收。
葡萄糖有氧代谢最终生成乙酸根。胆固醇体内合成是由乙酰辅酶A (C2)→异戊二烯(C5)→角鲨烯(C30)→胆固醇(C27) 共30步复杂生化反应组成, 其中限速步骤是C6的羟基甲基戊二酸还原成二羟基甲基戊酸, 催化该转化反应的酶系是羟基甲基戊二甲酰辅酶A还原酶(HMG-CoA reductase), 该还原酶已作为降胆固醇药物靶标上市了多款“他汀”类药物, 其中最成功的是阿托伐他汀(14, atorvastatin), 1995年上市, 迄今经久不衰。14有以下特点: ①不仅抑制胆固醇的体内合成, 也具有降低甘油三酯的作用; ②体内经CYP3A4氧化代谢, 苯环被羟基化(2-OH或4-OH) 仍保持活性, 70%降胆固醇作用来自于代谢产物; ③化学结构的上面部分为二羟基戊酸片段, 是所有他汀药物所共同的片段, 模拟底物HMG的结构, 但下面的疏水部分中阿托伐他汀含有的苯胺酰基是独有的基团, NH与Ser565羟基形成氢键, 苯环与Arg568发生阳离子-π相互作用, 这些特异性的结合反映在结合的热力学焓的贡献占50%以上, 而既往的他汀没有这样的极性基团, 结合能大多是增熵的贡献。图 5是14与HMG-CoA还原酶复合物的结合模式图[22]。
4.6.2 阻止肠道吸收胆固醇的依折麦布
研制之初认为负责胆固醇吸收的靶标蛋白是酰化辅酶A胆固醇酰基转移酶(acyl-coenzyme A cholesterol acyltransferase, ACAT), ACAT作为细胞内唯一催化游离胆固醇和长链脂肪酸合成胆固醇酯的酶系, 在体内胆固醇代谢平衡过程中起到关键的调控作用。抑制ACAT可以降低胆固醇的肠内吸收, 减少胆固醇从膳食的摄取量, 降低血浆中胆固醇水平。基于此, 研制出抑制肠道对胆固醇的吸收依折麦布(15, ezetimibe), 从而降低了LDL-C[23]。后来发现从膳食中摄取胆固醇是靠小肠的刷状膜上的称作NPC1L1蛋白介导内吞而吸收的。NPC1L1是含有1 332个氨基酸的膜蛋白, 包含有3个结构域, 具有结合胆固醇的功能的胞外区N端结构域(NTD)、跨膜结构域(TMD) 和结合依折麦布的中间结构域(MLD)。根据胆固醇水平的变化, NTD可以结合不同数量的胆固醇分子, 胆固醇水平越高, 会结合更多的胆固醇分子, 形成稳定的结构簇。依折麦布因结合MLD而引起蛋白构象的变化, 并破坏结构簇, 导致NPC1L1功能受到抑制, 阻止了对胆固醇的内吞化。图 6是依折麦布(黄色) 与NPC1L1的中间结构域结合的示意图[24]。
4.6.3 二联降脂药Atozet
默沙东公司于2013年研制成功依折麦布/阿托伐他汀钙(10 mg/10 mg) 组成的固定剂量复方口服片, 依据上述降血脂的不同机制, 从阻断外来胆固醇的吸收和抑制自身胆固醇的合成两个途径得到广泛的认可[25], 全球已有许多国家批准上市, 2023年全球销售总额5.2亿美元, 2023年11月也在我国获批上市, 商品名益立妥。
4.7 多巴脱羧酶抑制剂和多巴胺受体激动剂组成的卡左双多巴缓释片
4.7.1 帕金森综合征
帕金森综合征是由于大脑中多巴胺(16, dopamine) 含量减少导致的运动障碍性疾病。作为一种神经递质, 多巴胺参与调节运动功能。脑中缺乏多巴胺导致运动迟缓、肌肉僵硬等症状。多巴胺在体内极易代谢失活, 因为儿茶酚片段和伯胺基团易被氧化代谢, 所以不能直接用作治疗药。现有药物治疗的不足是未能完全控制所谓的开关现象。开关现象是指患者长期应用左旋多巴类药物出现的药效波动, 成为该类药物伴随的不良反应。“关”主要表现为突然出现肢体僵直, 运动不能, 举步维艰。“开”时尽管未加用任何相关治疗, 而突然活动正常, 肢体僵硬消失, 可以自如活动。变化速度非常快, 且不能预测, 这种生理现象犹如电源自发开关一样。
4.7.2 左旋多巴
左旋多巴(17, levodopa) 是治疗帕金森病中最常用的药物, 能够有效缓解运动迟缓和僵硬, 也能减轻震颤。17其实是多巴胺的前药, 口服后在小肠中经芳香族氨基酸转移酶通过主动转运而迅速吸收, 进入肝脏经首过效应、大部分脱羧基转变成多巴胺。但多巴胺不易穿越血脑屏障, 进入中枢神经系统的左旋多巴不到用量的1%, 而且在外周组织中脱羧形成大量多巴胺, 引起不良反应。这就是本复方制剂同时服用外周脱羧酶抑制剂卡比多巴的由来与根据。
4.7.3 芳香氨基酸脱羧酶的作用机制和抑制剂卡比多巴
为使多巴胺持续在脑中产生以维持治疗水平, 就须使外周血中维持其前药左旋多巴长时间的存留, 一种策略是抑制外周芳香氨基酸脱羧酶(AADC) 活性。AADC都是以磷酸吡哆醛(PLP) 为辅酶行使其催化脱羧功能的, PLP是维生素B6的活性形式, 是一种多功能辅酶。当AADC与辅酶PLP结合时, PLP与AADC上的Lys319缩合形成席夫碱(Schiff base), PLP的磷酸基团与Thr167、Ser168和Thr369之间形成氢键, 吡啶环上的氮与Asp287的侧链羧基形成盐桥, 这样, 将PLP与AADC以特定的结合方式启动催化脱羧(图 7a)。
当AADC与底物L-多巴相遇开启催化脱羧时, 来自底物的氨基对原已形成的PLP-Lys319缩合物作亲核进攻, 使原席夫碱断裂, PLP与底物α-氨基形成新席夫碱, 脱去α-羧基, 离去生成的CO2, 此时PLP与底物形成醌式中间体(quinonoid intermediate)。随后在广义酸/碱作用下, Tyr348将质子转移到醌式中间体上, 使该中间体分离成PLP及产物多巴胺, 从而完成对底物的脱羧, PLP与产物分离后, 重新与Lys319形成席夫碱, 迎接新的脱羧反应(图 7b)。
4.7.4 AADC抑制剂卡比多巴
卡比多巴(18, carbidopa) 可视作L-多巴的电子等排体, 肼基与PLP缩合成化学稳定的腙化合物, 抑制了AADC活性[26]。由于18是强极性的两性分子不能穿过血脑屏障, 所以只抑制外周的左旋多巴, 这样得以有更多的左旋多巴可经主动转运进入中枢系统中。美国FDA于2014年批准卡比多巴上市, 18是由Amerigens Pharmaceuticals公司研发的。
4.7.5 治疗帕金森综合征的Duodopa
2014年美国FDA批准艾伯维公司研发的药物Duodopa就是由多巴脱羧酶抑制剂卡比多巴(50 mg) 和多巴胺受体激动剂多巴胺前药左旋多巴(200 mg) 组成的二联FDC片剂, 治疗帕金森病。口服一剂的疗效可持续16 h以上, 显示外周较少游离的多巴胺, 提高了转运蛋白的生物利用度, 减少了恶心和呕吐不良反应[27]。2023年销售额达到4.7亿美元。
4.8 降高血钾药物环硅酸锆钠
4.8.1 高血钾症和环硅酸锆钠散剂
高钾血症是以血钾水平升高为特征的疾病, 通常是由心血管、肾脏和代谢疾病引起。慢性肾病和/或慢性心力衰竭患者会出现高钾血症, 可能导致心脏骤停和死亡。
2018年FDA批准阿斯利康公司的环硅酸锆钠(sodium zirconium cyclosilicate) 是新结构类型和新作用机制的无机化合物, 是由锆酸钠与硅酸形成的高分子复合物, 如图 8所示。
虽然本品是由锆酸钠和原硅酸混合而成, 形式上是两个无机化合物的混合物, 因而人们将其视作FDC, 其实形成的复合物呈现特殊的结构和特定的物理化学性质, 而单独的两个原料分子没有疗效。因而环硅酸锆钠作为上市药物具有特殊性, 商品名为Lokelma, 我国在2020年上市商品名为利倍卓(环硅酸锆钠散)。
4.8.2 环硅酸锆钠降血钾作用
人体的钾离子是肠道从膳食中摄取的。环硅酸锆钠对钾离子具有高选择性结合, 完全是物理化学作用。体外实验表明, 即使存在其他阳离子(例如钙和镁) 也不影响对钾的特异性结合。环硅酸锆钠捕获胃肠道中的钾(K+), 降低胃肠道腔中游离K+浓度, 导致肠道-血液两侧K+浓度差加大, 促使结肠向外分泌K+增加。由血入肠的K+进一步被本品结合, 致使血钾水平降低, 被结合的K+从粪便排出。所以本品不仅捕获膳食中的K+, 也促进降低血液中的高K+[28]。
环硅酸锆钠不溶于水, 口服剂量5 g或10 g, 最高15 g (视血钾水平而定) 散剂的悬浊液, 穿肠“吸钾”而过, 不被吸收。服药1 h后即开始起效, 达到正常血钾水平的中位时间是2 h, 48 h内98% 的患者达到正常血钾水平。未见不良反应。
4.8.3 环硅酸锆钠的钾结合机制
环硅酸锆钠的晶体结构如图 8b所示的笼状结构, 3个锆、4个硅和7个氧原子组成的孔隙, 经计算微孔的原子间距, 孔隙开口大约3 Å, 这大致与未水合K+的直径相当, 而Ca2+和Na+与孔隙契合较差, 结合作用不强, Ca2+或Mg2+的结合低于K+ 25倍以上, 所以对二价金属离子影响不大。图 9是环硅酸锆钠局部结构与这些离子结合的模式[29]。
4.9 抗菌药的二联FDC
4.9.1 青霉素和头孢类抑制细胞壁的生物合成
20世纪40年代Fleming等发现苄基青霉素并开创了抗生素的治疗领域, 迄今已研制出一大批西林和头孢类药物, 由于结构中都有β-内酰胺环, 所以统称β-内酰胺类药物。这类药物作用环节是阻断细菌的细胞壁合成。细菌合成细胞壁需要催化的酶系, 统称青霉素结合蛋白(penicillin-binding proteins, PBPs)。PBPs是位于细菌内膜的一组参与细菌细胞壁的合成酶, 包括转肽酶(transpeptidases, t-peptase)、羧肽酶(carboxypeptidases) 和内肽酶(endopeptidases) 等。
4.9.2 β-内酰胺的构象与D-丙氨酰-D-丙氨酸的构象相似
细胞壁的主要成分是肽聚糖, 合成原料是由N-乙酰葡糖胺(Glc-Nac) 和N-乙酰胞壁酸(Mur-Nac) 连接成链状聚糖短肽。短肽在肽聚糖转肽酶催化下发生交联反应, 完成细胞壁的合成。由于β-内酰胺的构象与肽聚糖的D-丙氨酰-D-丙氨酸(D-Ala-D-Ala) 的立体结构相似(图 10a、b), 亲电性的β-内酰胺竞争性地与转肽酶的活性中心结合, 发生不可逆的共价键结合, 产生抑制作用。图 10是D-丙氨酰-D-丙氨酸与β-内酰胺的构象示意图。
4.9.3 抗菌作用的核心—β-内酰胺抑制转肽酶
转肽酶催化甘氨酰片段取代肽聚糖的D-丙氨酰-D-丙氨酸中的一个D-丙氨酸, 是形成胞壁交联的关键步骤, 转肽酶活性中心的亲核基团向β-内酰胺羰基作亲核进攻, 酶被酰化而失活(图 11), 抑制了甘氨酸与D-丙氨酸的交换, 阻断了细胞壁的形成, 这是β-内酰胺类药物抗菌作用的核心。
青霉素和头孢类抗菌的核心结构是并合了非芳香性的五元/六元杂环的β-内酰胺, 提高了四元环的张力, 增加了羰基亲电性。在核心两侧的结构变换, 是为了优化药效/药代/物化等性质、克服耐药性和提升患者的应用依从性(例如口服代替注射, 长效使用药频次减少等), 迄今已上市了数代西林和头孢。
4.9.4 β-内酰胺酶及其抑制剂
过度使用β-内酰胺类抗生素导致耐药病菌的产生, 例如耐甲氧西林金黄色葡萄球菌(MRSA)、耐青霉素肺炎链球菌(PRSP) 和超广谱β-内酰胺酶(ESBL) 耐药菌等。细菌通过表达β-内酰胺酶来对抗β内酰胺类。β-内酰胺酶已知有4类A/B/C/D, 其中A/C/D的活性中心有丝氨酸残基的参与, 称作丝氨酸-β-内酰胺酶(Ser-BL), β-内酰胺酶B是由Zn2+介导参与酶的失活过程, 称作金属-β-内酰胺酶(Met-BL)。图 12是Ser-BL分解β内酰胺类药物的化学机制, 目标是基于底物有活泼的β内酰胺结构, 通过两次广义碱的催化分别提高丝氨酸残基和水分子的亲核性, 使β内酰胺开环失活, 而Ser-BL安然无恙。
临床上现用于防止β-内酰胺类抗生素降解的药物为第一类的Ser-BL, 第二类的Met-BL抑制剂现处于临床研究中。临床应用的Ser-BL抑制剂有克拉维酸(19, clavulanic acid, GSK1981)、舒巴坦(20, sulbactam, 辉瑞1986)、他唑巴坦(21, tazobactam, 默克2014)、阿维巴坦(22, avibactam, 安内特2015)、瑞来巴坦(23, relebactam, 默克2019) 和法硼巴坦(24, vaborbactam, Melinta 2017)。
19~21结构为β-内酰胺类型, 与β-内酰胺酶发生共价结合, 为不可逆抑制剂, 图 13是克拉维酸抑制Ser-BL的示意图, 活性中心被酰化和烷基化而失活。22和23是二氮杂双环辛烷抑制剂, 具有广谱抗β内酰胺酶活性, 强效结合A类(超广谱β内酰胺酶和KPC) 和C类(AmpC酶)。24是含硼抑制剂, 硼元素与活性中心的丝氨酸残基发生配位性不可逆结合[30], 24与美罗培南(meropenem) 配伍成FDC, 于2017年上市, 商品名为Vabomere, 治疗肾盂肾炎等复杂尿路感染和耐受碳青霉烯类的肠杆菌科感染[31]。
4.9.5 代表性的二联抗菌剂
应当提及的是, “巴坦”类β-内酰胺酶抑制剂本身的抗菌作用不显著, 是通过抑制Ser-BL保护“西林”和头孢的抗菌增效剂, 批准上市大都与头孢或西林合用作为FDC的组成部分。例如克拉维酸(19) 与阿莫西林(25, amoxicillin) 的复方制剂augmentin (安美汀) 1981年批准上市治疗上呼吸道感染和肺炎, 应用至今, 2023年销售额6.8亿美元。舒巴坦(20) 与头孢哌酮(26, cefoperazone) 配伍的sulperazon (舒哌酮), 治疗各种细菌的全身性或局部感染。2023年销售额7.6亿美元。阿维巴坦(22) 与头孢他啶(27, cefazidime) 的二联FDC称作Zavicefta (思福妥) 辉瑞公司2015年上市(我国2019年), 用于治疗复杂性腹腔内感染、医院获得性肺炎和呼吸机相关性肺炎。2023年全球销售额5.1亿美元。
4.10 抗新冠病毒COVID-19药物帕罗韦德
4.10.1 新冠病毒3CLPRO蛋白酶抑制剂奈玛特韦
为抗击2019年全球暴发的新冠病毒(COVID-19) 疫情, 辉瑞公司研制了一剂针对新冠病毒3CLPRO蛋白酶抑制剂奈玛特韦(28, nirmatrelvir), 通过抑制新冠病毒3CLPRO蛋白酶的活性, 阻断病毒的后续RNA复制过程。28与3CLPRO蛋白酶结合中的要素是氰基与Cys145巯基发生加成反应, 形成可逆性共价结合, 提高了选择性活性。如图 14所示[32]。奈玛特韦是CYP3A4底物, 在肝脏中被氧化代谢而半衰期很短, 为此, 在服用奈玛特韦同时服用CYP3A4抑制剂利托那韦。
4.10.2 细胞色素P450/3A4抑制剂利托那韦
利托那韦(29, ritonavir) 是人免疫缺陷病毒-1/-2 (HIV-1/-2) 天冬氨酸蛋白酶抑制剂, 阻断成熟HIV颗粒所需的口服药物, 使HIV颗粒停滞在未成熟的状态, 是治疗艾滋病的药物。
利托那韦也是细胞色素P450 CYP3A4强效抑制剂, 为肠道和肝脏中药物代谢酶的II型配体, 由于其结构完全适配于CYP3A4结合腔, 并通过噻唑与血红素铁发生不可逆的结合(S→Fe3+配位键), 阻断细胞色素P450的功能, 如图 15所示[33]。
4.10.3 抗新冠病毒二联治疗药帕罗韦德
辉瑞公司2023年被正式批准上市的帕罗韦德(Paxlovid) 是奈玛特韦片(150 mg) 联用利托那韦片(100 mg) 的二联口服药, 治疗COVID-19病毒感染。杀灭病毒的主药是奈玛特韦, 辅佐改善主药的药代动力学性质的是利托那韦。患者口服联合用药(奈玛特韦2片, 利托那韦1片), 每隔12 h服用一次, 连续5天通常病毒抗原转阴。此时, 奈玛特韦的平均半衰期为6.05 h, 原型药粪便中回收近50%, 尿液中回收35%, 提示利托那韦降低了奈玛特韦体内代谢, 提高了治疗效果。
5 结语
收起
药监部门每年批准上市的新药可分为两类: NME和FDC, 两类皆属于新药, 都是官方认可的满足临床/患者需要的有效药物。药物设计(drug design) 可细分为3个层面: 分子设计(molecular design)、制剂设计(formulation design) 和剂量设计(dosage design)。FDC属于制剂设计的范畴, 包括处方设计和工艺研究(本文未涉及辅料的兼容和选择以及过程研究), 制剂设计与剂量设计密切关联, 因为是最贴近临床治疗的环节。FDC的必要性在于, 一是复杂难治疾病只用针对单个靶标药物治疗往往效果不佳; 再者一个药物兼具药效、药代和安全性等诸多属性的最优化也难以达到(例如前述奈玛特韦的药代缺陷); 此外, FDC对患者的依从和药物经济学也是有益的形式。FDC的设计是临床/药理学家治疗实践的创造性成果, 是在对疾病病理过程和分子调控的洞悉基础上, 把控组成FDC各个药物的作用机制/药效/药代/物化配伍等环节组成的科技成果, 犹如NME的概念验证贯穿于研发始终乃至真实世界中的考量一样, FDC是新药研究的另一重要内容。
作者贡献: 郭宗儒撰写全文, 对内容进行修改和补充。
利益冲突: 不存在利益冲突。
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doi: 10.16438/j.0513-4870.2024-0797
  • 接收时间：2024-08-19
  • 首发时间：2025-11-07
  • 出版时间：2025-02-12
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  • 收稿日期：2024-08-19
  • 修回日期：2024-09-10
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    中国医学科学院、北京协和医学院药物研究所, 北京 100050

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*郭宗儒, E-mail:
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2种不同金属材料的力学参数
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Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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