貝達(dá)喹啉治療結(jié)核病的研究進(jìn)展

彭 蔚,黎友倫,彭 麗

貝達(dá)喹啉治療結(jié)核病的研究進(jìn)展

彭 蔚,黎友倫,彭 麗

結(jié)核病依然是全球重大公共衛(wèi)生問題。耐多藥和廣泛耐藥結(jié)核病的出現(xiàn)與蔓延是結(jié)核病控制面臨的一大挑戰(zhàn)。目前WHO推薦用于治療耐藥結(jié)核病的化療藥物存在種類少、療效欠佳、不良反應(yīng)多、療程長等不足，因此，開發(fā)新型作用機制的抗結(jié)核藥勢在必行。貝達(dá)喹啉，靶點為分枝桿菌ATP合成酶，具有作用機制新穎、耐藥率、半衰期長、特異性高、抗菌活性強、縮短耐多藥結(jié)核病療程，安全性良好等優(yōu)點，但是同時也存在難以解釋的高致死率等缺陷。本文主要從抗菌及耐藥機制、藥代動力學(xué)、抗菌活性、臨床試驗、安全性方面綜述貝達(dá)喹啉治療結(jié)核病的研究進(jìn)展。

結(jié)核??；貝達(dá)喹啉；耐藥結(jié)核病

WHO在2013結(jié)核病報告中指出2012年約860萬結(jié)核病例，而由結(jié)核病引起的死亡人數(shù)達(dá)130萬?？菇Y(jié)核資源有限、DOTS策略執(zhí)行不當(dāng)及病人依從性差等是結(jié)核病控制的屏障。自1963年以來，幾乎沒有新的抗結(jié)核藥物用于結(jié)核病治療。貝達(dá)喹啉(bedaquiline，BDQ)[1-3]，又稱TMC207、R207910、J，商品名：斯耐瑞(Sirturo)，作為聯(lián)合方案中的一部分，用于其他治療手段無效的成人耐多藥肺結(jié)核(multidrug resistance pulmonary tuberculosis,MDR-PTB)，在我國也適用于成人(前期)廣泛耐藥肺結(jié)核(pre-)extensively drug resistance pulmonary tuberculosis , (pre-)XDR-PTB)，是到目前為止最有前途的抗結(jié)核病新藥之一。本文就近年來國內(nèi)外貝達(dá)喹啉治療結(jié)核病的研究進(jìn)展作一綜述。

1 作用機制

貝達(dá)喹啉屬于二芳基喹啉類化合物，與分枝桿菌ATP合成酶c亞基結(jié)合，影響ATP合成酶質(zhì)子泵生物學(xué)功能，導(dǎo)致ATP耗竭和內(nèi)環(huán)境穩(wěn)態(tài)失衡，從而達(dá)到抑菌和(或)殺菌效果[4]。

2 耐藥機制

體外研究提示貝達(dá)喹啉致結(jié)核分枝桿菌(Mycobacterium tuberculosis,MTB)耐藥率為1×10-7～1×10-8[4]。

2.1 基因突變 Petrella等[5]指出MTB編碼ATP合成酶c亞基的atpE基因Ala63Pro(A63P)和(或)Ile66Met(I66M)點突變阻止其與貝達(dá)喹啉結(jié)合，導(dǎo)致MTB天然或獲得性耐藥。

2.2 外排泵 Gupta等[6]指出外排泵抑制劑異搏定使貝達(dá)喹啉針對MTB的最低抑菌濃度(minimal inhibitory concentration,MIC)降低8-16倍。Andries等[7]指出MTB MmpS5-MmpL5外排泵過表達(dá)使貝達(dá)喹啉針對MTB的MIC增加4倍，而異搏定使貝達(dá)喹啉針對MTB的MIC降低4倍。

2.3 交叉耐藥 體內(nèi)研究未發(fā)現(xiàn)貝達(dá)喹啉與異煙肼(isoniazid,INH)、利福平(rifampicin,RIF)、吡嗪酰胺(pyrazinamide,PZA)、阿米卡星(amikacin,AMK)、莫西沙星(moxifloxacin,Mfx)等發(fā)生交叉耐藥[8]。貝達(dá)喹啉與氯法齊明(clofazimine,Cfz)存在交叉耐藥，Andries等[7]指出其可能與兩者均是MmpL5外排泵的底物有關(guān)。

3 藥代動力學(xué)

貝達(dá)喹啉口服吸收良好，與食物同食時生物利用度是空腹的2倍，5 h達(dá)到血藥濃度峰值，與人血漿蛋白結(jié)合率超過99.9%，血漿半衰期173小時，組織中分布廣泛，穩(wěn)態(tài)時分布容積超過10 000 L，清除率低，終末消除半衰期達(dá)5.5月[8,9]。貝達(dá)喹啉主要經(jīng)CYP3A4，部分經(jīng)CYP2C8、CYP2C19脫甲基化形成代謝產(chǎn)物1～8(metabolites 1～8,M1～8)，其中最主要的是去甲基產(chǎn)物M2。M2生物活性僅為貝達(dá)喹啉的1/3～1/6，但具有更強細(xì)胞毒性且更易形成藥物誘導(dǎo)的磷脂質(zhì)病(drug-induced phospholipidosis,DIP)[9]。貝達(dá)喹啉及代謝產(chǎn)物絕大部分經(jīng)糞便排泄，只有1%～4%經(jīng)尿液排出[8]。貝達(dá)喹啉藥代動力學(xué)與年齡、性別、體重、種族、是否合并HIV感染無關(guān)[8]。貝達(dá)喹啉治療成人MDR-PTB的給藥方法和劑量為與食物同服，400 mg每天1次共2周接著200 mg每周3次共22周[8]。

4 抗菌活性

4.1 體外抗菌活性 Nacer等[10]在3種不同培養(yǎng)基條件下檢測到貝達(dá)喹啉針對增殖期MTB 標(biāo)準(zhǔn)株的MIC值分別為：7H11瓊脂培養(yǎng)基--MIC=0.03 μg/ml，接種5%牛血清蛋白的7H1l瓊脂培養(yǎng)基—MIC=1 μg/ml，改良羅氏培養(yǎng)基--MIC=14.33 μg/ml。貝達(dá)喹啉對體外增殖期藥敏(drug-susceptible,DS)和耐多藥(multidrug-resistant,MDR)MTB表現(xiàn)出幾乎同等強度的抗菌活性[4,11]。Koul等[12]指出貝達(dá)喹啉作用于靜止期MTB同樣有效，且靜止期生物活性更強，可能與靜止期代謝緩慢有關(guān)。貝達(dá)喹啉對大多數(shù)非結(jié)核分枝桿菌也有效，但至少有蟾分枝桿菌(Mycobacteriumxenopi)、石氏分枝桿菌(Mycobacteriumshimoidei)和新卡城分枝桿菌(Mycobacteriumnovocastrense)天然耐藥[4,11]。貝達(dá)喹啉具有分枝桿菌特異性，對其他革蘭陽性和革蘭陰性菌無效[4]。貝達(dá)喹啉的抗菌譜及MIC值見表1[2,4,11]。

4.2 體內(nèi)抗菌活性 在小鼠模型中，單用貝達(dá)喹啉(25 mg/kg，每周5次)與WHO推薦方案治療DS/MDR-PTB療效相當(dāng)，但單藥易致耐藥，所以采用替換和(或)添加推薦方案中任何一種藥物的方法[4,13]。BDQ-PZA-INH/RIF、BDQ-PZA-AMK-Mfx±乙硫異煙胺(ethionamide,ETH) 治療1月與推薦方案治療2月殺菌效果相當(dāng)，治療2月使肺臟或(和)脾臟培養(yǎng)陰性，提示含貝達(dá)喹啉的方案可能使DS/MDR-PTB療程縮短一半。Makarov等[14]指出貝達(dá)喹啉與含哌嗪的苯并噻唑169(piperazine-containing benzothiazinones 169,PBTZ169)具有協(xié)同作用，在小鼠模型中BDQ- PBTZ169-PZA療效優(yōu)于WHO推薦方案。Ibrahim等[15]指出貝達(dá)喹啉聯(lián)合推薦方案治療小鼠模型4月與單純推薦方案治療6月復(fù)發(fā)率相同，提示貝達(dá)喹啉可能降低PTB復(fù)發(fā)率。Shang等[16]指出貝達(dá)喹啉在豚鼠模型中也有相似療效。貝達(dá)喹啉既能殺菌也能降低復(fù)發(fā)率，但兩者并不完全一致。Andries等[17]指出BDQ-PZA-Mfx治療小鼠模型4周肺培養(yǎng)陰性，治療5月復(fù)發(fā)率與推薦方案治療6月相當(dāng)；而BDQ-PZA-利福噴丁(rifapentine,RFT)治療4周肺培養(yǎng)并未完全轉(zhuǎn)陰，而治療3月復(fù)發(fā)率與推薦方案治療6月相當(dāng)。Ibrahim等[18]指出BDQ與PZA具有協(xié)同殺菌作用，Veziris等[19]采用每周1次BDQ-PZA-RFT聯(lián)合方案治療小鼠模型，其療效優(yōu)于每周5次的推薦方案，且優(yōu)于任何已知周用藥方案，提示此三聯(lián)方案可能成為候選抗結(jié)核間歇方案。

在少菌的潛伏結(jié)核桿菌感染(latent TB infection, LTBI)小鼠模型中，zhang等[20-21]采用每周5次BDQ-RFT-PZA聯(lián)合方案治療1月肺培養(yǎng)陰性、復(fù)發(fā)率7%，提示此三聯(lián)方案可能使DS-LTBI療程縮短到1月；單用BDQ與INH-RIF治療3、4月復(fù)

表1 貝達(dá)喹啉針對結(jié)核分枝桿菌、非結(jié)核分枝桿菌、革蘭陽性菌和革蘭陰性菌的MIC值范圍和MIC50值發(fā)率水平相當(dāng)，提示BDQ可能使DR-LTBI療程縮短到3～4月。

Tab.1 Range and median minimal inhibitory concentration of bedaquiline forMycobacteriumtuberculosis, nontuberculous mycobacteria and relevant Gram-positive and Gram-negative bacteria

SpeciesMICrange(μg/mL)MIC50(μg/mL)BedaquilinesensitivespeciesDrug-sensitiveM.tuberculosis0.030-0.120/0.002-0.0600.060Multidrug-resistantM.tuberculosis0.030-0.030/0.004-0.1300.030Mycobacteriumavium0.007-0.010/0.03-0.1300.010Mycobacteriumintracellulare0.007-0.010/0.03-0.2500.010Mycobacteriumchelonae0.060-0.500-Mycobacteriumfortuitum0.007-0.010/0.13-0.250-Mycobacteriumkansasii0.003/0.03-Mycobacteriummalmoense0.50-Mycobacteriumgordonae0.03-Mycobacteriumscrofulaceum0.03-Mycobacteriummarinum0.003-Bedaquilinedrug-resistantspeciesMycobacteriumxenopi4.0-8.0-Mycobacteriumshimoidei8.0-Mycobacteriumnovocastrense8.0-Helicobacterpylori2to>44Nocardiaasteroides->16Nocardiafarcinica->16Escherichiacoli->32Haemophilusinfluenzae->32Streptococcuspneumoniae16-64>32Staphylococcusaureus->32

5 臨床試驗

早期殺菌活性(early bactericidal activity, EBA)試驗[22-23]將75例痰涂片陽性初治PTB病人隨機每天口服貝達(dá)喹啉25 mg、100 mg、400 mg和WHO推薦方案治療7天，結(jié)果表明每天口服400 mg貝達(dá)喹啉從第4天開始到研究終點其療效與推薦方案相當(dāng)，延遲的殺菌效應(yīng)與貝達(dá)喹啉誘導(dǎo)MTB重塑新陳代謝有關(guān)。Ⅱb期[8]C208試驗將208例痰涂片陽性初治MDR-PTB病人(大部分HIV陰性)隨機分為貝達(dá)喹啉組和對照組，前者按照貝達(dá)喹啉說明書給予貝達(dá)喹啉，后者給予安慰劑，分別聯(lián)合背景方案治療8或24周,之后背景方案繼續(xù)治療96周。C208第1階段(貝達(dá)喹啉 8周組)主要終點為第8周時貝達(dá)喹啉組痰培養(yǎng)中位陰轉(zhuǎn)時間縮短，痰陰轉(zhuǎn)率升高；次要終點為第24周時貝達(dá)喹啉組痰培養(yǎng)中位陰轉(zhuǎn)時間仍然縮短，第24、72周時兩組痰培養(yǎng)陰轉(zhuǎn)率差異無統(tǒng)計學(xué)意義。C208第2階段(貝達(dá)喹啉 24周組)主要終點為第24周時貝達(dá)喹啉組痰培養(yǎng)中位陰轉(zhuǎn)時間縮短，痰陰轉(zhuǎn)率升高;次要終點為第72周時貝達(dá)喹啉組痰培養(yǎng)中位陰轉(zhuǎn)持續(xù)縮短，而痰培養(yǎng)陰轉(zhuǎn)率兩組差異無統(tǒng)計學(xué)意義；次要終點第120周貝達(dá)喹啉組痰培養(yǎng)陰轉(zhuǎn)率升高。 C209試驗將233例MDR/XDR-PTB病人(大部分HIV陰性)采用貝達(dá)喹啉聯(lián)合個體化背景方案治療24周，第25周末終止試驗，主要終點為第24周時痰培養(yǎng)中位陰轉(zhuǎn)時間57天和痰陰轉(zhuǎn)率79.5%。貝達(dá)喹啉C208和C209臨床試驗結(jié)果見表2。

6 安全性

C208試驗[8]指出貝達(dá)喹啉組不良反應(yīng)大多為輕至中度，發(fā)生率依次為惡心(35.3%)、關(guān)節(jié)痛(29.4%)、頭痛(23.5%)、高尿酸血癥(22.5%)、嘔吐(20.6%)、咯血(16.7%)、嗜睡(12.7%)、耳聾(11.8%)、瘙癢(11.8%)、失眠(10.8%)等，而除了前三項外貝達(dá)喹啉組與安慰劑組差異無統(tǒng)計學(xué)意義。C209試驗[8]貝達(dá)喹啉組不良反應(yīng)發(fā)生率依次為高尿酸血癥(13.7%)、關(guān)節(jié)痛(11.6%)、惡心(10.7%)、嘔吐(8.6%)、頭痛(8.6%)、腹瀉(7.7%)、血尿酸升高(6.9%)、低鉀血癥(6.0%)、瘙癢(6.0%)、注射部位疼痛(5.6%)等。貝達(dá)喹啉組與安慰劑組3級或4級嚴(yán)重不良發(fā)應(yīng)發(fā)生率差異無統(tǒng)計學(xué)意義，貝達(dá)喹啉組主要表現(xiàn)為轉(zhuǎn)氨酶升高和心電圖QTc延長[8]。值得注意的是，C208第2階段試驗發(fā)現(xiàn)的死亡率貝達(dá)喹啉組(12.7%)高于安慰劑組(2.5%)，但具體原因尚不清楚。

表2 貝達(dá)喹啉C208和C209臨床試驗結(jié)果

Note: NA--not analysed;aThe number of participants analyzed consists of 21 subjects in the BDQ group and 23 subjects in placebo groups;bThe number of participants analyzed consists of 66 subjects in the BDQ group and 66 subjects in placebo groups;cThe number of participants analyzed consists of 205 subjects in the BDQ group;dBased on a Cox proportional hazards model with treatment as covariate;eBased on a logistic regression model with treatment as covariate.

貝達(dá)喹啉引起轉(zhuǎn)氨酶升高多為可逆性，與背景方案中轉(zhuǎn)氨酶升高藥物聯(lián)用可能增加藥物性肝損風(fēng)險。貝達(dá)喹啉引起的QTc延長多為可逆性，聯(lián)用QTc延長藥物(如唑類抗真菌藥)和(或)結(jié)核病合并某些心律失常(如尖端扭轉(zhuǎn)型室性心動過速)時QTc延長風(fēng)險增加，當(dāng)出現(xiàn)有臨床意義的室性心律失常或QTc>500 ms(經(jīng)過重復(fù)心電圖確定)時應(yīng)立即停用貝達(dá)喹啉[8]。

貝達(dá)喹啉與CYP3A4激動劑(如RIF)聯(lián)用時可能使貝達(dá)喹啉濃度降低而影響殺菌效應(yīng)，而與拮抗劑(如蛋白激酶抑制劑)聯(lián)用時可能使貝達(dá)喹啉累積而增加不良反應(yīng)[8]。在人體內(nèi)利福平與貝達(dá)喹啉同服時貝達(dá)喹啉血漿濃度降低50%，而在小鼠模型中發(fā)現(xiàn)兩者聯(lián)用并沒有影響貝達(dá)喹啉殺菌效應(yīng)[24]。Dooley等[25]指出貝達(dá)喹啉與抗逆轉(zhuǎn)錄藥物依法韋倫序貫口服并沒有相互影響其療效。因此，貝達(dá)喹啉血漿濃度可能與臨床效應(yīng)無關(guān)。

貝達(dá)喹啉及其主要代謝產(chǎn)物M2屬于陽離子兩親性藥物(cationic amphiphilic drugs,CAD)，易引起細(xì)胞內(nèi)磷脂質(zhì)聚積形成DIP。DIP具有可逆性，可逆程度取決于CAD與磷脂質(zhì)的分離率和在組織中的消除率[26]。在某些CAD(如胺碘酮)中，DIP與臨床毒性相關(guān)，但這種觀點與其他CAD是否一致尚有爭議。在臨床試驗中貝達(dá)喹啉與氯法齊明聯(lián)用時心臟毒性增加，可能與DIP有關(guān)。

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Bedaquiline for tuberculosis

PENG Wei,LI You-lun,PENG Li

(DepartmenofRespiratoryMedicine,theFirstAffiliatedHospitalofChongqingMedicalUniversity,Chongqing400016,China)

Tuberculosis is remaining a global public health problem. The apperance and spread of multidrug-resistant and extensively drug-resistant tuberculosis is a big challenge for tuberculosis control. Antituberculosis drugs which were recommended by World Health Organization for treatment of drug-resistant tuberculosis have many shortcomings, such as less kinds, poor curative effects, serious adverse events and long treatment course. Therefore, it is urgent to develop drugs with new action. Bedaquiline, which is target ATP synthase of mycobacterium, is possessed of merits with unique mechanism, low resistance rate, long haf-life, high specificity, strong antibacterial activity, reduced treatment duration for multidrug-resistant tuberculosis, well safety and so on. At the same time, it has defects with high fatality rate which is diffcut to explain and the like. The artical mainly focus on the research progress of bedaquiline about its action and resistance mechanism, pharmacokinetics, antibacteria activity, clinic trials and safety in antituberculosis.

tuberculosis; bedaquiline; drug-resistant tuberculosis

Li You-lun, Email: liyoulun83@163.com

國家臨床重點專科建設(shè)項目(No.2012-649)資助

黎友倫，Email:Liyoulun83@163.com

重慶醫(yī)科大學(xué)附屬第一醫(yī)院呼吸內(nèi)科，重慶 400016

10.3969/cjz.j.issn.1002-2694.2015.02.017

R378

A

1002-2694(2015)02-0174-05

2014-07-14；

2014-11-11

Supported by the State Key Clinical Specialty Construction Project (No. WeiBanYi ZhengHan[2012]No.649)