目前,全球结核病的控制并不理想。根据世界卫生组织(World Health Organization,WHO)“终结结核病战略”的预计目标,2015—2020年全球范围内结核病的发病率下降幅度应达到20%,死亡率下降幅度应达到35%,而实际上这5年间结核病的发病率和死亡率仅分别下降了11%和9.2%[1]。因此,要实现“终结结核病战略”的目标,逆转结核病控制不良的颓势,须在结核病的预防、筛查、诊断和治疗等各环节进行创新和完善。其中,药物和用药方案的创新是必不可少的一环。
Pretomanid(PA-824)暂译为普瑞玛尼,是被批准用于结核病治疗的最新药物之一。2019年8月,美国食品药品管理局(Food and Drug Administration,FDA)批准含普瑞玛尼的贝达喹啉+普瑞玛尼+利奈唑胺(BPaL)方案用于广泛耐药结核病(extensively drug-resistant tuberculosis,XDR-TB)和耐多药结核病(multidrug-resistant tuberculosis,MDR-TB)的治疗[2]。随后,普瑞玛尼又获准在印度附条件使用,并获得欧洲药品管理局(European Medicines Agency,EMA)的上市许可[3]。在2020年WHO更新的耐药结核病治疗整合指南(2022年更新)中,含普瑞玛尼的BPaL方案也被推荐用于耐氟喹诺酮类的多耐药结核病(polydrug-resistant tuberculosis,PDR-TB)治疗[4]。本文简要介绍普瑞玛尼的药理学特性,并根据已发表的临床研究综述其疗效和安全性。
1 普瑞玛尼的药理学 1.1 药效学普瑞玛尼是硝基咪唑并噁嗪类抗菌药物,在常规培养条件下,其对药物敏感、单耐药、耐多药和广泛耐药结核分枝杆菌的最低抑菌浓度(minimum inhibitory concentration,MIC)为0.005~0.48 μg/mL,且对静止期和复制期的分枝杆菌具有杀菌活性[5]。
对静止期分枝杆菌,普瑞玛尼以辅因子F420H2为还原剂,在细菌脱氮黄素依赖性硝基还原酶(deazaflavin-dependent nitroreductase,Ddn)催化下生成一系列具有杀菌作用的硝基化合物,如NO[6]。F420H2的生物合成依赖Fbia、Fbib、Fbic、Fbid等蛋白,氧化态F420与还原态F420H2之间的转化需要F420H2依赖的葡萄糖-6-磷酸脱氢酶(F420-dependent glucose-6-phosphate dehydrogenase,Fgd)的催化[3]。一项关于普瑞玛尼耐药性的体外研究显示,83%的耐药性可用编码上述过程中关键酶(Ddn、Fbia、Fbib、Fbic、Fbid、Fgh)的基因序列改变来解释[7]。对于复制期的结核分枝杆菌,普瑞玛尼可抑制分枝杆菌细胞壁的形成[8],一个可能的机制是其阻断了羟基分枝菌酸向酮分枝菌酸的转化,而分枝菌酸是分枝杆菌细胞壁脂质层的重要成分[9]。
1.2 药动学在单次口服50~200 mg剂量范围内,普瑞玛尼的浓度-时间曲线下面积(area under the concentration-time curve,AUC)和最大观测浓度(maximum observed concentration,Cmax)随口服剂量的增加成比例增加,但当单次口服剂量提高至200~1 000 mg时,AUC和Cmax以低于剂量增加的比例增加[10]。健康成年人空腹和饱腹时单次口服200 mg普瑞玛尼的Cmax分别为1.1 μg/mL和2.0 μg/mL,可见与禁食状态相比,普瑞玛尼与食物共同服用可显著增加其血药浓度[11]。普瑞玛尼与人体血浆蛋白的结合率为94%[12],动物实验显示其被吸收后在大鼠体内广泛分布,且可有效穿过血脑屏障[13]。普瑞玛尼可经多种氧化还原途径代谢,没有某一途径占主导地位。体外实验表明,通过细胞色素P450 3A4(cytochrome P450 3A4,CYP3A4)代谢的普瑞玛尼约占总量的20%[14]。在健康成年男性志愿者中,普瑞玛尼约53%经尿液排出,38%经粪便排出,仅1%以原型形式从尿液排出[15]。
与CYP3A4诱导剂(如依非韦伦或利福平)同时使用会降低普瑞玛尼的血药浓度,因此临床上应避免普瑞玛尼与中等强度以上的CYP3A4诱导剂同时使用[16]。体外研究还发现,普瑞玛尼可抑制药物代谢转运子OAT3(organic anion transporter 3)的转运活性,因此与OAT3底物如氨甲蝶呤同时使用时须密切监测氨甲蝶呤的血药浓度和不良反应[14]。
2 普瑞玛尼的临床疗效在各期抗结核单药和治疗方案的临床试验中,普瑞玛尼对药物敏感结核病(drug-susceptible tuberculosis,Ds-TB)和耐药结核病(drug-resistant tuberculosis,Dr-TB)均显示出显著的疗效[17]。
2.1 普瑞玛尼对Ds-TB的疗效 2.1.1 普瑞玛尼单药Diacon等[18]于2010年发表了首项关于普瑞玛尼临床疗效的随机对照试验(randomized controlled trial,RCT) CL-007(NCT00567840),以痰涂片阳性的Ds-TB患者为研究对象,试验组单次口服普瑞玛尼200、600、1 000或1 200 mg,每日一次,对照组采用Ds-TB标准治疗方案(异烟肼+利福平+吡嗪酰胺+乙胺丁醇(HRZE)),以早期杀菌活性(early bactericidal activity,EBA)为主要临床终点,0~14 d或2~14 d的lgCFU下降速率为评价EBA的主要指标。结果显示,普瑞玛尼具有与肺结核一线治疗药物相当的EBA,且4种剂量普瑞玛尼的EBA基本一致,表明当单次口服剂量达到200 mg时,继续增加普瑞玛尼的剂量并不会提高EBA。在CL-010试验(NCT00944021)中,Diacon等[19]进一步探究了单次口服50、100、150、200 mg普瑞玛尼的EBA,结果表明50 mg组的杀菌活性比100、150、200 mg组低,因此确定单次口服100~200 mg普瑞玛尼可达到最佳杀菌活性。
2.1.2 莫西沙星+普瑞玛尼+吡嗪酰胺(MPaZ)方案NC-001试验(NCT01215851)探索了普瑞玛尼联合吡嗪酰胺、普瑞玛尼联合贝达喹啉,以及MPaZ方案对Ds-TB的EBA,对照组采用HRZE方案[20]。结果显示,MPaZ方案的EBA与HRZE方案相当。NC-002试验(NCT01498419)在Ds-TB患者中研究了MPaZ方案的8周杀菌活性,同样以HRZE方案作为对照。在8周的治疗期内,MPaZ方案对Ds-TB表现出良好的杀菌活性[21]。NC-006试验(NCT02342886)探究了MPaZ方案在Ds-TB成人患者中治疗4~6个月的疗效及完成治疗6个月后的预后,对照组采用HRZE方案,临床终点为第12个月(从治疗第1天起算)的临床或细菌学治疗失败或复发[22]。令人意外的是,MPaZ方案的疗效劣于HRZE方案。可能的原因是:一方面,该RCT早期停止招募导致样本量不足,其真实性存疑;另一方面,该结果提示以细菌学指标衡量的杀菌活性不能直接与抗结核药物的临床疗效画等号。
2.1.3 贝达喹啉+普瑞玛尼+吡嗪酰胺(BPaZ)方案在NC-003试验(NCT01691534)中,BPaZ方案对Ds-TB的EBA与结核病标准治疗方案相当[23]。NC-005试验(NCT02193776)将BPaZ方案治疗时间和杀菌活性的研究延长至8周,结果显示BPaZ方案对Ds-TB具有强大的灭菌效果以及缩短疗程的潜力[24]。
2.2 普瑞玛尼对Dr-TB的疗效 2.2.1 MPaZ方案和BPaZ方案在与结核病标准治疗方案比较的同时,NC-002和NC-005试验还设置了MPaZ和BPaZ方案治疗利福平耐药结核病(rifampicin-resistant tuberculosis,Rr-TB)的单臂临床试验,探究含普瑞玛尼的新方案对Dr-TB的有效性。结果显示,在8周的治疗期内,MPaZ方案和BPaZ方案对Rr-TB表现出同样良好的杀菌活性[21, 24]。
2.2.2 BPaL方案Nix-TB试验(NCT02333799)证明了BPaL治疗XDR-TB及不耐受或无反应MDR-TB的疗效。Nix-TB是一项小型单臂临床试验,治疗方案为BPaL,疗程6~9个月,以细菌学或临床上的治疗失败和复发为临床终点。意向性(intention-to-treat,ITT)分析显示,109例患者中仅10%出现不良预后,而90%的患者治疗成功。相较于过去治疗XDR-TB需18个月到2年以上、多达7药的用药方案及平均14%的治疗成功率[25],采用BPaL方案治疗XDR-TB几乎取得了飞跃式的进步。但Nix-TB试验中利奈唑胺相关不良事件的发生率很高。随后进行的ZeNix试验(NCT03086486)评估了贝达喹啉、普瑞玛尼联合不同剂量和疗程的利奈唑胺治疗XDR-TB的疗效和预后,结果证实了BPaL方案对XDR-TB的疗效好,不仅治愈率较高,还降低了利奈唑胺的剂量(由1 200 mg降至600 mg)和(或)缩短了利奈唑胺的疗程(由6个月降至2个月),治疗的安全性有所提高[26]。
2.2.3 贝达喹啉+普瑞玛尼+利奈唑胺+莫西沙星(BPaLM)方案TB-PRACTECAL(NCT02589782)是一项在多国开展的开放标签、随机对照II/III期临床试验,该试验比较了含贝达喹啉、普瑞玛尼和利奈唑胺的3组短期治疗方案[BPaLM、贝达喹啉+普瑞玛尼+利奈唑胺+氯法齐明(BPaLC)、BPaL]与当地符合WHO推荐的MDR-TB标准治疗方案的疗效[27]。3组短期方案均表现出良好的疗效和安全性,其中BPaLM方案比标准治疗方案更有效且安全性更高。在2022年5月WHO全球结核病规划发布的快速通讯中,BPaLM方案在最新的耐药结核病治疗整合指南中被推荐用于治疗MDR-TB[28]。
3 普瑞玛尼的安全性在普瑞玛尼I期临床试验中,头痛是最常见的不良反应,其他治疗期不良事件主要包括血肌酐升高、消化道症状及皮肤和皮下组织病变。值得注意的是,虽然服用普瑞玛尼会引起血肌酐升高,但在数值上并无临床意义,相关研究也表明口服剂量的普瑞玛尼不影响肾功能[29]。在服用普瑞玛尼2周的临床研究中未发生治疗相关严重不良事件(serious adverse event,SAE)[18-20, 23]。NC-002试验中,MPaZ方案的SAE发生率(7/62,11%)高于标准治疗方案(1/59,2%)[21]。NC-005试验中各组因不良反应而停药的比例分别为:PaBdqZ组10%(6/59),PaBdq200Z组8%(5/60),HRZE组3%(2/61)[24]。Nix-TB试验中,所有患者在治疗期间至少发生了一种不良事件,17%患者发生了SAE。16%的患者出现了肝功能损害,48%出现了骨髓抑制,81%有周围神经和视神经病变,ITT分析显示第16周时患者QT间期平均延长10 ms,其中骨髓抑制和视神经病变是利奈唑胺的常见不良反应,QT间期延长是贝达喹啉的常见不良反应[25, 30]。
4 结语Dr-TB在我国的发现率低,治愈率低,传播风险大,中国是全球Dr-TB高负担国家之一。据估计,2021年我国Dr-TB新发病例数为3.3万,报告病例数1.69万,其中77%(约1.3万)的患者获得治疗,但治疗成功率仅为53%[31]。因此,我们迫切需要更安全、有效、便利的药物和治疗方案来提高Dr-TB的治疗率和治愈率[32]。
普瑞玛尼作为新兴抗结核药物,具有良好的杀菌活性、临床效能和安全性,其与贝达喹啉和利奈唑胺联用有望为治疗难治性PDR-TB和XDR-TB带来革新。因此,国内应加速普瑞玛尼的批准上市流程,积极开展相关临床和基础研究,完善患者应用普瑞玛尼的临床数据。从既往研究来看,普瑞玛尼的潜力不仅局限于与贝达喹啉、利奈唑胺的联合应用,其与吡嗪酰胺的协同作用表明其与其他强效安全抗结核药物的组合方案仍有更广阔的探索空间。总而言之,普瑞玛尼进入临床使用后有望为我国结核病治疗策略带来更多突破性的变化。
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