Assessment of the Efficacy of New Anti-Tuberculosis Drugs

Denis A. Mitchison; Geraint R. Davies

摘要

The pathology of tuberculosis in humans starts with an initial Ghon focus in the lungs followed by transmissionof bacilli though the blood and lymph to other regions in the lungs and to other organs. While these bacilli usually lie latentwithout causing further disease, some 10% start foci of adult type disease usually starting in the sub-apical regions ofthe lungs. Bacilli multiply, killing tissue by caseation and then forming colonies within the caseum. Cavities form connectingto the air in whose walls vigorous bacillary multiplication occurs. The history of the development of antituberculosischemotherapy is described, starting with the use of multi-drug regimens to prevent the emergence of drug resistanceand continuing with the shortening of the treatment period to 6 months by the incorporation in the regimens of rifampicinand pyrazinamide, which are the two drug responsible for bactericidal activity during treatment. Prospects forfurther shortening of treatment rest with the introduction of higher dosage with rifamycins and with new anti-tuberculosisdrugs. These new drugs include the 8methoxyfluoroquinolones moxifloxacin and gatifloxacin which inhibit topoisomerasesand protein formation, the diarylquinoline TM-207 which inhibits the mycobacterial ATP synthase and thusenergy formation, the nitroimidazopyran PA-824 and the closely related OPC-676832 which are pro-drugs with uncertainmodes of action and the pyrrole SQ-109, a cell wall inhibitor. Anti-tuberculosis drugs have widely variable pharmacokineticcharacteristics but as they work efficiently together, it is unnecessary to match these when giving drug combinations.The effects of drug-drug interactions are usually small though the interactions with anti-retroviral drugs can pose problems.Dose sizes have usually been chosen to minimize side effects while retaining activity and thus tend to have lowtherapeutic margins, the exception being the margin of about 20 for isoniazid. The role of high plasma binding, importantin limiting the efficacy of rifamycins, is uncertain for the newer drugs. Post antibiotic effects are vital to the prevention ofdrug resistance and need exploration for new drugs. The main aims of current drug development are (1) to shorten treatment,and (2) to make it more convenient, by for instance using widely intermittent regimens. The current techniques formeasuring efficacy during drug development start with in vitro models, including the Hu/Coates models, which shouldcontain bacterial populations resembling the bacterial persisters in lesions that are responsible for the long duration oftreatment. The next stage is the mouse model of the chemotherapy of established tuberculosis, which has proved remarkablyuseful in assessing the value of the different drugs. The main problem in clinical assessment arises from the use of relapseafter treatment as the main end-point, and the consequent need for very large numbers of patients required to providemeasurable relapse rates in final phase III licensing studies. For this reason, surrogate studies are necessary in phaseII which require much smaller numbers of patients. The first such investigations are phase IIA studies of early bactericidalactivity which establish whether the drug given alone has bactericidal activity on cavitary bacilli and which can estimatethe minimal effective dose of the drug, useful for decisions of dose size. The next step should be phase IIB studies whichmeasure the rate of elimination of viable bacilli in sputum during the initial 8-weeks of treatment with various combinationsof the new drug with established drugs. Measurement can be as (1) the proportion of patients with positive sputum atthe end of the 8-weeks period, the easiest method but the least sensitive, or (2) as the speed with which sputum culturesbecome negative in a survival analysis, or (3) as the mean regression in modeling of serial sputum collections colonycounts (SSCC). The relation between these surrogate estimates a

机译：人类结核病的病理学始于肺部最初的Ghon病灶，然后细菌通过血液和淋巴液传播到肺部其他区域和其他器官。尽管这些杆菌通常潜伏着不会引起进一步的疾病，但约有10％的成年型疾病的发病灶通常始于肺的根尖下区域。芽孢杆菌繁殖，通过干酪化杀死组织，然后在干酪中形成菌落。空腔形成与空气的连接，在空气中壁上发生强烈的细菌繁殖。描述了抗结核化学疗法的发展历史，从使用多药方案防止耐药性的出现开始，并通过将利福平和吡嗪酰胺的治疗方案合并为治疗方案，将治疗期缩短至6个月，这些都是在治疗过程中负责杀菌活性的两种药物。进一步缩短治疗的前景取决于引入更高剂量的利福霉素和新型抗结核药物。这些新药包括抑制拓扑异构酶和蛋白质形成的8甲氧基氟喹诺酮类莫西沙星和加替沙星，抑制分枝杆菌ATP合酶并因此形成能量的二芳基喹啉TM-207，硝基咪唑并吡喃PA-824和密切相关的OPC-676832，它们是不确定模式的前药作用和吡咯SQ-109（细胞壁抑制剂）。抗结核药具有广泛的药代动力学特性，但由于它们可以有效地协同工作，因此在给予药物组合时不必匹配这些药物。尽管与抗逆转录病毒药物的相互作用可能会引起问题，但药物与药物的相互作用通常很小。通常选择“异烟肼”以最大程度地减少副作用，同时保持活性，因此倾向于具有较低的治疗余量，但异烟肼的除草剂余量约为20。高血浆结合的作用，对于限制利福霉素的疗效很重要，对于新药尚不确定。抗生素后效应对于预防耐药性至关重要，需要探索新药。当前药物开发的主要目标是（1）缩短治疗时间，和（2）通过使用广泛的间歇治疗方案使其更方便。当前在药物开发过程中用于评估功效的技术始于体外模型，包括Hu / Coates模型，该模型应包含与病程长的病原菌相似的细菌种群。下一阶段是已建立的结核病化疗的小鼠模型，已证明在评估不同药物的价值方面非常有用。临床评估中的主要问题是由于使用治疗后的复发作为主要终点，因此最终III期许可研究中需要大量患者提供可测量的复发率。因此，在II期需要进行替代研究，该研究需要更少的患者。最初的此类研究是IIA期早期杀菌活性研究，该研究确定了单独服用的药物是否对空肠杆菌具有杀菌活性，并且可以估计药物的最小有效剂量，可用于确定剂量大小。下一步应该是IIB期研究，以新药与既有药物的各种组合治疗，测量在治疗的最初8周内痰中活菌的清除率。测量可以是（1）在8周结束时痰液阳性患者的比例，这是最简单的方法，但灵敏度最低，或者（2）在生存分析中痰液培养呈阴性的速度，或者（ 3）作为系列痰收集菌落计数（SSCC）建模的均值回归。这些替代估计之间的关系

Assessment of the Efficacy of New Anti-Tuberculosis Drugs

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