Davies G R, Nuermberger E L
Division of Infection and Immunity, Faculty of Medicine, University of Liverpool, Liverpool, UK.
Tuberculosis (Edinb). 2008 Aug;88 Suppl 1:S65-74. doi: 10.1016/S1472-9792(08)70037-4.
Optimization of dosing strategies and companion drugs prior to Phase III trials is currently a critical obstacle in the development of new anti-tuberculosis drugs. Pharmacokinetic-pharmacodynamic (PK-PD) methods have assumed an important role in improving the efficiency of this process across the pharmaceutical industry and in other areas of anti-infective therapy. Information gained using PK-PD methods from the earliest in vitro assessments right up to the end of Phase II development can underpin proof-of-concept and ensure that agents are fully pharmacologically optimized. Despite our limited understanding of the biology of bacillary elimination in vivo, such an approach has already provided key insights into these mechanisms and helped to identify the role of different drugs in therapy and assess their potential for progression to pivotal trials. While isoniazid appears historically to have been effectively exploited, human studies suggest that it does not play a key role in the sterilizing phase of treatment. Re-evaluation of the PK-PD of rifamycins by contrast suggests that there may be considerable scope for improving their activity by intensifying current dosing strategies. Various PK-PD analyses of the fluoroquinolone series demonstrate remarkable agreement concerning the ranking of their sterilizing activity, results which appear to be confirmed in recent human phase II studies. The pharmacological characteristics of completely new classes of drugs now entering clinical development suggest that experience with existing drugs, particularly EBA studies, should not prejudice evaluation of their pharmacodynamic activity which may differ qualitatively from that of many current agents. In conclusion, PK-PD analysis has a vital role to play in the rational development of new anti-tuberculosis drugs and combination regimens.
在开展III期试验之前优化给药策略和辅助药物，是目前新型抗结核药物研发中的一个关键障碍。药代动力学-药效学（PK-PD）方法在提高整个制药行业以及其他抗感染治疗领域这一过程的效率方面发挥了重要作用。从最早的体外评估直至II期研发结束，使用PK-PD方法获得的信息可为概念验证提供支持，并确保药物在药理学上得到充分优化。尽管我们对体内细菌清除生物学的了解有限，但这种方法已经为这些机制提供了关键见解，并有助于确定不同药物在治疗中的作用，以及评估它们进入关键试验的潜力。虽然异烟肼在历史上似乎已得到有效利用，但人体研究表明，它在治疗的杀菌阶段并不起关键作用。相比之下，对利福霉素PK-PD的重新评估表明，通过强化当前给药策略，可能有很大空间来提高其活性。对氟喹诺酮类药物的各种PK-PD分析显示，它们在杀菌活性排名方面具有显著一致性，最近的人体II期研究似乎证实了这一结果。目前进入临床研发的全新药物类别，其药理学特征表明，现有药物的经验，尤其是EBA研究，不应影响对其药效学活性的评估，因为其药效学活性可能在性质上与许多现有药物不同。总之，PK-PD分析在新型抗结核药物和联合治疗方案的合理研发中具有至关重要的作用。
