Translational predictions of phase 2a first-in-patient efficacy studies for antituberculosis drugs.
Translational predictions of phase 2a first-in-patient efficacy studies for antituberculosis drugs.
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DOI：
10.1183/13993003.00165-2023
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发表时间：
2023-08
影响因子：
24.3
通讯作者：
Savic, Rada M.
中科院分区：
文献类型：
--
作者：
Ernest, Jacqueline P.;Goh, Janice Jia Ni;Strydom, Natasha;Wang, Qianwen;Wijk, Rob C. van;Zhang, Nan;Deitchman, Amelia;Nuermberger, Eric;Savic, Rada M.
结核病的2a期试验通常使用早期杀菌活性（EBA），即痰液CFU在14天内的下降，作为测试药物作为单药治疗疗效的主要终点。 然而，2a期试验的平均成本可能在700万美元到1960万美元之间，而>30%的药物未能进展到3期。 因此，更好地利用临床前数据来预测和优先考虑最有可能成功的药物将有助于加速药物开发并降低成本。我们的目标是预测临床EBA使用临床前体内药代动力学（PK）-药效学（PD）数据和基于模型的转化药理学方法。首先，编制小鼠PK、PD和临床PK模型。其次，建立小鼠PK-PD模型以推导出确定性-响应关系。第三，使用小鼠PK-PD关系进行临床EBA研究的翻译预测，并通过临床PK模型和种属特异性蛋白质结合提供信息。根据小鼠模型准确预测是否存在临床疗效。在给药的前2天以及第2天和第14天之间，预测的CFU每日降低与临床观察结果一致。 该平台提供了一个创新的解决方案，为2a期EBA试验提供信息，甚至取代2a期EBA试验，弥合小鼠疗效研究与2b期和3期试验之间的差距，并大大加快药物开发。预测早期杀菌活性的转化药理学平台https://bit.ly/3NoO89J
Phase 2a trials in tuberculosis typically use early bactericidal activity (EBA), the decline in sputum CFU over 14 days, as the primary end-point for testing the efficacy of drugs as monotherapy. However, the cost of phase 2a trials can range from USD 7 million to USD 19.6 million on average, while >30% of drugs fail to progress to phase 3. Better utilising pre-clinical data to predict and prioritise the most likely drugs to succeed will thus help to accelerate drug development and reduce costs. We aim to predict clinical EBA using pre-clinical in vivo pharmacokinetic (PK)-pharmacodynamic (PD) data and a model-based translational pharmacology approach. First, mouse PK, PD and clinical PK models were compiled. Second, mouse PK-PD models were built to derive an exposure–response relationship. Third, translational prediction of clinical EBA studies was performed using mouse PK-PD relationships and informed by clinical PK models and species-specific protein binding. Presence or absence of clinical efficacy was accurately predicted from the mouse model. Predicted daily decreases of CFU in the first 2 days of treatment and between day 2 and day 14 were consistent with clinical observations. This platform provides an innovative solution to inform or even replace phase 2a EBA trials, to bridge the gap between mouse efficacy studies and phase 2b and phase 3 trials, and to substantially accelerate drug development. A translational pharmacology platform to predict early bactericidal activity https://bit.ly/3NoO89J
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DOI：
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发表时间：
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影响因子：
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影响因子：
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DOI：
10.1146/annurev-pharmtox-030920-011143
发表时间：
2021-01-06
影响因子：
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作者：
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通讯作者：
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