A Holistic Review of the Preclinical Landscape for Long-Acting Anti-infective Drugs Using HIV as a Paradigm.
A Holistic Review of the Preclinical Landscape for Long-Acting Anti-infective Drugs Using HIV as a Paradigm.
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以 HIV 为范例对长效抗感染药物的临床前情况进行全面回顾。
DOI：
10.1093/cid/ciac685
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Olagunju,Adeniyi
中科院分区：
文献类型：
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作者：
Neary,Megan;Owen,Andrew;Olagunju,Adeniyi
缺乏可预测的临床前模型是药物开发中急剧损耗率的关键因素。如果旨在确定任何新的不确定性的临床前研究能够预测人类暴露和反应，那么对于新的化学实体或现有批准的重新配制的长效（LA）给药，成功的临床转化可能会更高。在这篇综述中，我们以人类免疫缺陷病毒LA疗法的临床前开发为范例，概述了用于LA配方和递送系统的标准临床前评估。综述了新型LA抗逆转录病毒制剂和递送系统临床前开发的关键进展，包括双特异性宽中和单克隆抗体和小分子技术，用于共同递送具有不同溶解度特性的多种药物。利用组织工程和三维体外建模的最新发展，有新的机会来推进抗感染活性的临床前建模，发育和生殖毒性评估，并应用定量建模和模拟策略。这些发展可能会在未来几年推动更多的LA抗感染药物和多用途技术进入临床开发。
Lack of predictive preclinical models is a key contributor to the steep attrition rate in drug development. Successful clinical translation may be higher for new chemical entities or existing approved drugs reformulated for long-acting (LA) administration if preclinical studies designed to identify any new uncertainties are predictive of human exposure and response. In this review, we present an overview of standard preclinical assessments deployed for LA formulations and delivery systems, using human immunodeficiency virus LA therapeutics preclinical development as a paradigm. Key progress in the preclinical development of novel LA antiretrovirals formulations and delivery systems are summarized, including bispecific broadly neutralizing monoclonal antibody and small molecule technologies for codelivery of multiple drugs with disparate solubility properties. There are new opportunities to take advantage of recent developments in tissue engineering and 3-dimensional in vitro modeling to advance preclinical modeling of anti-infective activity, developmental and reproductive toxicity assessment, and to apply quantitative modeling and simulation strategies. These developments are likely to drive the progression of more LA anti-infective drugs and multipurpose technologies into clinical development in the coming years.