Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
Br J Pharmacol. 2010 Jan;159(1):25-33. doi: 10.1111/j.1476-5381.2009.00530.x.
Non-clinical QT-related assays aligned to the pharmaceutical drug discovery and development phases are used in several ways. During the early discovery phases, assays are used for hazard identification and wherever possible for hazard elimination. The data generated enable us to: (i) establish structure-activity relationships and thereby; (ii) influence the medicinal chemistry design and provide tools for effective decision making; and provide structure-activity data for in silico predictive databases; (iii) solve problems earlier; (iv) provide reassurance for compound or project to progress; and (v) refine strategies as scientific and technical knowledge grows. For compounds progressing into pre-clinical development, the 'core battery' QT-related data enable an integrated risk assessment to: (i) fulfil regulatory requirements; (ii) assess the safety and risk-benefit for compound progression to man; (iii) contribute to defining the starting dose during the phase I clinical trials; (iv) influence the design of the phase I clinical trials; (v) identify clinically relevant safety biomarkers; and (vi) contribute to the patient risk management plan. Once a compound progresses into clinical development, QT-related data can be applied in the context of risk management and risk mitigation. The data from 'follow-up' studies can be used to: (i) support regulatory approval; (ii) investigate discrepancies that may have emerged within and/or between non-clinical and clinical data; (iii) understand the mechanism of an undesirable pharmacodynamic effect; (iv) provide reassurance for progression into multiple dosing in humans and/or large-scale clinical trials; and (v) assess drug-drug interactions. Based on emerging data, the integrated risk assessment is then reviewed in this article, and the benefit-risk for compound progression was re-assessed. Project examples are provided to illustrate the impact of non-clinical data to support compound progression throughout the drug discovery and development phases, and regulatory approval.
非临床 QT 相关检测与药物发现和开发阶段相匹配，有多种用途。在早期发现阶段，检测用于识别危害，尽可能消除危害。生成的数据使我们能够：(i) 建立结构-活性关系，从而；(ii) 影响药物化学设计并提供有效的决策工具，并为计算机预测数据库提供结构-活性数据；(iii) 更早地解决问题；(iv) 为化合物或项目的进展提供保证；以及 (v) 在科学和技术知识增长的情况下完善策略。对于进入临床前开发的化合物，“核心电池”QT 相关数据可进行综合风险评估，以：(i) 满足监管要求；(ii) 评估化合物进入人体的安全性和风险效益；(iii) 有助于确定 I 期临床试验的起始剂量；(iv) 影响 I 期临床试验的设计；(v) 确定临床相关的安全生物标志物；以及 (vi) 为患者风险管理计划做出贡献。一旦化合物进入临床开发，QT 相关数据可应用于风险管理和风险缓解。“后续”研究的数据可用于：(i) 支持监管批准；(ii) 调查非临床和临床数据内部和/或之间可能出现的差异；(iii) 了解不良药效学作用的机制；(iv) 为在人体中进行多次给药和/或大规模临床试验的进展提供保证；以及 (v) 评估药物相互作用。基于新出现的数据，本文对综合风险评估进行了回顾，并重新评估了化合物进展的获益-风险。提供了项目示例，说明非临床数据在支持化合物整个药物发现和开发阶段以及监管批准中的作用。
