Clinical Pharmacology Modelling and Simulation, GSK, London, UK.
Clinical Pharmacology, Modelling and Simulation, Parexel International, Dublin, Ireland.
Clin Transl Sci. 2024 Jun;17(6):e13831. doi: 10.1111/cts.13831.
The systemic exposure at the no-observed-adverse-effect-level (NOAEL) estimated from animals is an important criterion commonly applied to guard the safety of participants in clinical trials of investigational drugs. However, the discrepancy in toxicity profile between species is widely recognized. The objective of the work reported here was to assess, via simulation, the level of uncertainty in the NOAEL estimated from an animal species and the effectiveness of applying its associated exposure value to minimizing the toxicity risk to human. Simulations were conducted for dose escalation of an investigational new chemical entity with hypothetical exposure-response models for the dose-limiting toxicity under a variety of conditions, in terms of between-species relative sensitivity to the toxicity and the between-subject variability in the key parameters determining the sensitivity and pharmacokinetics. Results show a high uncertainty in the NOAEL estimation. Notably, even when the animal species and humans are assumed to have the same sensitivity, which may not be realistic, limiting clinical dose to the exposure at the NOAEL that has been identified in the animals carries a high risk of either causing toxicity or under-dosing, hence undermining the therapeutic potential of the drug candidate. These findings highlight the importance of understanding the mechanism of the toxicity profile and its cross-species translatability, as well as the importance of understanding the dose requirement for achieving adequate pharmacology.
从动物身上估计的无观察到不良效应水平（NOAEL）的全身暴露是一个常用的标准，用于保护临床试验中研究药物参与者的安全。然而，物种间毒性特征的差异是广泛公认的。这里报告的工作的目的是通过模拟来评估从动物物种估计的 NOAEL 水平的不确定性程度，以及应用其相关暴露值来最小化人类毒性风险的有效性。在各种条件下，对具有假设的暴露-反应模型的新型化学实体进行剂量递增模拟，以评估对毒性的物种间相对敏感性和决定敏感性和药代动力学的关键参数的个体间变异性。结果表明，NOAEL 估计存在高度不确定性。值得注意的是，即使假设动物和人类对毒性的敏感性相同（这可能不现实），将限制临床剂量限制在动物中确定的 NOAEL 暴露水平，也会带来毒性或剂量不足的高风险，从而破坏候选药物的治疗潜力。这些发现强调了理解毒性特征的机制及其跨物种可转移性的重要性，以及理解实现充分药理学所需的剂量要求的重要性。
