Novartis Pharma AG, Novartis Business Services, Postfach, CH-4002, Basel, Switzerland.
Novartis Institutes for BioMedical Research, Cambridge, USA; Roche Innovation Center Zurich, Wagistrasse 10, CH-8952, Schlieren, Switzerland.
Regul Toxicol Pharmacol. 2021 Jun;122:104891. doi: 10.1016/j.yrtph.2021.104891. Epub 2021 Feb 12.
In the early stages of drug research and development, there are only a few or no toxicological data available for newly synthesized small molecule drug candidates (DC). Calculation of the DC's occupational exposure limit (OEL) without toxicological data is not possible. Nevertheless, an OEL is needed to indicate the level of protection required to minimize risks for laboratory researchers and technicians. For this reason, simplified guidance is required to predict possible health hazards of DCs and their corresponding safe inhalation exposure levels. Here, we evaluated 860 drug substances (DS) with OELs calculated by Novartis and grouped the DSs by disease area (DA) and then their mode of action (MoA). 28% of the evaluated DSs (n = 242) had an OEL <10 μg/m and 72% (n = 618) had an OEL ≥10 μg/m. Our evaluation confirms that in the absence of any compound-specific data, the default OEL of 10 μg/m is a reasonably safe exposure limit for small molecule DCs. Furthermore, our analysis suggests certain DAs and MoAs as valid criteria that may be integrated into a company's specific strategy for the assessment of data-poor compounds in order to identify DCs in an early stage of their development which require a default OEL <10 μg/m.
在药物研发的早期阶段，新合成的小分子药物候选物（DC）可能只有很少或没有毒理学数据。没有毒理学数据，就不可能计算 DC 的职业接触限值（OEL）。然而，需要有一个 OEL 来表示为将实验室研究人员和技术人员的风险降到最低所需的保护水平。出于这个原因，需要简化指导来预测 DC 可能存在的健康危害及其相应的安全吸入暴露水平。在这里，我们评估了诺华计算出 OEL 的 860 种药物物质（DS），并按疾病领域（DA）对 DS 进行分组，然后按作用方式（MoA）进行分组。评估的 DS 中有 28%（n=242）的 OEL<10μg/m，72%（n=618）的 OEL≥10μg/m。我们的评估证实，在没有任何特定化合物数据的情况下，默认的 10μg/m 的 OEL 是小分子 DC 合理的安全暴露限值。此外，我们的分析表明，某些 DA 和 MoA 可以作为有效的标准，可能会被纳入公司特定的策略中，以评估数据匮乏的化合物，以便在药物开发的早期阶段识别出需要默认 OEL<10μg/m 的 DC。
