DMPK, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
Clin Pharmacol Ther. 2020 Aug;108(2):298-305. doi: 10.1002/cpt.1846. Epub 2020 May 10.
The in vitro affinity of a compound for its target is an important feature in drug discovery, but what remains is how predictive in vitro properties are of in vivo therapeutic drug exposure. We assessed the relationship between in vitro potency and clinically efficacious concentrations for marketed small molecule drugs (n = 164) and how they may differ depending on therapeutic indication, mode of action, receptor type, target localization, and function. Approximately 70% of compounds had a therapeutic unbound plasma exposure lower than in vitro potency; the median ratio of exposure in relation to in vitro potency was 0.32, and 80% had ratios within the range of 0.007 to 8.7. We identified differences in the in vivo-to-in vitro potency ratio between indications, mode of action, target type, and matrix localization, and whether or not the drugs had active metabolites. The in vitro-assay variability contributions appeared to be the smallest; within the same drug target and mode of action the within-variability was slightly broader; but both were substantially less compared with the overall distribution of ratios. These data suggest that in vitro potency conditions, estimated in vivo potency, required level of receptor occupancy, and target turnover are key components for further understanding the link between clinical drug exposure and in vitro potency.
化合物与靶标的体外亲和力是药物发现的一个重要特征，但仍然存在的问题是，体外特性在多大程度上可以预测体内治疗药物的暴露情况。我们评估了已上市小分子药物（n=164）的体外效价与临床有效浓度之间的关系，以及它们可能因治疗指征、作用模式、受体类型、靶标定位和功能而有所不同。大约 70%的化合物的治疗性游离血浆暴露低于体外效价；暴露与体外效价的中位数比值为 0.32，80%的比值在 0.007 至 8.7 之间。我们发现，在不同的适应证、作用模式、靶标类型和基质定位，以及药物是否有活性代谢物的情况下，体内效价与体外效价的比值存在差异。体外检测变异性的贡献似乎最小；在相同的药物靶标和作用模式中，变异性稍宽，但与比值的总体分布相比，两者都要小得多。这些数据表明，体外效价条件、体内效价估计、所需受体占有率和靶标周转率是进一步了解临床药物暴露与体外效价之间联系的关键因素。
