https://doi.org/10.1016/j.apsb.2022.02.002
In this new article publication from Acta Pharmaceutica Sinica B, authors Duxin Sun, Wei Gao, Hongxiang Hu and Simon Zhou from the University of Michigan, Ann Arbor, MI, USA and Bristol Meyer Squibb Company, Summit, NJ, USA discuss how ninety percent of clinical drug development fails and how this figure can be improved.
Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization are overlooked?
Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity–relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity.
The authors of this article propose structure‒tissue exposure/selectivity–activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early.
STAR may improve drug optimization and clinical studies for the success of clinical drug development.
Article reference: Duxin Sun, Wei Gao, Hongxiang Hu, Simon Zhou, Why 90% of clinical drug development fails and how to improve it?, Acta Pharmaceutica Sinica B, 2022, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2022.02.002.
Keywords: Drug development; Drug optimization; Clinical trial; Structure‒tissue exposure/selectivity relationship (STR); Structure‒tissue exposure/selectivity–activity relationship (STAR)
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383522000521-ga1_lrg.jpg Caption: Structure‒tissue exposure/selectivity–activity relationship (STAR) selects drug candidates and balances clinical dose/efficacy/toxicity.
