Acta Pharmaceutica Sinica B (May 2022)

Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety

  • Wei Gao,
  • Hongxiang Hu,
  • Lipeng Dai,
  • Miao He,
  • Hebao Yuan,
  • Huixia Zhang,
  • Jinhui Liao,
  • Bo Wen,
  • Yan Li,
  • Maria Palmisano,
  • Mohamed Dit Mady Traore,
  • Simon Zhou,
  • Duxin Sun

Journal volume & issue
Vol. 12, no. 5
pp. 2462 – 2478

Abstract

Read online

Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.

Keywords