Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety.
10.1016/j.apsb.2022.02.015
- Author:
Wei GAO
1
;
Hongxiang HU
1
;
Lipeng DAI
1
;
Miao HE
1
;
Hebao YUAN
1
;
Huixia ZHANG
1
;
Jinhui LIAO
1
;
Bo WEN
1
;
Yan LI
2
;
Maria PALMISANO
2
;
Mohamed Dit Mady TRAORE
1
;
Simon ZHOU
2
;
Duxin SUN
1
Author Information
1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
2. Translational Development and Clinical Pharmacology, Bristol Myers Squibb, Summit, NJ 07920, USA.
- Publication Type:Journal Article
- Keywords:
Clinical efficacy/toxicity;
Drug development;
Drug optimization;
Structure-tissue exposure/selectivity relationship (STR);
Structure‒activity-relationship (SAR)
- From:
Acta Pharmaceutica Sinica B
2022;12(5):2462-2478
- CountryChina
- Language:English
-
Abstract:
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.
