Wenlock M C
InSilicoLynx Ltd , BioHub at Alderley Park , Mereside, Alderley Park , Cheshire , SK10 4TG , UK . Email:
Medchemcomm. 2017 Jan 20;8(3):571-577. doi: 10.1039/c6md00706f. eCollection 2017 Mar 1.
Designing an oral drug such that its estimated dose to humans is both efficacious and safe is challenging. During the early design stage, where or preclinical species safety data are limited, heuristic-based criteria often related to physicochemical properties are used for guidance. The causal relationship between a compound's log and its human toxicity is considered. With respect to designing efficacious oral drugs that potentially have reduced toxicity liabilities, an alternative heuristic-based criterion is proposed based on the amount of compound in the body at steady state. In humans, a threshold for the amount of compound in the body at steady state of 0.5 mg kg is suggested. The criterion is based on the minimum toxic blood-plasma concentration that produces clinically relevant side effects or symptoms in humans for 242 oral drugs. It can be used to estimate a therapeutic window against which a compound's estimated plasma levels for a particular dose size and frequency can be assessed. The relationship between this criterion and acceptable oral dose sizes for different charge types with different plasma clearances is discussed.
设计一种口服药物，使其对人类的估计剂量既有效又安全，这是一项具有挑战性的任务。在早期设计阶段，临床前物种的安全数据有限，通常使用基于启发式的、与物理化学性质相关的标准作为指导。人们会考虑化合物的log 与人类毒性之间的因果关系。关于设计可能具有降低毒性风险的有效口服药物，基于稳态下体内化合物的量，提出了一种基于启发式的替代标准。在人类中，建议稳态下体内化合物量的阈值为0.5 mg/kg。该标准基于242种口服药物在人体中产生临床相关副作用或症状的最低有毒血浆浓度。它可用于估计一个治疗窗口，据此可以评估特定剂量大小和给药频率下化合物的估计血浆水平。本文讨论了该标准与不同电荷类型、不同血浆清除率的可接受口服剂量大小之间的关系。
