Designing safer oral drugs.

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.