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Issue 3, 2017
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Designing safer oral drugs

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Abstract

Designing an oral drug such that its estimated dose to humans is both efficacious and safe is challenging. During the early design stage, where in vitro or preclinical species in vivo safety data are limited, heuristic-based criteria often related to physicochemical properties are used for guidance. The causal relationship between a compound's log P and its human in vivo 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−1 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 in vivo 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 in vivo plasma clearances is discussed.

Graphical abstract: Designing safer oral drugs

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Publication details

The article was received on 20 Dec 2016, accepted on 16 Jan 2017 and first published on 20 Jan 2017


Article type: Research Article
DOI: 10.1039/C6MD00706F
Citation: Med. Chem. Commun., 2017,8, 571-577
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    Designing safer oral drugs

    M. C. Wenlock, Med. Chem. Commun., 2017, 8, 571
    DOI: 10.1039/C6MD00706F

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