Better prediction of the local concentration-effect relationship: the role of physiologically based pharmacokinetics and quantitative systems pharmacology and toxicology in the evolution of model-informed drug discovery and development.

Better prediction of the local concentration-effect relationship: the role of physiologically based pharmacokinetics and quantitative systems pharmacology and toxicology in the evolution of model-informed drug discovery and development. Drug Discov Today. 2019 May 24;: Authors: Polak S, Tylutki Z, Holbrook M, Wiśniowska B Abstract Model-informed drug discovery and development (MID3) is an umbrella term under which sit several computational approaches: quantitative systems pharmacology (QSP), quantitative systems toxicology (QST) and physiologically based pharmacokinetics (PBPK). QSP models are built using mechanistic knowledge of the pharmacological pathway focusing on the putative mechanism of drug efficacy; whereas QST models focus on safety and toxicity issues and the molecular pathways and networks that drive these adverse effects. These can be mediated through exaggerated on-target or off-target pharmacology, immunogenicity or the physiochemical nature of the compound. PBPK models provide a mechanistic description of individual organs and tissues to allow the prediction of the intra- and extra-cellular concentration of the parent drug and metabolites under different conditions. Information on biophase concentration enables the prediction of a drug effect in different organs and assessment of the potential for drug-drug interactions. Together, these modelling approaches can inform the exposure-response relationship and hence sup...
Source: Drug Discovery Today - Category: Drugs & Pharmacology Authors: Tags: Drug Discov Today Source Type: research