Prodrugs: ADMET Fundamentals, Bioactivation Kinetics, and Their Role in Clinical Pharmacokinetics and Toxicology

A prodrug is a pharmacologically inactive or substantially less active compound that undergoes enzymatic or chemical conversion in the body to release its active therapeutic moiety, a design strategy used to improve oral absorption, solubility, target-site delivery, or duration of action relative to the active moiety administered directly (Rautio et al., 2008). This article examines the ADMET fundamentals specific to this drug category, the assays used to characterize bioactivation kinetics and converting-enzyme identity, the toxicology considerations relevant to a molecule that exists in two pharmacologically distinct forms, and the clinical pharmacokinetic study design implications of characterizing both prodrug and active moiety simultaneously. The article closes with recommendations for regulatory affairs and clinical pharmacology professionals developing a prodrug program.