Oral Small-Molecule Kinase Inhibitors: ADMET Fundamentals, Cytochrome P450-Mediated Drug-Drug Interactions, and Their Role in Clinical Pharmacokinetics and Toxicology

Oral small-molecule kinase inhibitors are among the most common targeted oncology and inflammatory-disease drug classes in contemporary development, and their clinical pharmacokinetics are shaped predominantly by cytochrome P450-mediated hepatic metabolism, creating a drug-drug interaction risk profile that is central to both their nonclinical and clinical development programs (van Leeuwen et al., 2014). This article examines the ADMET fundamentals specific to this drug category, the in vitro and clinical assays used to characterize cytochrome P450-mediated metabolism and transporter-mediated disposition, the food-effect and formulation considerations common to this drug class, the toxicology considerations specific to kinase inhibition, and the internal-versus-outsourcing considerations relevant to drug-drug interaction study support. The article closes with recommendations for regulatory affairs and clinical pharmacology professionals developing an oral kinase inhibitor program.