Drug metabolism is a major determinant of drug concentrations in the body. Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs can lead to alteration in the exposure of the victim drug, raising safety or effectiveness concerns. Assessment of the DDI potential starts with in vitro experiments to determine kinetic parameters and identify risks associated with the use of comedication that can inform future clinical studies. The diverse range of experimental models and techniques has significantly contributed to the examination of potential DDIs. Cytochrome P450 (CYP) enzymes are responsible for the biotransformation of many drugs on the market, making them frequently implicated in drug metabolism and DDIs. Consequently, there has been a growing focus on the assessment of DDI risk for CYPs. This review article provides mechanistic insights underlying CYP inhibition/induction and an overview of the in vitro assessment of CYP-mediated DDIs.

Small molecule kinase inhibitors are one of the fastest growing classes of drugs, which are approved by the US Food and Drug Administration (FDA) for cancer and non-cancer indications. As of September 2023, there were over 70 FDA-approved small molecule kinase inhibitors on the market, 42 of which were approved in the past five years (2018-2023). This minireview discusses recent advances in our understanding of the pharmacology, metabolism, and toxicity profiles of recently approved kinase inhibitors with a central focus on tyrosine kinase inhibitors (TKIs). In this minireview we discuss the most common therapeutic indications and molecular target(s) of kinase inhibitors FDA-approved 2018-2023. We also describe unique aspects of the metabolism, bioactivation, and drug-drug interaction (DDI) potential of kinase inhibitors; discuss drug toxicity concerns related to kinase inhibitors, such as drug-induced liver injury; and highlight clinical outcomes and challenges relevant to TKI therapy. Case examples are provided for common TKI targets, metabolism pathways, DDI potential, and risks for serious adverse drug reactions. The minireview concludes with a discussion of perspectives on future research to optimize TKI therapy to maximize efficacy and minimize drug toxicity. Significance Statement This minireview highlights important aspects of the clinical pharmacology and toxicology of small molecule kinase inhibitors FDA-approved 2018-2023. We describe key advances in the therapeutic indications and molecular targets of tyrosine kinase inhibitors (TKIs). The major metabolism pathways and toxicity profiles of recently approved TKIs are discussed. Clinically relevant case examples are provided that demonstrate the risk for hepatotoxic drug interactions involving TKIs and co-administered drugs.

Interindividual variability in drug metabolism can significantly affect drug concentrations in the body and subsequent drug response. Understanding an individual9s drug metabolism capacity is important for predicting drug exposure and developing precision medicine strategies. The goal of precision medicine is to individualize drug treatment for patients to maximize efficacy and minimize drug toxicity. While advances in pharmacogenomics have improved our understanding of how genetic variations in drug-metabolizing enzymes (DMEs) affect drug response, non-genetic factors are also known to influence drug metabolism phenotypes. This minireview will discuss approaches beyond pharmacogenetic testing to phenotype DMEs- particularly the cytochrome P450 enzymes- in clinical settings. Several phenotyping approaches have been proposed: traditional approaches include phenotyping with exogenous probe substrates and the use of endogenous biomarkers; newer approaches include evaluating circulating non-coding RNAs (ncRNAs) and liquid biopsy-derived markers relevant to DME expression and function. The goals of this minireview are to: 1) provide a high-level overview of traditional and novel approaches to phenotype individual drug metabolism capacity; 2) describe how these approaches are being applied or can be applied to pharmacokinetic studies; and 3) discuss perspectives on future opportunities to advance precision medicine in diverse populations. Significance Statement This minireview provides an overview of recent advances in approaches to characterize individual drug metabolism phenotypes in clinical settings. Herein, we highlight the integration of existing pharmacokinetic biomarkers with novel approaches; also discussed are current challenges and existing knowledge gaps. The article concludes with perspectives on the future deployment of a liquid biopsy-informed physiologically based pharmacokinetic (PBPK) strategy for patient characterization and precision dosing.