Role of CYP3A4 in the metabolism of tyrosine kinase inhibitors in non-small cell lung cancer therapy.

Tyrosine kinase inhibitors (TKIs) are a critical aspect of therapeutic strategy in non-small cell lung cancer (NSCLC), acting against oncogenic driver alterations, including epidermal growth factor receptor mutations, anaplastic lymphoma kinase gene rearrangements, and ROS proto-oncogene 1 fusion, etc. The clinical efficacy and safety of these agents are highly dependent on their pharmacokinetic properties, particularly metabolic pathways. Among the drug-metabolizing enzymes, cytochrome P450 3A4 (CYP3A4) plays a major role in the metabolism of many clinically used TKIs in NSCLC, generating both active and inactive metabolites that significantly influence therapeutic outcomes. While the active metabolite may retain pharmacological activity, the inactive metabolites facilitate drug elimination and prevent drug accumulation in the body. In addition, several TKIs modulate CYP3A4 activity and undergo drug-drug interactions with other CYP3A4 inhibitors and inducers, which can significantly alter systemic drug exposure, leading to toxicity or reduced efficacy. Furthermore, interindividual variability in CYP3A4 activity driven by patient-specific factors such as age, sex, comorbidities, and genetic polymorphisms is another clinical concern that necessitates individualized dosing approaches for these TKI agents. This review summarizes CYP3A4-mediated metabolism of TKIs used in NSCLC therapy and addresses the metabolites formed, providing structural insights into metabolic hot spots and guiding drug development, optimization, and prodrug strategies. It also discusses potential drug-drug interactions, compares the apparent in vivo CYP3A4 dependence of clinically used TKIs, and highlights the patient-related factors associated with TKIs, which are critical determinants of the individualized dosing strategy needed for an effective therapeutic response in patients with NSCLC. SIGNIFICANCE STATEMENT: CYP3A4 is a key regulator of the pharmacokinetics, efficacy, and safety of commonly used tyrosine kinase inhibitors in non-small cell lung cancer. This review discusses the predominant role of CYP3A4 in the metabolism of these agents, highlighting the active and inactive metabolites, the clinically relevant drug-drug interactions, and the impact of patient-specific factors on metabolic variability and systemic drug exposure. These provide critical insights into drug development and optimization strategies, and underscore the implementation of individualized dosing approaches to improve clinical outcomes in patients with non-small cell lung cancer.