Research progress in pharmacokinetics and therapeutic drug monitoring of tyrosine kinase inhibitors in the treatment of gastrointestinal stromal tumors
Tyrosine kinase inhibitors(TKIs)represent a class of small-molecule targeted drugs that improve the survival time of patients with gastrointestinal stromal tumor(GIST).Imatinib,sunitinib,regorafenib,ripretinib,and avapritinib are commonly used TKIs in the clinical treatment of various types of GIST.This article provides a comprehensive review of the pharmacokinetics and therapeutic drug monitoring(TDM)of these five drugs,finding that there is significant individual variability in the pharmacokinetics of these drugs.Among them,the absorption of imatinib,regorafenib,and avapritinib are influenced by food intake.Imatinib should be taken with meals and 200 mL of water,regorafenib is taken with a low-fat meal,while avapritinib is taken on an empty stomach.TKIs are mainly metabolized by cytochrome P450 3A4(CYP3A4),and when used in combination with CYP3A4 inducers or inhibitors,drug exposure levels will significantly change;apart from metabolic enzymes,the exposure levels of TKIs are also influenced by interactions with the transporter proteins P-glycoprotein and breast cancer resistance protein.Currently,research on TDM for TKIs is still in the exploratory stage,with a substantial amount of literature reporting the effective concentrations of imatinib,sunitinib and regorafenib.However,the precise relationship between exposure levels and efficacy/toxicity needs further exploration.Currently,there is a lack of research on the correlation between exposure levels and efficacy/toxicity of ripretinib and avapritinib.It is recommended to implement TDM in patients taking these drugs and explore their therapeutic window in combination with pharmacokinetic models.The commonly used methods for clinical TDM of TKIs include immunoassay,chromatography,and surface-enhanced Raman spectroscopy,providing a technical basis for clarifying the therapeutic window of TKIs.
gastrointestinal stromal tumortyrosine kinase inhibitorspharmacokineticsdrug-drug interactiontherapeutic drug monitoring
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