[Clinical pharmacokinetics of small molecule tyrosine kinase inhibitors]

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Human protein tyrosine kinases are crucial in cancer development and are key targets for drug development.
• Eight small molecule tyrosine kinase inhibitors (TKIs) were approved by China's FDA by 2012 for cancer therapy.

Purpose of the Study:

• To review the pharmacokinetic properties (absorption, distribution, metabolism, excretion) of approved TKIs.
• To examine the drug-drug interaction profiles of these approved TKIs.

Main Methods:

• Literature review of pharmacokinetic data for eight approved TKIs.
• Analysis of drug-drug interaction studies, including metabolism and transporter interactions.

Main Results:

• TKIs show rapid peak plasma concentrations, extensive distribution, and high protein binding (>90%).
• Primary metabolism occurs via CYP3A4, with most TKIs affected by CYP3A4 modulators (except sorafenib).
• Excretion is predominantly fecal, with minor urinary elimination; TKIs are substrates for ABCB1 (P-gp) and ABCG2 (BCRP) transporters.

Conclusions:

• Approved TKIs share common pharmacokinetic and drug interaction characteristics, primarily involving CYP3A4 and efflux transporters.
• Potential for significant drug-drug interactions exists due to CYP450/UGT enzyme inhibition and transporter interactions.
• Reactive metabolites formed from gefitinib, erlotinib, dasatinib, and sunitinib pose risks of covalent binding to biomolecules.