Imatinib, sunitinib and pazopanib: From flat-fixed dosing towards a pharmacokinetically guided personalized dose

Area of Science:

• Pharmacology
• Oncology
• Drug Metabolism and Pharmacokinetics

Background:

• Tyrosine kinase inhibitors (TKIs) are crucial anti-cancer drugs targeting tyrosine kinases involved in cellular processes.
• Current fixed-dose administration of oral TKIs like imatinib, sunitinib, and pazopanib for solid tumors overlooks significant interpatient pharmacokinetic (PK) variability.
• Established exposure-outcome relationships and therapeutic windows for these TKIs highlight the potential for dose optimization.

Purpose of the Study:

• To review current knowledge on therapeutic drug monitoring (TDM)-guided individualized dosing of imatinib, sunitinib, and pazopanib in solid tumor treatment.
• To summarize preclinical and clinical data defining efficacy and toxicity thresholds for these TKIs.
• To outline PK models, influencing factors, and pharmacological interventions for optimizing TKI plasma concentrations.

Main Methods:

• Comprehensive literature review of preclinical and clinical studies.
• Analysis of pharmacokinetic (PK) models and factors affecting drug variability.
• Summary of established exposure-treatment outcome relationships and therapeutic windows.

Main Results:

• Significant interpatient PK variability exists for imatinib, sunitinib, and pazopanib, impacting treatment outcomes.
• Established thresholds for efficacy and toxicity allow for the definition of therapeutic windows.
• TDM-guided individualized dosing strategies can potentially enhance efficacy and reduce toxicity.

Conclusions:

• TDM is a valuable tool for optimizing imatinib, sunitinib, and pazopanib dosing in solid tumor patients.
• Individualized dosing based on measured blood concentrations can improve therapeutic outcomes by managing PK variability.
• This review provides guidance on methods for optimizing exposure to these critical anti-cancer agents.