A thin-film molecularly imprinted polymer for the measurement of tyrosine kinase inhibitors in human plasma

Abstract

Tyrosine kinase inhibitors (TKIs) are a class of drugs that have found broad application in cancer therapies. These include imatinib, the first TKI used as an inhibitor of BCR-ABL kinase to treat chronic myelogenous leukemia, as well as second generation (e.g., nilotinib and dasatinib) and third generation (e.g., ponatinib) TKIs with increased potency, specificity, and binding site affinity specificity. Although the evolution of TKIs have brought dramatic increases to life expectancy, adverse events are likely due to the relatively high dosage required for treatment and the high pharmacokinetic variability between individuals. Therapeutic drug monitoring can be employed to fine tune the dosage for better control of the treatment. In this work, we present an extraction system that incorporates a novel molecularly imprinted polymer (MIP) capable of the rapid extraction of four TKIs: imatinib, nilotinib, dasatinib, and ponatinib from human plasma. The system is comprised of 96 thin-film microextraction devices in a standard flat-bottomed 96-well plate, which allows for rapid and reproducible concurrent TKIs extraction with determination by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Extraction, washing, and desorption protocols are simplified, with minimal manual handling and can be fully automated. Inter-device and batch-to-batch variability is low (∼5%), commending these for single-use applications. The linear ranges for all four TKIs are broad, with limits of detection and quantification far below the lowest clinically significant values and upper limits above the therapeutic ranges. Overall, these devices would be suitable for clinical applications or therapeutic drug monitoring of dasatinib, imatinib, nilotinib, and ponatinib, either individually or in any combination.