An article by Marina V. Antunes et al at several institutions in Brazil published in the January 2023 edition of the Journal of Pharmaceutical and Biochemical Analysis, validated an assay measuring imatinib mesylate and its main metabolite from finger-stick blood microsamples for therapeutic drug monitoring (TDM). The paper is entitled “Volumetric dried blood microsampling for monitoring imatinib mesylate therapy: Method development and clinical application in patients with chronic myeloid leukemia.”
Chronic myeloid leukemia (CML) is a blood cancer of hematopoietic stem cells leading to increased myeloid hyperplasia of the bone marrow. Detection of the Philadelphia (Ph+) chromosome, a genetic abnormality of chromosome 22 through the formation of a fusion gene called BCR-ABL, is used to confirm diagnosis.
Imatinib mesylate (IM) is a tyrosine kinase inhibiter (TKI) drug used as a first line treatment of chronic myeloid leukemia in patients who have the Ph+ chromosome. Imatinib was invented by biochemist Micholas Lyndon working at Ciba-Geigy (now Novartis), and the drug was approved by the US Food and Drug Administration (FDA) in May 2001. Imatinib acts to inhibit several tyrosine kinases (TK), including the TK produced from the BCR-ABL fusion gene, which acts to switch off signaling pathways that promote leukemogenesis.
IM is mainly metabolized by the cytochrome P450 system, and the primary metabolite is a N-demethylated (NIM) derivative which has similar pharmacological activity as the parent drug. According to previous studies quoted in the paper, IM has a narrow therapeutic window where plasma concentrations above 1000 ng/ml1 have a higher probability of both therapeutic and molecular responses.
In fact, the paper quoted one previous study in which increasing the intake of IM from 90 to 100%, was found to increase treatment response likelihood by up to 2-fold. Conversely, plasma concentrations above 3000 ng/ml-1 have been linked to adverse side effects from IM, such as neutropenia and edema.
The study authors underlined the benefits of remote, home collection of dried capillary samples, as a more comfortable and convenient approach for patients. This sampling approach is also easier for study coordinators, because dried blood samples can be shipped via standard mail to a central lab without cold shipping or complicated logistics – just a standard shipping envelope and postage.
In terms of pharmacokinetic measurement, home collection approaches (using Mitra devices with VAMS, for example), allow more flexibility for samples to be collected at different time points. This flexibility inspired the research group to develop a VAMS assay to measure both IM and its main metabolite as a possible tool for remote collection of IM samples.
One reason for choosing VAMS was that a successful assay to measure IM had been previously developed as part of a panel of 8 TKIs. To further advance the work that had already been reported, the group embarked on developing a method to measure both the main metabolite (NIM) and parent drug (IM) from CML patients. An important outcome of the new study was to understand the impact of remote, at-home sampling on patient satisfaction and treatment adherence.
Clinical Processes:
Feedback provided by study volunteers via the questionnaire showed some promising results:
This paper demonstrates the importance of developing high-quality TDM assays for potential deployment across broad geographical areas, where the sheer size of the country makes transportation of traditionally collected wet samples challenging and costly.
The results of the study volunteer questionnaire demonstrated that 87% felt less discomfort using Mitra devices with VAMS compared to venipuncture. All reported either no pain or little pain on the pain score related to lancing their fingers to collect the blood samples. This study’s findings may negate the need to resort to other more costly blood sampling solutions available.
This article was summarized for our readers by James Rudge, PhD, Technical Director. This is curated content. To learn more about the important research outlined in this blog, visit the original article in the Journal of Pharmaceutical and Biochemical Analysis.
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