Fatemeh Aghai-Trommeschlaeger

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Topic

Development of liquid chromatography methods for the quantification of kinase inhibitors and letermovir in human serum for the application during therapeutic drug monitoring in haemato-oncological patients

Abstract (plain language summary):

This dissertation focuses on improving cancer treatment by making sure patients receive the right amount of medication. Special drugs called kinase inhibitors, often taken by cancer patients, can have very different effects from person to person. Some people may not get enough of the drug, while others may get too much and experience harmful side effects. A similar issue applies to letermovir, a drug used to prevent infections after stem cell transplants.

To address this, new laboratory methods were developed to measure how much of these drugs are present in the blood. These methods were used in real-life clinical settings and showed that drug levels can vary a lot between patients, even if they take the same dose. These findings support the idea that measuring drug levels in the blood can help doctors adjust treatments more precisely, improving safety and effectiveness.

Abstract (Scientific audience)

This dissertation presents validated HPLC-DAD and LC-MS/MS methods for quantifying ten kinase inhibitors and letermovir in human serum, with the goal of supporting therapeutic drug monitoring (TDM) in haemato-oncological patients. The methods comply with FDA and EMA guidelines and were applied to clinical samples to assess interindividual variability in drug exposure.

Results revealed substantial variability in serum concentrations despite fixed dosing, particularly for cabozantinib, dabrafenib, nilotinib, osimertinib, ruxolitinib, and trametinib. Specific analysis in melanoma and GvHD patients indicated exposure–toxicity relationships, underlining the need for individualized dosing. A PBPK model quantified the interaction between ruxolitinib and posaconazole, showing increased drug exposure without supporting a general 50% dose reduction.

Letermovir levels also showed wide interindividual variation, raising concerns about under- or overexposure and potential resistance. The developed methods provide a foundation for implementing TDM to optimize therapeutic efficacy and minimize adverse effects in complex clinical scenarios.

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