Orally administered, small-molecule anticancer drugs with tumor-specific cellular protein targets (OACD) have revolutionized oncological pharmacotherapy. Nevertheless, the differences in exposure to these drugs in the systemic circulation and extravascular fluid compartments have led to several cases of therapeutic failure, in addition to posing unknown risks of toxicity. The therapeutic drug monitoring (TDM) of OACDs in therapeutically relevant peripheral fluid compartments is therefore essential. In this work, the available knowledge regarding exposure to OACD concentrations in these fluid spaces is summarized. A review of the literature was conducted by searching Embase, PubMed, and Web of Science for clinical research articles and case reports published between 10 May 2001 and 31 August 2022. Results show that, to date, penetration into cerebrospinal fluid has been studied especially intensively, in addition to breast milk, leukocytes, peripheral blood mononuclear cells, peritoneal fluid, pleural fluid, saliva and semen. The typical clinical indications of peripheral fluid TDM of OACDs were (1) primary malignancy, (2) secondary malignancy, (3) mental disorder, and (4) the assessment of toxicity. Liquid chromatography–tandem mass spectrometry was most commonly applied for analysis. The TDM of OACDs in therapeutically relevant peripheral fluid spaces is often indispensable for efficient and safe treatments.
Összefoglaló. Bevezetés: Az onkológia, így a hemato-onkológia területén a szájon át alkalmazható, nem hormonhatású, specifikus fehérje támadásponttal rendelkező (ismertebb nevén célzott terápiás) daganatellenes gyógyszerek megjelenése új fejezetet nyitott, sőt, napjainkra a 10 leggyakrabban használt onkológiai szer közé bekerült a hemato-onkológiában használt ruxolitinib és imatinib. E gyógyszerek alkalmazásának fő előnye a kíméletes (nem parenterális adagolású), speciális intézményi környezetet nem igénylő gyógyszerelés, valamint a kedvezőbb mellékhatásprofil. Legfontosabb hátrányuk, hogy a kezelések költségesek, és megjelenik a per os farmakoterápiák esetében jellemző adherencia kockázat, ami – a gyógyszer-interakciók és a betegek állapota miatt sajátos farmakokinetikai jellemzőkkel együtt – a terápia monitorozását alapvetően fontossá teszi. Mivel a klasszikus gyógyszerszint-monitorozás (TDM) esetében megszokott terápiás tartományok ezen a területen nem állnak rendelkezésre, a klinikum és a TDM laboratórium közötti fokozott együttműködés az evidenciaalapú, egyénre szabott, sikeres kezelésekhez nélkülözhetetlen. Közleményünkben bemutatjuk a számos hemato-onkológiai kórfolyamat esetében alkalmazott tirozin-kináz-gátló gyógyszerek használatának kockázatait, és rájuk vonatkozóan megoldást javaslunk a gyógyszerszint-monitorozással támogatott, egyénre szabott terápiák megvalósításához. Ezek klinikai gyakorlatba történő mielőbbi bevezetésének elősegítéséhez információt nyújtunk a Semmelweis Egyetemen elérhető onkológiai TDM-szolgáltatásról. Summary. Introduction: A new era has begun in the field of oncological therapies, including hemato-oncological treatments, with the recent introduction of orally administered, non-hormonal antineoplastic drugs with specific protein targets (also known as targeted therapies). Two of these entities, ruxolitinib and imatinib, are already on the list of the ten most prescribed anticancer agents. Their primary advantage is the patient-centric, non-parenteral application which does not require a specialized healthcare infrastructure, and in most cases associated with less severe adverse effects. The major disadvantages associated with their use, on the other hand, are their considerable costs, the increased risk of therapy non-adherence, the poor predictability of pharmacokinetic characteristics because of the frequently altered physiological status of oncological patients, and the real potential of possible drug interactions. Monitoring the course of the treatment is therefore pivotal. Since therapeutic concentration ranges employed in the classical framework of therapeutic drug monitoring (TDM) are not available, an intensive collaboration of the clinical team and the TDM laboratory is required for guiding individualized, evidence-based therapies using these substances. The aim of this work is to present the risks associated with the use of tyrosine kinase inhibitors employed for the treatment of various hemato-oncological disorders and solid tumors, and to make recommendations for guiding individually tailored therapies supported by the TDM of these novel drugs. Specific information is provided to enhance the translation of these concepts into clinical practice with the support of the existing oncological TDM service available at Semmelweis University.
Ibrutinib (IBR) is an oral anticancer medication that inhibits Bruton tyrosine kinase irreversibly. Due to the high risk of adverse effects and its pharmacokinetic variability, the safe and effective use of IBR is expected to be facilitated by precision dosing. Delivering suitable clinical laboratory information on IBR is a prerequisite of constructing fit-for-purpose population and individual pharmacokinetic models. The validation of a dedicated high-throughput method using liquid chromatography–mass spectrometry is presented for the simultaneous analysis of IBR and its pharmacologically active metabolite dihydrodiol ibrutinib (DIB) in human plasma. The 6 h benchtop stability of IBR, DIB, and the active moiety (IBR+DIB) was assessed in whole blood and in plasma to identify any risk of degradation before samples reach the laboratory. In addition, four regression algorithms were tested to determine the optimal assay error equations of IBR, DIB, and the active moiety, which are essential for the correct estimation of the error of their future nonparametric pharmacokinetic models. The noncompartmental pharmacokinetic properties of IBR and the active moiety were evaluated in three patients diagnosed with chronic lymphocytic leukemia to provide a proof of concept. The presented methodology allows clinical laboratories to efficiently support pharmacokinetics-based precision pharmacotherapy with IBR.
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