Therapeutic drug monitoring and tyrosine kinase inhibitors

Abstract

Abstract. The therapeutic activity of drugs can be optimized by establishing an individualized dosage, based on the measurement of the drug concentration in the serum, particularly if the drugs are characterized by an inter-individual variation in pharmacokinetics that results in an under-or overexposure to treatment. In recent years, several tyrosine kinase inhibitors (TKIs) have been developed to block intracellular signaling pathways in tumor cells. These oral drugs are candidates for therapeutic drug monitoring (TDM) due to their high inter-individual variability for therapeutic and toxic effects. Following a literature search on PubMed, studies on TKIs and their pharmacokinetic characteristics, plasma quantification and inter-individual variability was studied. TDM is commonly used in various medical fields, including cardiology and psychiatry, but is not often applied in oncology. Plasma concentration monitoring has been thoroughly studied for imatinib, in order to evaluate the usefulness of TDM. The measurement of plasma concentration can be performed by various analytical techniques, with liquid chromatography-mass spectrometry being the reference method. This method is currently used to monitor the efficacy and tolerability of imatinib treatments. Although TDM is already being used for imatinib, additional studies are required in order to improve this practice with the inclusion of other TKIs.

Simple Determination of Plasma Ponatinib Concentration Using HPLC

“…Some TKIs have a narrow therapeutic range, and they are known to have large interindividual variations according to the acidity of gastric absorption, possible detoxification based on the polymorphisms in genes of metabolic enzymes, and drug-drug interactions. 5,6) Currently, ponatinib is the only effective TKI for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia with the acquired T315I-mutant BCR-ABL, which shows absolute resistance to other TKIs. [7][8][9] Ponatinib is known to be associated with frequent adverse events that either may be controllable events (rash: 25.7%, increased lipase: 31.4%, and hypertension: 37.1%) or severe vascular adverse events.…”

Effect of various anticoagulants on the bioanalysis of drugs in rat blood: implication for pharmacokinetic studies of anticancer drugs

“…To the best of our knowledge, this is the first study which has systematically evaluated anticoagulant effects on the bioanalysis of drugs used in cancer care. Since some of these drugs are good candidates for pharmacokinetics guided dose optimization or TDM (Moriyama et al 2015; De Keukeleire et al 2016), and there is evidence emerging in case of some others (Herviou et al 2016), the findings of this study clearly underscore the importance of choosing the right anticoagulant for pharmacokinetic studies and bioanalysis of TDM samples. The findings are also relevant to other fields including forensic medicine where plasma drug levels are often analyzed.…”

Critical Considerations in Anticancer Drug Development and Dosing Strategies: The Past, Present, and Future

“…As is the case with the TDM for drugs such as immunosuppressants or antiepileptics, trough concentrations provide a convenient, standard collection point to confirm intended concentrations are maintained. 110,111 More fundamentally, aside from monitoring absolute neutrophil count, there are few examples that have served to argue for routine TDM of anticancer drugs, although there have been articles arguing for the potential utility of TDM, particularly for anticancer MAbs 112 which often exhibit target-mediated drug disposition and high between-subject variability. However, the value of TDM and PK-guided adjustment of subsequent doses has not been incorporated into the laterstage clinical studies of the drug or thus in the approved labeling and dosing of drugs.…”