Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology – an analysis of the closed cohorts of a multicentre prospective study

• Published in: British journal of cancer Vol. 131; no. 5; pp. 843 - 851
• Main Authors: van der Kleij, Maud B. A., Guchelaar, Niels A. D., Meertens, Marinda, Westerdijk, Kim, Giraud, Eline L., Bleckman, Roos F., Groenland, Stefanie L., van Eerden, Ruben A. G., Imholz, Alex L. T., Vulink, Annelie J. E., Otten, Hans-Martin, Fiebrich-Westra, Helle-Brit, Lubberman, Floor J. E., Desar, Ingrid M. E., Moes, Dirk-Jan A. R., Touw, Daan J., Koolen, Stijn L. W., Gelderblom, Hans, Reyners, An K. L., van Erp, Nielka P., Mathijssen, Ron H. J., Huitema, Alwin D. R., Steeghs, Neeltje
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2024; Nature Publishing Group
• Subjects: 692/4028/67/1059; 692/4028/67/1059/602; Administration, Oral; Anilides - administration & dosage; Anilides - pharmacokinetics; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Benzamides; Biomedical and Life Sciences; Biomedicine; Cancer Research; Drug development; Drug Monitoring - methods; Drug Resistance; Epidemiology; Everolimus - administration & dosage; Everolimus - pharmacokinetics; Feasibility Studies; Female; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacokinetics; Male; Molecular Medicine; Molecular Targeted Therapy; Neoplasms - drug therapy; Nitriles - administration & dosage; Nitriles - pharmacokinetics; Oncology; Oximes - administration & dosage; Oximes - pharmacokinetics; Pharmacokinetics; Phenylthiohydantoin - administration & dosage; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacokinetics; Phenylurea Compounds; Piperazines; Prospective Studies; Pyridines - administration & dosage; Pyridines - pharmacokinetics; Pyridones; Pyrimidinones; Therapeutic drug monitoring
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-024-02789-2

Background Therapeutic drug monitoring (TDM) – performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets – could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. Methods We evaluated drug cohorts from the Dutch Pharmacology Oncology Group – TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. Results For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. Conclusions Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.