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Therapeutic drug monitoring in cancer--are we missing a trick?
Christophe Bardin1, Gareth Veal2, Angelo Paci3
1Unité fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, Paris, France; Service de Pharmacie clinique, Hôpital Cochin, Paris, France.
Abstract:
Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
Insights
Therapeutic drug monitoring (TDM) aids personalized cancer treatment by measuring drug levels. While challenging for cytotoxic drugs, TDM shows promise for targeted therapies to optimize efficacy and reduce toxicity.
Area of Science:
- Pharmacology
- Oncology
- Clinical Pharmacy
Background:
- Therapeutic drug monitoring (TDM) involves measuring drug concentrations in biological samples to personalize treatment, improve efficacy, and reduce toxicity.
- Cytotoxic drugs have steep dose-response curves and narrow therapeutic windows, with significant inter-individual pharmacokinetic (PK) variability.
- TDM implementation in oncology is hindered by challenges in setting concentration targets, combination chemotherapy use, and limited trial data.
Purpose of the Study:
- To explore the role and challenges of therapeutic drug monitoring (TDM) in modern cancer therapy, particularly for targeted agents.
- To review the current evidence and future directions for TDM in the context of oral targeted therapies and monoclonal antibodies (mAbs).
Main Methods:
- Review of existing literature on TDM in oncology, focusing on cytotoxic drugs, targeted therapies, and mAbs.
- Analysis of factors influencing PK variability in targeted therapies, including pharmacogenetics, patient characteristics, and environmental factors.
- Examination of retrospective studies correlating drug exposure with treatment response for various targeted agents.
Main Results:
- Inter-individual PK variability is substantial for both cytotoxic and targeted therapies.
- Retrospective data suggest a correlation between drug exposure and treatment response for several oral targeted therapies (e.g., imatinib, nilotinib, sunitinib).
- Evidence supporting TDM for monoclonal antibodies (mAbs) is currently limited, despite some encouraging results with rituximab and cetuximab.
Conclusions:
- TDM is particularly relevant for oral targeted therapies, especially in cases of non-response, toxicity, drug interactions, or adherence concerns.
- Further research, including defining concentration-effect relationships and conducting randomized trials, is crucial for optimizing TDM strategies in targeted cancer therapy.
- While TDM shows promise for targeted agents, its application for cytotoxic drugs and mAbs requires more robust scientific evidence and validation.
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