title: Therapeutic drug monitoring in cancer--are we missing a trick?
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.
authors.affiliation: Unité fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, Paris, France; Service de Pharmacie clinique, Hôpital Cochin, Paris, France. Electronic address: christophe.bardin@htd.aphp.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Bardin
authors.affiliation: Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Veal
authors.affiliation: Department of Pharmacology and Drug Analysis, Gustave Roussy Cancer Campus Grand Paris, Université Paris-Sud, Villejuif, France.
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.affiliation: EA4553 Institut Claudius-Regaud, Université Paul-Sabatier, Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.affiliation: Department of Pharmacy, CNRS-UMR 7054, School of Medicine Paris 12, Henri Mondor University Hospitals, Créteil, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Astier
authors.affiliation: Service de Pharmacie, Hôpital Hautepierre, Strasbourg, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Levêque
authors.affiliation: Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland; Pharmacie des Hôpitaux de l'Est Lémanique, Vevey, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Widmer
authors.affiliation: Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Stotervaart Hospital, Amsterdam, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Beijnen
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D003603:Cytotoxins / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins
keywords: Chemotherapy; Cytotoxics; Monoclonal antibodies; Oncology; Pharmacokinetics; Target concentration; Targeted therapies; Therapeutic drug monitoring; Tyrosine kinase inhibitors; Variability