title: Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics.
abstract: Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1 = Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.
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: Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Veal
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: 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
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: EA4553 Institut Claudius-Regaud, Université Paul-Sabatier, Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000633:toxicity; D002986:Clinical Trials as Topic; 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: 5-Fluorouracil; Busulfan; Chemotherapy; Cytotoxics; Methotrexate; Mitotane; Oncology; Paediatric oncology; Pharmacokinetics; Therapeutic drug monitoring