title: Review of therapeutic drug monitoring of anticancer drugs part two--targeted therapies.
abstract: Most of oral targeted therapies are tyrosine kinase inhibitors (TKIs). Oral administration generates a complex step in the pharmacokinetics (PK) of these drugs. Inter-individual PK variability is often large and variability observed in response is influenced not only by the genetic heterogeneity of drug targets, but also by the pharmacogenetic background of the patient (e.g. cytochome P450 and ABC transporter polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure, reflected in the area under the plasma concentration-time curve (AUC) correlates with treatment response (efficacy/toxicity) in various cancers. Nevertheless levels of evidence for therapeutic drug monitoring (TDM) are however heterogeneous among these agents and TDM is still uncommon for the majority of them. 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/or concerns over adherence treatment. Interpatient PK variability observed with monoclonal antibodies (mAbs) is comparable or slightly lower to that observed with TKIs. There are still few data with these agents in favour of TDM approaches, even if data showed encouraging results with rituximab, cetuximab and bevacizumab. At this time, 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: 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: 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: EA4553 Institut Claudius-Regaud, Université Paul-Sabatier, Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
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: 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: Service de Pharmacie, Hôpital Hautepierre, Strasbourg, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Levêque
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 Pharmacy, CNRS-UMR 7054, School of Medicine Paris 12, Henri Mondor University Hospitals, Créteil, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Astier
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics; D002986:Clinical Trials as Topic; D016903:Drug Monitoring / Q000379:methods*; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D056572:Histone Deacetylase Inhibitors; D047428:Protein Kinase Inhibitors
keywords: Monoclonal antibodies; Pharmacokinetics; Protein kinase inhibitors; Target concentration; Targeted therapies; Therapeutic drug monitoring; Tyrosine kinase inhibitors; Variability