Review of therapeutic drug monitoring of anticancer drugs part two – Targeted therapies

• Published in: European journal of cancer (1990) 2014-08, Vol.50 (12), p.2020-2036
• Main Authors: Widmer, Nicolas, Bardin, Christophe, Chatelut, Etienne, Paci, Angelo, Beijnen, Jos, Levêque, Dominique, Veal, Gareth, Astier, Alain
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - toxicity; Antineoplastic Agents, Hormonal - pharmacokinetics; Biological and medical sciences; Clinical Trials as Topic; Drug Monitoring - methods; Hematology, Oncology and Palliative Medicine; Histone Deacetylase Inhibitors - pharmacokinetics; Humans; Medical sciences; Molecular Targeted Therapy; Monoclonal antibodies; Neoplasms - drug therapy; Pharmacokinetics; Pharmacology. Drug treatments; Protein kinase inhibitors; Protein Kinase Inhibitors - pharmacokinetics; Target concentration; Targeted therapies; Therapeutic drug monitoring; Tumors; Tyrosine kinase inhibitors; Variability
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2014.04.015

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.