title: Moving towards dose individualization of tyrosine kinase inhibitors.
abstract: Molecular targeted therapies with tyrosine kinase inhibitors (TKIs) have been a recent breakthrough in cancer treatment. These small molecules are mainly used at a fixed dose ignoring the possible need for dose individualization. Fixed dosing may indeed result in suboptimal treatment or excessive toxicity considering the high inter-individual variability in the pharmacokinetics (PK) of these therapies. The PK, toxicity and efficacy of ten commonly used molecular targeted anti-cancer therapies were reviewed in order to optimize their prescription. A wide interpatient variability in the pharmacokinetics of these small molecules is demonstrated. Moreover associations between certain toxicities and the treatment efficacy have also been demonstrated for some agents, such as erlotinib and skin rash, that may be used as a surrogate marker. Other biomarkers intended to substitute for a clinical endpoint have been described for some TKIs and may be useful for dose individualization. Promising alternatives to fixed dosing were explored such as therapeutic drug monitoring, genotype and phenotype adjusted dosing, and toxicity-adjusted dosing. Prospective studies are needed to validate these methods so that dosing algorithms may be developed in the near future in order to personalize therapeutics to the individual needs of each cancer patient.
authors.affiliation: Department of Medical Oncology, Academic Medical Center, University of Amsterdam, 1100DD Amsterdam, The Netherlands. h.klumpen@amc.uva.nl
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Klümpen
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Samer
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Howard
authors.initials: H
authors.lastname: Gurney
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood; D006801:Humans; D058990:Molecular Targeted Therapy / Q000639:trends*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases