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Invest New Drugs ; 33(1): 257-68, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25344452

ABSTRACT

INTRODUCTION: Sunitinib is a multikinase inhibitor active in various cancers types including renal cancers and endocrine tumors. The study analyzed the influence of the lean body mass (LBM) and of pharmacogenetic variants on the exposure to sunitinib and its active metabolite, SU12662, and on sunitinib toxicity and clinical activity. MATERIALS AND METHODS: Exposure to sunitinib and SU12662 was assessed on days 10 and 21 during the first treatment cycle. Acute toxicity was graded using the NCI 4.0 CTCAE ver. 4.0. The LBM and 14 common single nucleotide polymorphisms in the CYP3A4/3A5, NR1I2, NR1I3, ABCB1, and ABCG2 genes were analyzed according to the drug exposure at day 10. Determinants (including sunitinib exposure and pharmacogenetic variants) for toxicities were assessed, as well as the relationship between drug exposure and survival in renal cancer patients. RESULTS: Ninety-two patients (60 % with renal cancer) were assessable for pharmacokinetics, toxicity and survival, and 66 for genetic analysis. The LBM (p < 0.0001) and a polymorphism in the ABCG2 transporter (421C>A) (p = 0.014) were two independent parameters accounting for the variability of composite (sunitinib + SU12662) exposure. Advanced age (OR = 1.47 [1.01-2.15], p = 0.048) and high sunitinib exposure (OR = 1.16 [1.05-1.28], p = 0.005) were independently associated with any grade ≥ 3 acute toxicity, and high SU12662 exposure was associated with grade ≥ 2 thrombocytopenia (OR = 1.27 [1.03-1.57], p = 0.028). A high composite area under the curve (AUC) >1,973 ng/mL∙h at day 21 was associated with a doubled survival (35.2 vs 16.7 months; log-rank p = 0.0051) in renal cancer patients. CONCLUSIONS: This study indicates that LBM and drug monitoring may be helpful in the management of sunitinib-treated patients.


Subject(s)
ATP-Binding Cassette Transporters/genetics , Angiogenesis Inhibitors , Body Weight , Indoles , Neoplasm Proteins/genetics , Neoplasms/drug therapy , Protein Kinase Inhibitors , Pyrroles , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Aged , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/therapeutic use , Constitutive Androstane Receptor , Cytochrome P-450 CYP3A/genetics , Female , Humans , Indoles/adverse effects , Indoles/blood , Indoles/pharmacokinetics , Indoles/therapeutic use , Male , Middle Aged , Neoplasms/genetics , Neoplasms/metabolism , Pharmacogenetics , Polymorphism, Genetic , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrroles/adverse effects , Pyrroles/blood , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Receptors, Steroid/genetics , Sunitinib , Treatment Outcome
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