title: Role of the lean body mass and of pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of sunitinib in cancer patients.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Biochimie, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Narjoz
authors.forename: A
authors.initials: A
authors.lastname: Cessot
authors.forename: A
authors.initials: A
authors.lastname: Thomas-Schoemann
authors.forename: J L
authors.initials: JL
authors.lastname: Golmard
authors.forename: O
authors.initials: O
authors.lastname: Huillard
authors.forename: P
authors.initials: P
authors.lastname: Boudou-Rouquette
authors.forename: A
authors.initials: A
authors.lastname: Behouche
authors.forename: F
authors.initials: F
authors.lastname: Taieb
authors.forename: J P
authors.initials: JP
authors.lastname: Durand
authors.forename: A
authors.initials: A
authors.lastname: Dauphin
authors.forename: R
authors.initials: R
authors.lastname: Coriat
authors.forename: M
authors.initials: M
authors.lastname: Vidal
authors.forename: M
authors.initials: M
authors.lastname: Tod
authors.forename: J
authors.initials: J
authors.lastname: Alexandre
authors.forename: M A
authors.initials: MA
authors.lastname: Loriot
authors.forename: F
authors.initials: F
authors.lastname: Goldwasser
authors.forename: B
authors.initials: B
authors.lastname: Blanchet
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001835:Body Weight; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011987:Receptors, Steroid / Q000235:genetics; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D020533:Angiogenesis Inhibitors; D000090702:Constitutive Androstane Receptor; D007211:Indoles; C000716327:NR1I3 protein, human; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011987:Receptors, Steroid; C544393:SU 12662; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077210:Sunitinib