title: Functional and clinical evidence of the influence of sorafenib binding to albumin on sorafenib disposition in adult cancer patients.
abstract: OBJECTIVE
  Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is highly bound to plasma proteins (>99.5%). Little is known about the influence of variations in sorafenib protein binding on its disposition. The aims of this study were to characterize in vitro sorafenib binding properties to albumin using the quenching fluorescence method and investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in 54 adult cancer patients.
  
  
  RESULTS
  In vitro estimate of sorafenib dissociation constant (Kd) for albumin was 0.22 μM [CI95 0.20-0.23]. In physiological conditions, sorafenib unbound fraction would increase 1.7-fold as albuminemia decreased from 45 g/L (680 μM) to 30 g/L (453 μM). In presence of bilirubin, apparent Kd of sorafenib was ~1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In clinical settings, median sorafenib clearance (CL) was 1.42 L/h (0.75-2.13 L/h). In univariate analysis, sex, body mass index, and albuminemia were associated with CL (p = 0.04, 0.048, and 0.008, respectively). In multivariate analysis, albuminemia (p = 0.0036) was the single parameter independently associated with CL.
  
  
  CONCLUSIONS
  These findings highlight the major influence of albuminemia on sorafenib clearance and its disposition in cancer patients.
authors.affiliation: Pharmacie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69000 Lyon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Tod
authors.forename: Olivier
authors.initials: O
authors.lastname: Mir
authors.forename: Natacha
authors.initials: N
authors.lastname: Bancelin
authors.forename: Romain
authors.initials: R
authors.lastname: Coriat
authors.forename: Audrey
authors.initials: A
authors.lastname: Thomas-Schoemann
authors.forename: Fabrice
authors.initials: F
authors.lastname: Taieb
authors.forename: Pascaline
authors.initials: P
authors.lastname: Boudou-Rouquette
authors.forename: Stanislas
authors.initials: S
authors.lastname: Ropert
authors.forename: Judith
authors.initials: J
authors.lastname: Michels
authors.forename: Halim
authors.initials: H
authors.lastname: Abbas
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Durand
authors.forename: Alain
authors.initials: A
authors.lastname: Dauphin
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
authors.forename: Francois
authors.initials: F
authors.lastname: Goldwasser
authors.forename: Benoit
authors.initials: B
authors.lastname: Blanchet
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism*; D001557:Benzenesulfonates / Q000097:blood / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D009961:Orosomucoid / Q000378:metabolism; D010671:Phenylurea Compounds; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000378:metabolism*; D011725:Pyridines / Q000097:blood / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism*; D000077157:Sorafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D009961:Orosomucoid; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012709:Serum Albumin; D009536:Niacinamide; D000077157:Sorafenib; D001663:Bilirubin