title: Variability of sorafenib toxicity and exposure over time: a pharmacokinetic/pharmacodynamic analysis.
abstract: BACKGROUND
  Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity.
  
  
  METHODS
  We analyzed the severity and kinetics of sorafenib-induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography.
  
  
  RESULTS
  For 83 patients (median age, 62 years; range, 21-84 years), median sorafenib 12-hour area under the curve (AUC(0-12)) was 52.8 mg · h/L (range: 11.8-199.6). A total of 51 patients (61%) experienced grade 3-4 toxicities, including hand-foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC(0-12) preceding grade 3-4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose-normalized AUC(0-12) on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand-foot skin reactions significantly decreased over time.
  
  
  CONCLUSIONS
  Sorafenib AUC(0-12) decreases over time, similarly to the incidence of hypertension and hand-foot skin reactions. Monitoring of sorafenib plasma concentrations may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression.
authors: Center for Research on Angiogenesis Inhibitors, Department of Medical Oncology, Cochin Teaching Hospital, AP-HP, Paris Descartes University, Sorbonne Paris Cité, 27 Rue du Faubourg Saint Jacques, Paris, France. pascaline.boudou@cch.aphp.fr
authors: Pascaline
authors: P
authors: Boudou-Rouquette
authors: Stanislas
authors: S
authors: Ropert
authors: Olivier
authors: O
authors: Mir
authors: Romain
authors: R
authors: Coriat
authors: Bertrand
authors: B
authors: Billemont
authors: Michel
authors: M
authors: Tod
authors: Laure
authors: L
authors: Cabanes
authors: Nathalie
authors: N
authors: Franck
authors: Benoit
authors: B
authors: Blanchet
authors: François
authors: F
authors: Goldwasser
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D000077157:Sorafenib; D018675:Toxicity Tests / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib