title: Decreased exposure to sunitinib due to concomitant administration of ifosfamide: results of a phase I and pharmacokinetic study on the combination of sunitinib and ifosfamide in patients with advanced solid malignancies.
abstract: BACKGROUND
  This study aimed to define the maximally tolerated dose (MTD) of sunitinib combined with two different infusion schedules of ifosfamide.
  
  
  METHODS
  Patients with advanced solid tumours, good performance score, good organ function, and no standard therapy available were eligible. Continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 g m(-2) for 3 days or 6 g m(-2) for 5 days, administered every 3 weeks. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed.
  
  
  RESULTS
  With growth-factor support, the MTD of sunitinib combined with either ifosfamide schedule was 12.5 mg in 32 patients enrolled. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed.
  
  
  CONCLUSIONS
  With growth-factor support, the MTD of sunitinib with both ifosfamide schedules was 12.5 mg. Ifosfamide produced decreased sunitinib blood levels because of CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this also holds true for anti-tumour activity needs to be further explored.
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center Daniel Den Hoed Cancer Center, Rotterdam, The Netherlands. a.hamberg@erasmusmc.nl
authors.forename: P
authors.initials: P
authors.lastname: Hamberg
authors.forename: N
authors.initials: N
authors.lastname: Steeghs
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: D
authors.initials: D
authors.lastname: van de Biessen
authors.forename: M
authors.initials: M
authors.lastname: den Hollander
authors.forename: M
authors.initials: M
authors.lastname: Tascilar
authors.forename: J
authors.initials: J
authors.lastname: Verweij
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.forename: S
authors.initials: S
authors.lastname: Sleijfer
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000077210:Sunitinib
chemical_list: D007211:Indoles; D011758:Pyrroles; D007069:Ifosfamide; D000077210:Sunitinib