title: Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours.
abstract: OBJECTIVE
  To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours.
  
  
  METHODS
  In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib.
  
  
  RESULTS
  In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C (ss,max), 36 for AUC(ss). gMean AUC(ss) and C (ss,max) for cediranib 20 mg increased by 21 % (94 % CI 9-35 %) and 26 % (94 % CI 10-43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C (ss,max) and 41 for AUC(ss). gMean AUC(ss) and C (ss,max) for cediranib 45 mg decreased by 39 % (90 % CI 34-43 %) and 23 % (90 % CI 16-30 %), respectively, in the presence of rifampicin. gMean ratios for AUC(ss) and C (ss,max) were >1 for ketoconazole and <1 for rifampicin and CIs were outside the pre-specified equivalence boundaries, indicating a statistically significant effect. Significant inter-patient variability in cediranib AUC(ss) and C (ss,max) was observed. The safety profile of cediranib was similar to that reported previously.
  
  
  CONCLUSIONS
  Co-administration of ketoconazole or rifampicin had statistically significant effects on steady-state pharmacokinetics of cediranib in patients with advanced solid tumours. Therefore, caution is advised when administering cediranib with potent enzyme inhibitors or inducers.
authors.affiliation: Department of Oncology 5072, The Finsen Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. ulrik.lassen@rh.regionh.dk
authors.forename: U
authors.initials: U
authors.lastname: Lassen
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.forename: S
authors.initials: S
authors.lastname: Hotte
authors.forename: T R J
authors.initials: TR
authors.lastname: Evans
authors.forename: C
authors.initials: C
authors.lastname: Kollmansberger
authors.forename: D
authors.initials: D
authors.lastname: Adamson
authors.forename: D L
authors.initials: DL
authors.lastname: Nielsen
authors.forename: J
authors.initials: J
authors.lastname: Spicer
authors.forename: E
authors.initials: E
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Meyer
authors.forename: K
authors.initials: K
authors.lastname: Brown
authors.forename: R
authors.initials: R
authors.lastname: Rafi
authors.forename: M B
authors.initials: MB
authors.lastname: Sawyer
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000009:adverse effects / Q000494:pharmacology*; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011799:Quinazolines / Q000493:pharmacokinetics*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012293:Rifampin / Q000494:pharmacology*; D055815:Young Adult; D007211:Indoles
chemical_list: D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D007654:Ketoconazole; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D012293:Rifampin; C510163:CYP3A4 protein, human; C500926:cediranib; D007211:Indoles