title: Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole.
abstract: BACKGROUND
  Vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), is a developmental oncology drug, that is in part metabolized by cytochrome P450 (CYP) 3A4. Clinical studies were performed to assess the potential for 3A4 inhibitors and inducers to affect exposure to vandetanib.
  
  
  OBJECTIVE
  The aim of this study was to investigate the effects of a potent CYP3A4 inducer, rifampicin (Study A), and a potent CYP3A4 inhibitor, itraconazole (Study B), on the pharmacokinetics of a single 300 mg dose of vandetanib in healthy subjects.
  
  
  METHODS
  Two phase I, randomized, open-label, two-way crossover, single-center studies.
  
  
  METHODS
  Study A: 18 healthy male subjects aged 21-44 years were randomized to receive each of the following two regimens, separated by a ≥6-week washout period: (i) oral rifampicin 600 mg/day on days 1-31 with a single oral dose of vandetanib 300 mg on day 10; and (ii) a single oral dose of vandetanib 300 mg on day 1. Study B: 16 healthy male subjects aged 20-44 years were randomized to receive each of the following two regimens, separated by a 3-month washout period: (i) oral itraconazole 200 mg/day on days 1-24 with a single oral dose of vandetanib 300 mg on day 4; and (ii) a single oral dose of vandetanib 300 mg on day 1.
  
  
  METHODS
  Blood samples for measurement of vandetanib (both studies) concentrations and its metabolites, N-desmethylvandetanib and vandetanib N-oxide (Study A only), were collected before and at various timepoints after vandetanib administration for up to 28 days (Study A) and 37 days (Study B). Pharmacokinetic parameters were determined using non-compartmental methods. The area under the plasma concentration-time curve from time 0 to 504 hours (AUC(504)) and maximum plasma concentration (C(max)) of vandetanib were compared in the presence and absence of rifampicin, and in the presence and absence of itraconazole.
  
  
  RESULTS
  Study A: coadministration of vandetanib with rifampicin resulted in a statistically significant reduction in AUC(504) (geometric least square [GLS]mean ratio [vandetanib + rifampicin/vandetanib alone] 0.60; 90% CI 0.58, 0.63). There was no significant difference in C(max) of vandetanib (GLSmean ratio 1.03; 90% CI 0.95, 1.11). AUC(504) and C(max) of N-desmethylvandetanib increased by 266.0% and 414.3%, respectively, in the presence of rifampicin compared with vandetanib alone. Exposure to vandetanib N-oxide was very low compared with that of vandetanib, but was increased in the presence of rifampicin. Study B: coadministration of vandetanib with itraconazole resulted in a significant increase in AUC(504) (GLSmean ratio [vandetanib + itraconazole/vandetanib alone] 1.09; 90% CI 1.01, 1.18) and no significant change in C(max) (GLSmean ratio 0.96; 90% CI 0.83, 1.11). Vandetanib was well tolerated in both studies.
  
  
  CONCLUSIONS
  Exposure to vandetanib, as assessed by AUC(504) in healthy subjects, was reduced by around 40% when a single dose was given in combination with the potent CYP3A4 inducer rifampicin. Because of this, it may be appropriate to avoid coadministration of potent CYP3A4 inducers with vandetanib. Vandetanib exposure was increased by about 9% when it was taken in combination with the CYP3A4 inhibitor itraconazole. It is unlikely that coadministration of vandetanib and potent CYP3A4 inhibitors will need to be contraindicated.
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK. paul.martin@astrazeneca.com
authors.forename: Paul
authors.initials: P
authors.lastname: Martin
authors.forename: Stuart
authors.initials: S
authors.lastname: Oliver
authors.forename: Jane
authors.initials: J
authors.lastname: Robertson
authors.forename: Sarah-Jane
authors.initials: SJ
authors.lastname: Kennedy
authors.forename: Jessica
authors.initials: J
authors.lastname: Read
authors.forename: Thierry
authors.initials: T
authors.lastname: Duvauchelle
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D065692:Cytochrome P-450 CYP3A Inhibitors; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D010880:Piperidines; D011799:Quinazolines; D017964:Itraconazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D012293:Rifampin; C452423:vandetanib