title: Evaluation of food effect on pharmacokinetics of vismodegib in advanced solid tumor patients.
abstract: OBJECTIVE
  Vismodegib, an orally bioavailable small-molecule Smoothened inhibitor, is approved for treatment of advanced basal cell carcinoma (BCC). We conducted a pharmacokinetic study of vismodegib in patients with advanced solid tumors to explore the effects of food on drug exposure.
  
  
  METHODS
  In part I, patients were randomized to fasting overnight (FO), a high fat meal (HF), or a low fat meal (LF) before a single dose of vismodegib 150 mg. Plasma concentrations of vismodegib were determined by a validated liquid chromatography-tandem mass spectrometry assay. Primary endpoints were C(max) and area under the curve (AUC(0-168)). In part II, patients randomized to FO or HF in part I took vismodegib 150 mg daily after fasting; those randomized to LF took it after a meal. Primary endpoints after two weeks were C(max) and AUC(0-24).
  
  
  RESULTS
  Sixty (22 FO, 20 HF, 18 LF) and 52 (25 fasting, 27 fed) patients were evaluable for primary endpoints in parts I and II, respectively. Mean C(max) and AUC(0-168) after a single dose were higher in HF than FO patients [ratios of geometric means (90% CI) = 1.75 (1.30, 2.34) and 1.74 (1.25, 2.42), respectively]. There were no significant differences in C(max) or AUC(0-24) between fasting and fed groups after daily dosing. The frequencies of drug-related toxicities were similar in both groups.
  
  
  CONCLUSIONS
  A HF meal increases plasma exposure to a single dose of vismodegib, but there are no pharmacokinetic or safety differences between fasting and fed groups at steady-state. Vismodegib may be taken with or without food for daily dosing.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Manish R
authors.initials: MR
authors.lastname: Sharma
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Karrison
authors.forename: Bethany
authors.initials: B
authors.lastname: Kell
authors.forename: Kehua
authors.initials: K
authors.lastname: Wu
authors.forename: Michelle
authors.initials: M
authors.lastname: Turcich
authors.forename: David
authors.initials: D
authors.lastname: Geary
authors.forename: Soonmo P
authors.initials: SP
authors.lastname: Kang
authors.forename: Naoko
authors.initials: N
authors.lastname: Takebe
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
authors.forename: Michael L
authors.initials: ML
authors.lastname: Maitland
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C538724:HhAntag691; D011725:Pyridines
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