title: A study to determine the effects of food and multiple dosing on the pharmacokinetics of vorinostat given orally to patients with advanced cancer.
abstract: OBJECTIVE
  This phase I study, conducted in advanced-stage cancer patients, assessed the safety and tolerability of oral vorinostat (suberoylanilide hydroxamic acid), single-dose and multiple-dose pharmacokinetics of vorinostat, and the effect of a high-fat meal on vorinostat pharmacokinetics.
  
  
  METHODS
  Patients (n = 23) received single doses of 400 mg vorinostat on day 1 (fasted) and day 5 (fed) with 48 hours of pharmacokinetic sampling on both days. Patients received 400 mg vorinostat once daily on days 7 to 28. On day 28, vorinostat was given (fed) with pharmacokinetic sampling for 24 hours after dose.
  
  
  RESULTS
  The apparent t(1/2) of vorinostat was short (approximately 1.5 hours). A high-fat meal was associated with a small increase in the extent of absorption and a modest decrease in the rate of absorption. A short lag time was observed before detectable levels of vorinostat were observed in the fed state, and T(max) was delayed. Vorinostat concentrations were qualitatively similar following single-dose and multiple-dose administration; the accumulation ratio based on area under the curve was 1.21. The elimination of vorinostat occurred primarily through metabolism, with <1% of the given dose recovered intact in urine. The most common vorinostat-related adverse experiences were mild to moderate nausea, anorexia, fatigue, increased blood creatinine, and vomiting.
  
  
  CONCLUSIONS
  Vorinostat concentrations were qualitatively similar after single and multiple doses. A high-fat meal increased the extent and modestly decreased the rate of absorption of vorinostat; this effect is not anticipated to be clinically meaningful. Continued investigation of 400 mg vorinostat given once daily in phase II and III efficacy studies is warranted.
authors.affiliation: The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903-2681, USA. ehrubin@umdnj.edu
authors.forename: Eric H
authors.initials: EH
authors.lastname: Rubin
authors.forename: Nancy G B
authors.initials: NG
authors.lastname: Agrawal
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Friedman
authors.forename: Pamela
authors.initials: P
authors.lastname: Scott
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Mazina
authors.forename: Linda
authors.initials: L
authors.lastname: Sun
authors.forename: Lihong
authors.initials: L
authors.lastname: Du
authors.forename: Justin L
authors.initials: JL
authors.lastname: Ricker
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Frankel
authors.forename: Keith M
authors.initials: KM
authors.lastname: Gottesdiener
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Marian
authors.initials: M
authors.lastname: Iwamoto
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004041:Dietary Fats / Q000008:administration & dosage*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography; D005260:Female; D005502:Food; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D004041:Dietary Fats; D006877:Hydroxamic Acids; D000077337:Vorinostat