title: A single supratherapeutic dose of vorinostat does not prolong the QTc interval in patients with advanced cancer.
abstract: OBJECTIVE
  This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval.
  
  
  METHODS
  A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C(max) of vorinostat.
  
  
  RESULTS
  Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC(0-infinity) and C(max) values attained were on the order of approximately 1.93- and approximately 1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated.
  
  
  CONCLUSIONS
  Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation.
authors.affiliation: Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Munster
authors.forename: Eric H
authors.initials: EH
authors.lastname: Rubin
authors.forename: Simon
authors.initials: S
authors.lastname: Van Belle
authors.forename: Evan
authors.initials: E
authors.lastname: Friedman
authors.forename: Jaclyn K
authors.initials: JK
authors.lastname: Patterson
authors.forename: Kristien
authors.initials: K
authors.lastname: Van Dyck
authors.forename: Xiadong
authors.initials: X
authors.lastname: Li
authors.forename: Wendy
authors.initials: W
authors.lastname: Comisar
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Chodakewitz
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Marian
authors.initials: M
authors.lastname: Iwamoto
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004562:Electrocardiography / Q000379:methods*; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy*; D010919:Placebos; D012306:Risk; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D010919:Placebos; D000077337:Vorinostat