title: Daily dosing of vismodegib to steady state does not prolong the QTc interval in healthy volunteers.
abstract: BACKGROUND
  Vismodegib was assessed as being of low risk for QT interval prolongation based on prior nonclinical and clinical experience. A dedicated study was conducted to further assess the potential for vismodegib to prolong the QTc interval.
  
  
  RESULTS
  Given the nonlinear pharmacokinetics of vismodegib, a thorough QTc study as is typically designed was not possible, and an innovative design was employed. This dedicated QTc study was powered to exclude a 20-millisecond change from the baseline QTc interval. The subjects were administered daily oral 150 mg of vismodegib for 7 days, or a single dose of 400 mg of moxifloxacin, with corresponding matching placebos. The upper limits of the 90% confidence intervals for the difference in ΔQTcF between vismodegib and placebo at steady state were <20 milliseconds at all timepoints with a maximum of 10 milliseconds at 12 hours postdose. Exposure-response analysis yielded an estimated slope equal to 0.11 ms/μM, which was not statistically significant. After a single dose of moxifloxacin was administered, the lower limits of the 90% confidence interval of the difference in ΔQTcF between moxifloxacin and placebo were >5 milliseconds from 1-12 hours postdose, thereby establishing assay sensitivity.
  
  
  CONCLUSIONS
  There was no effect of vismodegib on the QTc interval when dosed daily at 150 mg to steady state.
authors.affiliation: Genentech, Inc, South San Francisco, CA 94080, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Graham
authors.forename: Ilsung
authors.initials: I
authors.lastname: Chang
authors.forename: Jin Yan
authors.initials: JY
authors.lastname: Jin
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dufek
authors.forename: Jean A
authors.initials: JA
authors.lastname: Ayache
authors.forename: Farkad
authors.initials: F
authors.lastname: Ezzet
authors.forename: Kenn
authors.initials: K
authors.lastname: Zerivitz
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dresser
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000813:Anilides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000008:administration & dosage; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D005602:France; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008875:Middle Aged; D008954:Models, Biological; D000077266:Moxifloxacin; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; C538724:HhAntag691; D011725:Pyridines; D011804:Quinolines; D000077266:Moxifloxacin