gdc-0449 and Long-QT-Syndrome

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.. 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.. There was no effect of vismodegib on the QTc interval when dosed daily at 150 mg to steady state.

Topics: Administration, Oral; Aged; Anilides; Antineoplastic Agents; Aza Compounds; Double-Blind Method; Drug Administration Schedule; Electrocardiography; Female; Fluoroquinolones; France; Heart Rate; Humans; Linear Models; Long QT Syndrome; Middle Aged; Models, Biological; Moxifloxacin; Pyridines; Quinolines; Risk Assessment; Time Factors