Details

Autor(en) / Beteiligte

• Munster, Pamela N
• Rubin, Eric H
• Van Belle, Simon
• Friedman, Evan
• Patterson, Jaclyn K
• Van Dyck, Kristien
• Li, Xiadong
• Comisar, Wendy
• Chodakewitz, Jeffery A
• Wagner, John A
• Iwamoto, Marian

Titel

A Single Supratherapeutic Dose of Vorinostat Does Not Prolong the QTc Interval in Patients with Advanced Cancer

Ist Teil von

• Clinical cancer research, 2009-11, Vol.15 (22), p.7077-7084

Ort / Verlag

United States: American Association for Cancer Research

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• Purpose: 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. Experimental Design: 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-∞ and C max values attained were on the order of ∼1.93- and ∼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. (Clin Cancer Res 2009;15(22):7077–84)