DIQTA 1.0: Drug-Induced QT Prolongation Atlas

VORINOSTAT

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Ambiguous

Severity Score:1.0

Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF

CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac electrophysiology
A randomized, partially-blind, placebo-controlled, 2-period crossover study was performed to assess the effects of a single 800-mg dose of vorinostat on the QTc interval in 24 patients with advanced cancer. This study was conducted to assess the impact of vorinostat on ventricular repolarization. The upper bound of the 90% confidence interval of the placebo-adjusted mean QTc interval change-from-baseline was less than 10 msec at every time point through 24 hours. Based on these study results, administration of a single supratherapeutic 800-mg dose of vorinostat does not appear to prolong the QTc interval in patients with advanced cancer; however the study did not include a positive control to demonstrate assay sensitivity. In the fasted state, oral administration of a single 800-mg dose of vorinostat resulted in a mean AUC and Cmax and median Tmax of 8.6±5.7 µM∙hr and 1.7±0.67 µM and 2.1 (0.5-6) hours, respectively.
In clinical studies in patients with CTCL, three of 86 CTCL patients exposed to 400 mg once daily had Grade 1 (>450-470 msec) or 2 (>470-500 msec or increase of >60 msec above baseline) clinical adverse reactions of QTc prolongation. In a retrospective analysis of three Phase 1 and two Phase 2 studies, 116 patients had a baseline and at least one follow-up ECG. Four patients had Grade 2 (>470-500 msec or increase of >60 msec above baseline) and 1 patient had Grade 3 (>500 msec) QTc prolongation. In 49 non-CTCL patients from 3 clinical trials who had complete evaluation of QT interval, 2 had QTc measurements of >500 msec and 1 had a QTc prolongation of >60 msec.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24079

Other ADRs

4004

38377583

Odds Ratio = 5.175

Drug Property Information

ATC Code(s):

L01XH01 - vorinostat

L01XH -
L01X - OTHER ANTINEOPLASTIC AGENTS
L01 - ANTINEOPLASTIC AGENTS
L - ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Active Ingredient:VORINOSTAT

Active Ingredient UNII:58IFB293JI

Drugbank ID:DB02546

PubChem Compound:5311

CTD ID: D000077337

PharmGKB:PA164748224

CAS Number:149647-78-9

Dosage Form(s):capsule

Route(s) Of Administrator:oral

Daily Dose:

Chemical Structure:

SMILE Code:
ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1

Reference

1: A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome.

[Kirschbaum Mark,Gojo Ivana,Goldberg Stuart L,Bredeson Christopher,Kujawski Lisa A,Yang Allen,Marks Peter,Frankel Paul,Sun Xing,Tosolini Alessandra,Eid Joseph E,Lubiniecki Gregory M,Issa Jean-Pierre]
Br J Haematol,2014 Oct;167(2):185-93. PMID: 25040094

2: A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2.

[Holkova Beata,Supko Jeffrey G,Ames Matthew M,Reid Joel M,Shapiro Geoffrey I,Perkins Edward Brent,Ramakrishnan Viswanathan,Tombes Mary Beth,Honeycutt Connie,McGovern Renee M,Kmieciak Maciej,Shrader Ellen,Wellons Martha D,Sankala Heidi,Doyle Austin,Wright John,Roberts John D,Grant Steven]
Clin Cancer Res,2013 Apr 1;19(7):1873-83. PMID: 23515411

3: QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: a case report and review of the literature.

[Lynch Donald R,Washam Jeffrey B,Newby L Kristin]
Cardiol J,2012;19(4):434-8. PMID: 22825908

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