title: Electrocardiographic studies of romidepsin demonstrate its safety and identify a potential role for K(ATP) channel.
abstract: OBJECTIVE
  Romidepsin is a histone deacetylase inhibitor (HDI) approved for the treatment of both cutaneous and peripheral T-cell lymphoma (CTCL and PTCL). During development, a thorough assessment of cardiac toxicity was conducted.
  
  
  METHODS
  A phase II single-agent nonrandomized study of romidepsin was conducted in patients with CTCL or PTCL who had progressed after at least 1 prior systemic therapy.
  
  
  RESULTS
  Results for the first 42 patients enrolled on the NCI 1312 phase II study of romidepsin in CTCL or PTCL showed no cardiac toxicity based on serial electrocardiograms (ECG), troponins, and MUGA scans/echocardiograms. The cardiac assessments reported herein confirm the safety of romidepsin among 131 enrolled patients, while supporting a role for electrolyte replacement. Heart rate increased an average 11 bpm following romidepsin infusion; there was no evidence of increased arrhythmia. Criteria for potassium/magnesium replacement were met before 55% of 1365 romidepsin doses; an association with hypoalbuminemia was confirmed. We propose a mechanism for ST segment flattening and depression, the most common ECG abnormalities observed: HDI-induced alteration of the activity or expression of KATP channels. In addition, examination of the variants of the active transporter of romidepsin, ABCB1, showed a trend toward smaller heart rate changes in the peri-infusion period among wild-type than variant diplotypes.
  
  
  CONCLUSIONS
  We conclude that in the context of appropriate attention to electrolyte levels, the data support the cardiac safety of romidepsin.
authors.affiliation: Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Noonan
authors.forename: Robin A
authors.initials: RA
authors.lastname: Eisch
authors.forename: David J
authors.initials: DJ
authors.lastname: Liewehr
authors.forename: Tristan M
authors.initials: TM
authors.lastname: Sissung
authors.forename: David J
authors.initials: DJ
authors.lastname: Venzon
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Flagg
authors.forename: Mark C
authors.initials: MC
authors.lastname: Haigney
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Richard L
authors.initials: RL
authors.lastname: Piekarz
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D047630:Depsipeptides / Q000009:adverse effects*; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects*; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008274:Magnesium / Q000097:blood; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin; D008274:Magnesium; D011188:Potassium