Nonclinical safety assessment of the histone deacetylase inhibitor vorinostat.
Vorinostat (SAHA, Zolinza), a histone deacetylase inhibitor, is assessed in nonclinical studies to support its approval for cutaneous T-cell lymphoma. Vorinostat is weakly mutagenic in the Ames assay; is clastogenic in rodent (ie, CHO) cells but not in normal human lymphocytes; and is weakly positive in an in vivo mouse micronucleus assay. No effects are observed on potassium ion currents in the hERG assay up to 300 microM (safety margin approximately 300-fold the approximately 1 microM serum concentration associated with the 400 mg/d maximum recommended human dose. No rat respiratory or central nervous system effects are found at 150 mg/kg (>2-fold maximum recommended human dose). No cardiovascular effects, including effects on QTc interval, are observed after a single oral dose (150 mg/kg) in dogs. Vorinostat is orally dosed daily in rats (controls, 20, 50, or 150 mg/kg/d) and dogs (controls, 60, 80, or 100/125/160 mg/kg/d) for 26 weeks with a 4-week recovery. Rat vorinostat-related adverse findings are decreased food consumption, weight loss, and hematologic changes; a no observed adverse effects level is not established. In dogs, adverse effects are primarily gastrointestinal; the no observed adverse effects level is 60 mg/kg/d (approximately 6-fold maximum recommended human dose). Toxicities are reversible and can be monitored in the clinic.
Kerr
Janet S
JS
Safety Assessment, Merck Research Laboratories, West Point, PA 19486, USA. Janet_Kerr@Merck.com
Galloway
Sheila
S
Lagrutta
Armando
A
Armstrong
Michael
M
Miller
Thomas
T
Richon
Victoria M
VM
Andrews
Paul A
PA
D000818:Animals; D001773:Blood Cells / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000187:drug effects; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D006655:Histone Deacetylases; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D015162:Micronucleus Tests; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D018675:Toxicity Tests; D000077337:Vorinostat; D015431:Weight Loss / Q000187:drug effects
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D004247:DNA; D006655:Histone Deacetylases