title: A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies.
abstract: OBJECTIVE
  Phenylbutyrate (PB) is an aromatic fatty acid with multiple mechanisms of action including histone deacetylase inhibition. Preclinically, PB demonstrates both cytotoxic and differentiating effects at a concentration of 0.5 mM. We conducted a Phase I trial of p.o. PB patients with refractory solid tumor malignancies to evaluate toxicity, pharmacokinetic parameters, and feasibility of p.o. administration.
  
  
  METHODS
  Twenty-eight patients with refractory solid tumor malignancies were enrolled on this dose-escalation to maximally tolerated dose trial. Five dose levels of PB were studied: 9 g/day (n = 4), 18 g/day (n = 4), 27 g/day (n = 4), 36 g/day (n = 12), and 45 g/day (n = 4). Pharmacokinetic studies were performed and included an p.o. bioavailability determination. Compliance data were also collected.
  
  
  RESULTS
  The recommended Phase II dose is 27 g/day. Overall the drug was well tolerated with the most common toxicities being grade 1-2 dyspepsia and fatigue. Nonoverlapping dose-limiting toxicities of nausea/vomiting and hypocalcemia were seen at 36 g/day. The p.o. bioavailability of PB was 78% for all dose levels, and the biologically active concentration of 0.5 mM was achieved at all dose levels. Compliance was excellent with 93.5% of all possible doses taken. No partial remission or complete remission was seen, but 7 patients had stable disease for more than 6 months while on the drug.
  
  
  CONCLUSIONS
  PB (p.o.) is well tolerated and achieves the concentration in vivo that has been shown to have biological activity in vitro. PB may have a role as a cytostatic agent and should be additionally explored in combination with cytotoxics and other novel drugs.
authors.affiliation: Division of Medical Oncology, Department of Oncology, The Johns Hopkins University School of Medicine, 1 M88 Bunting-Blaustein Cancer Research Building, 2650 Orleans Street, Baltimore, MD 21231-1000, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gilbert
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
authors.forename: M K
authors.initials: MK
authors.lastname: Bowling
authors.forename: L
authors.initials: L
authors.lastname: Grochow
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: Y
authors.initials: Y
authors.lastname: Zabelina
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
authors.forename: M A
authors.initials: MA
authors.lastname: Carducci
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005973:Glutamine / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D006996:Hypocalcemia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced; D010648:Phenylacetates / Q000097:blood; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D010648:Phenylacetates; D010654:Phenylbutyrates; D005973:Glutamine; C003089:phenylacetylglutamine; C025136:phenylacetic acid