title: A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule.
abstract: OBJECTIVE
  Sodium phenylbutyrate (PB) demonstrates potent differentiating capacity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to characterize the maximum tolerated dose, toxicities, pharmacokinetics, and antitumor effects in patients with refractory solid tumors.
  
  
  METHODS
  Patients were treated with a 120-h PB infusion every 21 days. The dose was escalated from 150 to 515 mg/kg/day. Pharmacokinetics were performed during and after the first infusion period using a validated high-performance liquid chromatographic assay and single compartmental pharmacokinetic model for PB and its principal metabolite, phenylacetate.
  
  
  RESULTS
  A total of 24 patients were enrolled on study, with hormone refractory prostate cancer being the predominant tumor type. All patients were evaluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessive somnolence and confusion and accompanied by clinically significant hypokalemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and another at 345 mg/kg/day experienced this DLT. Toxicity resolved < or =12 h of discontinuing the infusion. Other toxicities were mild, including fatigue and nausea. The maximum tolerated dose was 410 mg/kg/day for 5 days. Pharmacokinetics demonstrated that plasma clearance of PB increased in a continuous fashion beginning 24 h into the infusion. In individuals whose V(max) for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB concentrations (at 410 mg/kg/day) remained above the targeted therapeutic threshold of 500 micromol/liter required for in vitro activity.
  
  
  CONCLUSIONS
  The DLT in this Phase I study for infusional PB given for 5 days every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h.
authors.affiliation: Division of Medical Oncology, The Johns Hopkins Oncology Center, 1 M88 Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231, USA. carducci@jhmi.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Carducci
authors.forename: J
authors.initials: J
authors.lastname: Gilbert
authors.forename: M K
authors.initials: MK
authors.lastname: Bowling
authors.forename: D
authors.initials: D
authors.lastname: Noe
authors.forename: M A
authors.initials: MA
authors.lastname: Eisenberger
authors.forename: V
authors.initials: V
authors.lastname: Sinibaldi
authors.forename: Y
authors.initials: Y
authors.lastname: Zabelina
authors.forename: T L
authors.initials: TL
authors.lastname: Chen
authors.forename: L B
authors.initials: LB
authors.lastname: Grochow
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005973:Glutamine / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D007008:Hypokalemia / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D010352:Patient Dropouts; D010648:Phenylacetates / Q000097:blood; D010654:Phenylbutyrates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017430:Prostate-Specific Antigen / Q000097:blood / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014527:Uric Acid / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D010648:Phenylacetates; D010654:Phenylbutyrates; D005973:Glutamine; D014527:Uric Acid; C075773:4-phenylbutyric acid; C003089:phenylacetylglutamine; D017430:Prostate-Specific Antigen; C025136:phenylacetic acid