A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule

Clin Cancer Res. 2001 Oct;7(10):3047-55.


Purpose: 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.

Patients and 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.

Conclusion: 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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Chromatography, High Pressure Liquid
  • Disorders of Excessive Somnolence / chemically induced
  • Dose-Response Relationship, Drug
  • Fatigue / chemically induced
  • Female
  • Glutamine / analogs & derivatives*
  • Glutamine / blood
  • Humans
  • Hypokalemia / chemically induced
  • Infusions, Intravenous
  • Male
  • Metabolic Clearance Rate
  • Nausea / chemically induced
  • Neoplasms / drug therapy*
  • Neutropenia / chemically induced
  • Patient Dropouts
  • Phenylacetates / blood
  • Phenylbutyrates / adverse effects
  • Phenylbutyrates / pharmacokinetics
  • Phenylbutyrates / therapeutic use*
  • Prostate-Specific Antigen / blood
  • Prostate-Specific Antigen / drug effects
  • Prostatic Neoplasms / blood
  • Prostatic Neoplasms / drug therapy
  • Time Factors
  • Tumor Cells, Cultured
  • Uric Acid / blood


  • Antineoplastic Agents
  • Phenylacetates
  • Phenylbutyrates
  • Glutamine
  • Uric Acid
  • 4-phenylbutyric acid
  • phenylacetylglutamine
  • Prostate-Specific Antigen
  • phenylacetic acid