A Phase I Clinical and Pharmacological Evaluation of Sodium Phenylbutyrate on an 120-h Infusion Schedule

• Published in: Clinical cancer research 2001-10, Vol.7 (10), p.3047-3055
• Main Authors: CARDUCCI, Michael A, GILBERT, Jill, BOWLING, M. Katherine, NOE, Dennis, EISENBERGER, Mario A, SINIBALDI, Victoria, ZABELINA, Yelena, CHEN, Tian-Ling, GROCHOW, Louise B, DONEHOWER, Ross C
• Format: Article
• Language: English
• Subjects: Adult; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Chemotherapy; 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; Medical sciences; Metabolic Clearance Rate; Nausea - chemically induced; Neoplasms - drug therapy; Neutropenia - chemically induced; Patient Dropouts; Pharmacology. Drug treatments; 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
• ISSN: 1078-0432; 1557-3265

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 ≤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 μmol/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.