A phase I clinical and pharmacological evaluation of sodium phenylbutyrateon an 120-h infusion schedule

Purpose: Sodium phenylbutyrate (PB) demonstrates potent differentiating cap acity in multiple hematopoietic and solid tumor cell lines. We conducted a Phase I and pharmacokinetic study of PB by continuous infusion to character ize 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 validate d high -performance liquid chromatographic assay and single compartmental p harmacokinetic model for PB and its principal metabolite, phenylacetate. Results: A total of 24 patients were enrolled on study, with hormone refrac tory prostate cancer being the predominant tumor type. All patients were ev aluable for toxicity and response. A total of 89 cycles were administered. The dose-limiting toxicity (DLT) was neuro-cortical, exemplified by excessi ve somnolence and confusion and accompanied by clinically significant hypok alemia, hyponatremia, and hyperuricemia. One patient at 515 mg/kg/day and a nother at 345 mg/kg/day experienced this DLT. Toxicity resolved less than o r equal to 12 It 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 incr eased in a continuous fashion beginning 24 It into the infusion. In individ uals whose V-max for drug elimination was less than their drug-dosing rate, the active metabolite phenylacetate accumulated progressively. Plasma PB c oncentrations (at 410 mg/kg/day) remained above the targeted therapeutic th reshold of 500 mu mol/liter required for in vitro activity. Conclusion: The DLT in this Phase I study for infusional PB given for 5 day s every 21 days is neuro-cortical in nature. The recommended Phase II dose is 410 mg/kg/day for 120 h.