A Phase I And Pharmacokinetic Study of Intravenous Phenylacetate in Patients with Cancer

Alain Thibault*, Michael R. Cooper, William D. Figg, David J. Venzon, A. Oliver Sartor, Anne C. Tompkins, Maribeth S. Weinberger, Donna J. Headlee, Natalie A. McCall, Dvorit Samid, Charles E. Myers

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

166 Scopus citations


Phenylacetate has recently been shown to suppress tumor growth and promote differentiation in experimental models. A phase I trial of phenylacetate was conducted in 17 patients with advanced solid tumors. Each patient received a single i.v. bolus dose followed by a 14-day continuous i.v. infusion of the drug. Twenty-one cycles of therapy were administered at four dose levels, achieved by increasing the rate of the continuous Lv. infusion. Phenylacetate displayed nonlinear pharmacokinetics [Km = 105.1 - 44.5 (SD) μg/ml, Vmax = 24.1 - 5.2 mg/kg/h and Vd = 19.2 - 3.3L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was accounted for by conversion to phenylac-etylghitamine, which was excreted in the urine. Continuous i.v. infusion rates resulting in serum phenylacetate concentrations exceeding Km often resulted in rapid drug accumulation and dose-limiting toxicity, which consisted of reversible central nervous system depression, preceded by emesis. Three of nine patients with metastatic, hormone-refractory prostate cancer maintained stable prostatic specific antigen levels for more than 2 months; another had less bone pain. One of six patients with glioblastoma multiforme, whose steroid dosage has remained unchanged for the duration of therapy, has sustained functional improvement for more than 9 months. The use of adaptive control with feedback for the dosing of each patient enabled us to safely maintain stable phenylacetate concentrations up to the range of 200-300 μg/ml which resulted in clinical improvement in some patients with advanced disease.

Original languageEnglish
Pages (from-to)1690-1694
Number of pages5
JournalCancer Research
Issue number7
StatePublished - Apr 1994
Externally publishedYes


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