A PHASE-I AND PHARMACOKINETIC STUDY OF INTRAVENOUS PHENYLACETATE IN PATIENTS WITH CANCER

Phenylacetate has recently been shown to suppress tumor growth and pro mote differentiation in experimental models. A phase I trial of phenyl acetate was conducted in 17 patients with advanced solid tumors. Each patient received a single i.v. bolus dose followed by a 14-day continu ous i.v. infusion of the drug. Twenty-one cycles of therapy were admin istered at four dose levels, achieved by increasing the rate of the co ntinuous i.v. infusion. Phenylacetate displayed nonlinear pharmacokine tics [K(m) = 105.1 +/- 44.5 (SD) mug/ml, V(max) = 24.1 +/- 5.2 mg/kg/h and V(d) = 19.2 +/- 3.3 L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was account ed for by conversion to phenylacetylglutamine, which was excreted in t he urine. Continuous i.v. infusion rates resulting in serum phenylacet ate concentrations exceeding K(m) often resulted in rapid drug accumul ation and dose-limiting toxicity, which consisted of reversible centra l nervous system depression, preceded by emesis. Three of nine patient s with metastatic, hormone-refractory prostate cancer maintained stabl e prostatic specific antigen levels for more than 2 months; another ha d less bone pain. One of six patients with glioblastoma multiforme, wh ose 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 enabl ed us to safely maintain stable phenylacetate concentrations up to the range of 200-300 mug/ml, which resulted in clinical improvement in so me patients with advanced disease.