A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer.
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 i.v. infusion. Phenylacetate displayed nonlinear pharmacokinetics [Km = 105.1 +/- 44.5 (SD) microgram/ml, Vmax = 24.1 +/- 5.2 mg/kg/h and Vd = 19.2 +/- 3.3 L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was accounted for by conversion to phenylacetylglutamine, 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 micrograms/ml, which resulted in clinical improvement in some patients with advanced disease.
Thibault
A
A
Clinical Pharmacology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Cooper
M R
MR
Figg
W D
WD
Venzon
D J
DJ
Sartor
A O
AO
Tompkins
A C
AC
Weinberger
M S
MS
Headlee
D J
DJ
McCall
N A
NA
Samid
D
D
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D005973:Glutamine / Q000097:blood; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010648:Phenylacetates / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*
D000970:Antineoplastic Agents; D010648:Phenylacetates; D005973:Glutamine; C025136:phenylacetic acid