title: Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study.
abstract: We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.
authors.affiliation: The New Approaches to Brain Tumor Therapy CNS Consortium, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. s_phuphanich@emoryhealthcare.org
authors.forename: Surasak
authors.initials: S
authors.lastname: Phuphanich
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Carson
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.forename: Joy D
authors.initials: JD
authors.lastname: Fisher
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality; D010654:Phenylbutyrates / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D015173:Supratentorial Neoplasms / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D010654:Phenylbutyrates; D003577:Cytochrome P-450 Enzyme System