Oral sodium phenylbutyrate in patients with recurrent malignant gliomas

A dose escalation and pharmacologic study

Surasak Phuphanich, Sharyn D. Baker, Stuart A Grossman, Kathryn Anne Carson, Mark R. Gilbert, Joy D. Fisher, Michael A Carducci

Research output: Contribution to journalArticle

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 concent ' rations of 706, 818, 1225, and 1605 μM 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.

Original languageEnglish (US)
Pages (from-to)177-182
Number of pages6
JournalNeuro-Oncology
Volume7
Issue number2
DOIs
StatePublished - Apr 2005

Fingerprint

Phenylbutyrates
Glioma
Maximum Tolerated Dose
Anticonvulsants
Pharmacokinetics
Time and Motion Studies
Survival
4-phenylbutyric acid
Cytochrome P-450 Enzyme System
Fatigue
Pharmacology
Population
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas : A dose escalation and pharmacologic study. / Phuphanich, Surasak; Baker, Sharyn D.; Grossman, Stuart A; Carson, Kathryn Anne; Gilbert, Mark R.; Fisher, Joy D.; Carducci, Michael A.

In: Neuro-Oncology, Vol. 7, No. 2, 04.2005, p. 177-182.

Research output: Contribution to journalArticle

@article{dbf619949d244fc4a364cd6df33a6acd,
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 concent ' rations of 706, 818, 1225, and 1605 μM 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.",
author = "Surasak Phuphanich and Baker, {Sharyn D.} and Grossman, {Stuart A} and Carson, {Kathryn Anne} and Gilbert, {Mark R.} and Fisher, {Joy D.} and Carducci, {Michael A}",
year = "2005",
month = "4",
doi = "10.1215/S1152851704000183",
language = "English (US)",
volume = "7",
pages = "177--182",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "2",

}

TY - JOUR

T1 - Oral sodium phenylbutyrate in patients with recurrent malignant gliomas

T2 - A dose escalation and pharmacologic study

AU - Phuphanich, Surasak

AU - Baker, Sharyn D.

AU - Grossman, Stuart A

AU - Carson, Kathryn Anne

AU - Gilbert, Mark R.

AU - Fisher, Joy D.

AU - Carducci, Michael A

PY - 2005/4

Y1 - 2005/4

N2 - 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 concent ' rations of 706, 818, 1225, and 1605 μM 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.

AB - 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 concent ' rations of 706, 818, 1225, and 1605 μM 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.

UR - http://www.scopus.com/inward/record.url?scp=17844410310&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17844410310&partnerID=8YFLogxK

U2 - 10.1215/S1152851704000183

DO - 10.1215/S1152851704000183

M3 - Article

VL - 7

SP - 177

EP - 182

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 2

ER -