A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

E. Berry-Kravis, David R Hessl, S. Coffey, C. Hervey, A. Schneider, J. Yuhas, J. Hutchison, M. Snape, M. Tranfaglia, D. V. Nguyen, Randi J Hagerman

Research output: Contribution to journalArticle

289 Citations (Scopus)

Abstract

Objective: A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). Methods: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition. Results: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. Conclusions: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.

Original languageEnglish (US)
Pages (from-to)266-271
Number of pages6
JournalJournal of Medical Genetics
Volume46
Issue number4
DOIs
StatePublished - Apr 2009

Fingerprint

Fragile X Syndrome
Pharmacokinetics
Sensory Gating
Vital Signs
fenobam
Animal Models
Outcome Assessment (Health Care)
Safety

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. / Berry-Kravis, E.; Hessl, David R; Coffey, S.; Hervey, C.; Schneider, A.; Yuhas, J.; Hutchison, J.; Snape, M.; Tranfaglia, M.; Nguyen, D. V.; Hagerman, Randi J.

In: Journal of Medical Genetics, Vol. 46, No. 4, 04.2009, p. 266-271.

Research output: Contribution to journalArticle

Berry-Kravis, E, Hessl, DR, Coffey, S, Hervey, C, Schneider, A, Yuhas, J, Hutchison, J, Snape, M, Tranfaglia, M, Nguyen, DV & Hagerman, RJ 2009, 'A pilot open label, single dose trial of fenobam in adults with fragile X syndrome', Journal of Medical Genetics, vol. 46, no. 4, pp. 266-271. https://doi.org/10.1136/jmg.2008.063701
Berry-Kravis, E. ; Hessl, David R ; Coffey, S. ; Hervey, C. ; Schneider, A. ; Yuhas, J. ; Hutchison, J. ; Snape, M. ; Tranfaglia, M. ; Nguyen, D. V. ; Hagerman, Randi J. / A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. In: Journal of Medical Genetics. 2009 ; Vol. 46, No. 4. pp. 266-271.
@article{cfc3a5f02128484a872ff9aaea240968,
title = "A pilot open label, single dose trial of fenobam in adults with fragile X syndrome",
abstract = "Objective: A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). Methods: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition. Results: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20{\%} over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. Conclusions: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.",
author = "E. Berry-Kravis and Hessl, {David R} and S. Coffey and C. Hervey and A. Schneider and J. Yuhas and J. Hutchison and M. Snape and M. Tranfaglia and Nguyen, {D. V.} and Hagerman, {Randi J}",
year = "2009",
month = "4",
doi = "10.1136/jmg.2008.063701",
language = "English (US)",
volume = "46",
pages = "266--271",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "4",

}

TY - JOUR

T1 - A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

AU - Berry-Kravis, E.

AU - Hessl, David R

AU - Coffey, S.

AU - Hervey, C.

AU - Schneider, A.

AU - Yuhas, J.

AU - Hutchison, J.

AU - Snape, M.

AU - Tranfaglia, M.

AU - Nguyen, D. V.

AU - Hagerman, Randi J

PY - 2009/4

Y1 - 2009/4

N2 - Objective: A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). Methods: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition. Results: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. Conclusions: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.

AB - Objective: A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). Methods: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition. Results: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. Conclusions: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.

UR - http://www.scopus.com/inward/record.url?scp=65949096495&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65949096495&partnerID=8YFLogxK

U2 - 10.1136/jmg.2008.063701

DO - 10.1136/jmg.2008.063701

M3 - Article

C2 - 19126569

AN - SCOPUS:65949096495

VL - 46

SP - 266

EP - 271

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 4

ER -