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.

Figure 1

Change in prepulse inhibition (PPI) in adults with fragile X syndrome (FXS) after single dose fenobam compared to variation in a prior control group with FXS (18.70 (9.56) years) that underwent test-retest with a similar PPI protocol performed at the same study sites over the same time frame. Four of six males (67%) and two of six females (33%) had PPI increases of 20% or more (improvement criterion) after fenobam compared to two of 13 with FXS (15%) in the test-retest control group.

Figure 2

Plasma concentrations of fenobam following oral administration. Panel A shows plasma values in n = 3 male healthy adult volunteers administered a single dose of 150 mg fenobam monohydrate. The mean (SEM) plasma concentration achieved was 67.1 (37.8) ng/ml at 120 min post dose. Healthy volunteers were tested through a different phase I pharmacokinetic study of the formulation of fenobam to be used in the fragile X syndrome (FXS) study. These individuals were tested at Qualia Clinical Services, Inc, Nebraska, USA, during 2007 after they signed informed consent. The protocol for pharmacokinetic testing in the volunteers was approved by the Qualia Clinical Services Inc independent institutional review board (IRB) and submitted to the US Food and Drug Administration. Time points for collection of the pharmacokinetic data were slightly different from those used in the subjects with FXS. Panel B shows plasma values of fenobam following administration of 50 mg (n = 2), 100 mg (n = 2) and 150 mg (n = 8) to male and female adults with FXS. Samples were obtained from patients during the duration of a single outpatient visit. Following administration of 150 mg fenobam to patients the mean (SEM) plasma concentration achieved was 39.7 (18.4) ng/ml at 180 min post dose. The difference between mean peak values after administration of 150 mg fenobam was not significant when normal healthy adults males were compared to subjects with FXS (t = 0.47, df = 2, p = 0.67). The mean peak plasma values obtained after administration of 150 mg fenobam to males and females with FXS were also not significant (t = 0.28, df = 6, p = 0.79). Panel C shows mean (SEM) plasma values achieved following administration of 50 mg (n = 2), 100 mg (n = 2) and 150 mg (n = 8) fenobam monohydrate in male and female adult patients with FXS. The mean peak plasma value achieved was related to dose.