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. 2014 Mar 4:2014:652750.
doi: 10.1155/2014/652750. eCollection 2014.

Metabotropic glutamate receptor 5 negative modulation in phase I clinical trial: potential impact of circadian rhythm on the neuropsychiatric adverse reactions-do hallucinations matter?

Khalid Abou Farha  1 , Richard Bruggeman  1 , Corine Baljé-Volkers  2
Affiliations

Metabotropic glutamate receptor 5 negative modulation in phase I clinical trial: potential impact of circadian rhythm on the neuropsychiatric adverse reactions-do hallucinations matter?

Khalid Abou Farha et al. ISRN Psychiatry. .

Abstract

Metabotropic Glutamate Receptor 5 (mGluR5) negative allosteric modulators (NAMs) may play a role in some psychiatric disorders such as anxiety and depression. The pharmacokinetic profile and pharmacodynamics effects of mGluR5-NAMs have been previously reported. We performed a post hoc analysis of pharmacological and clinical data obtained from 18 young healthy female subjects who received a mGluR5-NAM in the context of a phase I drug-drug interaction study between a mGluR5 NAM and a monophasic oral contraceptive. mGluR5-NAM was administered in an escalating bidaily dose level design. There was no interaction between the OC and mGluR5-NAM. Higher morning mGluR5-NAM plasma concentrations were found compared to evening concentrations. Most of the observed clinically significant neuropsychiatric adverse reactions occurred nocturnally and included visual (pseudo) hallucinations, insomnia accompanied by secondary behavioural disorders, and cognitive dysfunction symptoms of sufficient severity to interfere with daily functioning. Circadian rhythm-related physiological variations in drug absorption and disposition may explain this pharmacokinetics-pharmacodynamics apparently disproportionate relationship. We suggest that clinical trials evaluating basic pharmacokinetic properties of psychiatric medications consider potential drug's chronopharmacokinetics. This may assist with dose optimization and minimize serious neuropsychiatric adverse reactions in the vulnerable psychiatric patient.

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Figures

Figure 1
Figure 1
Mean plasma concentrations (ng/mL) obtained 2 hours after morning and evening dosage, during the up-titration phase and Days 1 and 7 of the steady state period. UPT = up-titration phase; SS = steady state period.
Figure 2
Figure 2
Boxplot of the data values obtained on Days 1 and 7 of steady state period; M = morning, E = evening.
Figure 3
Figure 3
Individual data values obtained on Days 1 and 7 of steady state; M = morning, E = evening.
Figure 4
Figure 4
Day 7 of steady state period, individual plasma concentrations (ng/mL), morning at 2 h postdose and evening at 2 h and 4 h postdose time points.
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