Abstract
CPP-115, a next-generation γ-amino butyric acid (GABA)-aminotransferase (AT) inhibitor, shows comparable pharmacokinetics, improved safety and tolerability, and a more favorable toxicity profile when compared with vigabatrin. The pharmacodynamic characteristics of CPP-115 remain to be evaluated. The present study employed state-of-the-art proton magnetic resonance spectroscopy techniques to measure changes in brain GABA+ (the composite resonance of GABA, homocarnosine, and macromolecules) concentrations in healthy subjects receiving oral daily doses of CPP-115 or placebo. Six healthy adult males were randomized to receive either single daily 80 mg doses of CPP-115 (n=4) or placebo (n=2) for 6, 10, or 14 days. Metabolite-edited spectra and two-dimensional J-resolved spectroscopy data were acquired from the parietal–occipital cortex and supplementary motor area in all subjects. Four scans were performed in each subject that included a predrug baseline measure, two scans during the dosing timeframe, and a final scan that occurred 1 week after drug cessation. CPP-115 induced robust and significant increases in brain GABA+ concentrations that ranged between 52 and 141% higher than baseline values. Elevated GABA+ concentrations returned to baseline values following drug clearance. Subjects receiving placebo showed no significant changes in GABA+ concentration. CPP-115-induced changes were exclusive to GABA and homocarnosine, and CPP-115 afforded brain GABA+ concentration changes comparable to or greater than previous vigabatrin spectroscopy studies in healthy epilepsy-naive subjects. The return to baseline GABA+ concentration indicates the reversible GABA-AT resynthesis following drug washout. These preliminary data warrant further spectroscopy studies that characterize the acute pharmacodynamic effects of CPP-115 with additional dose-descending measures.
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Acknowledgements
We thank the study participants and are grateful for the logistical assistance provided by staff at PRA Health Sciences, UT. This work was entirely supported by Catalyst Pharmaceuticals, whose role was to supply study drug (CPP-115 and placebo) and to consult on any medical issues that arose during the study. PFR is supported by the National Institute on Drug Abuse (NIDA) funding award (NIDA K24 DA015116).
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Prescot, A., Miller, S., Ingenito, G. et al. In Vivo Detection of CPP-115 Target Engagement in Human Brain. Neuropsychopharmacol. 43, 646–654 (2018). https://doi.org/10.1038/npp.2017.156
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DOI: https://doi.org/10.1038/npp.2017.156
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