Results and evaluation of a first-in-human study of RG7342, an mGlu5 positive allosteric modulator, utilizing Bayesian adaptive methods

British Journal of Clinical Pharmacology
Stefan SturmGiuseppe Palermo

Abstract

The objectives of this first-in-human study were to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, and maximum tolerated dose (MTD) of single ascending oral doses of RG7342, a positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGlu5) for the treatment of schizophrenia, in healthy male subjects. This was a single-centre, randomized, double-blind, adaptive study of 37 subjects receiving single ascending oral doses of RG7342 (ranging from 0.06-1.2 mg, n = 27) or placebo (n = 10). A modified continual reassessment method, with control for the probability of overdosing based on the occurrence of dose-limiting events (DLEs), was applied to inform the subsequent dose decisions for RG7342. DLEs consisted of dizziness, nausea and vomiting, and the incidence and severity of these adverse events increased in a concentration-dependent manner. RG7342 doses of 1.2 mg under fasting conditions, which reached a mean maximum plasma concentration (Cmax ) of 10.2 ng ml-1 , were not tolerated (four out of six subjects experienced DLEs). RG7342 showed dose-proportional pharmacokinetics, with rapid absorption and a biphasic decline, and a mean terminal half-life estimated to be >1000 h. Single ...Continue Reading

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Citations

Jan 23, 2019·Psychiatry and Clinical Neurosciences·Yota Uno, Joseph T Coyle
Nov 6, 2020·Clinical Pharmacology and Therapeutics·Ewoud-Jan van HoogdalemMartin Kappler
Jan 14, 2021·International Journal of Environmental Research and Public Health·Alessandra Giovagnoli
Mar 12, 2021·Pharmacology & Therapeutics·Johannes PetzoldEdythe D London

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