Intravenous Dosing as an Alternate Approach to Safely Achieve Supratherapeutic Exposure for Assessments of Cardiac Repolarization: A Randomized Clinical Trial with Mavoglurant (AFQ056)

Purpose: The conduct of thorough QTc (TQT) studies is often challenging with compounds that are characterized by limited tolerability in healthy individuals. This is applicable to several central nervous system drugs, including mavoglurant acting as a selective allosteric modulator of metabotropic glutamate receptor 5. This TQT study describes the use of a single intravenous dosing regimen as an alternate approach allowing for sufficiently high C-max values while controlling tolerability. Methods: This study was a randomized, placebo and active-controlled, 4-period, crossover, TQT study composed of 2 sequential phases. In the pilot phase, the safety and tolerability profile of 10-minute infusions of 25, 37.5, and 50 mg of mavoglurant was assessed in 36 healthy individuals. In the TQT phase, individuals received in random sequence single intravenous doses of mavoglurant (25 and 50 mg) and placebo and an oral dose of moxifloxacin (400 mg). Findings: Mavoglurant was well tolerated up to a single intravenous dose of 50 mg, and supratherapeutic C-max values were achieved that were approximately 2-fold higher than at the multiple maximum tolerated dose and more than 3-fold higher relative to therapeutic plasma concentrations. The upper bound of the 2-sided 90% CI of Fridericia-corrected placebo- and baseline-adjusted QTc intervals (QTcFs) did not exceed 10 milliseconds at any postdose time point for both mavoglurant doses. The pharmacokinetic and pharmacodynamic analysis confirmed the lack of an association Present affiliation: ICON pls, Thiruvananthapuram, India. tPresent affiliation: Roche Pharma AG, Basel, Switzerland. between mavoglurant plasma concentrations and Delta Delta QTcF data over the entire range of plasma concentration data at 25 and 50 mg of mavoglurant. An outlier analysis revealed no individuals with newly identified QTcF intervals >480 milliseconds or any QTcF prolongations >60 milliseconds compared with baseline in any of the treatment groups. Hence, the lack of any clinically relevant QTc prolongation was found for therapeutic and supratherapeutic single intravenous doses of 25 and 50 mg of mavoglurant. (C) 2016 Elsevier HS Journals, Inc. All rights reserved.