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



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).



Mavoglurant was well tolerated up to a single intravenous dose of 50 mg, and supratherapeutic Cmaxvalues 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 between mavoglurant plasma concentrations and ΔΔQTcF 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.



This TQT study describes the use of single intravenous dosing as an alternate approach to achieve supratherapeutic plasma concentrations as required per the International Council for Harmonisation E14 guideline with compounds characterized by exposure related tolerability limitations. The increased Cmax/AUC ratio compared with conventional oral dosing may contribute to a reduced incidence of adverse events that appear more related to overall exposure.
Novartis Pharma AG, Basel, Switzerland. Electronic address: mike.ufer@novartis.com.
Mike
M
Ufer
Novartis Pharma AG, Basel, Switzerland.
Alexandros
A
Sagkriotis
Novartis Healthcare Pvt Ltd, Hyderabad, India.
Atish
A
Salunke
Novartis Healthcare Pvt Ltd, Hyderabad, India.
Subramanian
S
Ganesan
Novartis Pharma AG, Basel, Switzerland.
Anne
A
Tisserant
Novartis Pharma AG, Basel, Switzerland.
Angela
A
Dodman
Novartis Pharma AG, Basel, Switzerland.
Emilie
E
Voltz
Novartis Pharma AG, Basel, Switzerland.
Ralph
R
Woessner
Novartis Pharma AG, Basel, Switzerland.
Pierre
P
Jordaan
Novartis Pharma AG, Basel, Switzerland.
Eric
E
Legangneux
D061605:Administration, Intravenous; D000328:Adult; D000494:Allosteric Regulation; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D024841:Fluoroquinolones / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D000077266:Moxifloxacin; D010865:Pilot Projects; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*
D024841:Fluoroquinolones; D007211:Indoles; D064529:Receptor, Metabotropic Glutamate 5; C581397:mavoglurant; D000077266:Moxifloxacin
QTc interval; cardiac repolarization; central nervous system; healthy individuals; intravenous