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Tolerability and Pharmacokinetics of ACT-280778, a Novel Nondihydropyridine Dual L/T-type Calcium Channel Blocker: Early Clinical Studies in Healthy Male Subjects Using Adaptive Designs

Mueller, Markus S. PhD*; Shakeri-Nejad, Kasra MD*; Gutierrez, Marcelo M. PhD*; Krause, Andreas PhD*; Täubel, Jörg MD; Sanderson, Brian MD; Dingemanse, Jasper PhD, PharmD, FCP*

Journal of Cardiovascular Pharmacology: February 2014 - Volume 63 - Issue 2 - p 120–131
doi: 10.1097/FJC.0000000000000030
Original Article

Abstract: ACT-280778 is a novel nondihydropyridine dual L/T-type calcium channel blocker. Two clinical studies (AC-067-101 and AC-067-102) were conducted to characterize its safety, tolerability, and pharmacokinetics in healthy male subjects after oral administration of single and multiple doses. Both trials were single-center, randomized, double-blind, placebo-controlled, adaptive design, ascending-dose studies, in which ACT-280778 was administrated as single doses of 2, 5, 15, or 40 mg, or as once-daily doses of 5 or 15 mg for 7 days. Single and multiple doses up to and including 15 mg were well tolerated, and no serious or severe adverse event was reported in either study. A single dose of 40 mg was associated with abnormal electrocardiogram findings resulting in the discontinuation of further treatment at this dose or higher doses. ACT-280778 was rapidly absorbed, and larger than dose-proportional increases of the maximum plasma concentration and area under the plasma concentration–time curve were observed. Food intake delayed the time to maximum plasma concentration and doubled exposure. Urinary excretion of unchanged ACT-280778 was negligible, and accumulation at steady state was modest. Overall, pharmacokinetic and tolerability profiles of ACT-280778 observed in these 2 studies warranted further evaluation of ACT-280778 in a proof-of-concept study in patients with hypertension.

*Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland;

Richmond Pharmacology Ltd, St George's University of London, London, United Kingdom; and

Chiltern (Early Phase) Ltd, Dundee, United Kingdom.

Reprints: Jasper Dingemanse, PhD, PharmD, FCP, Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland (e-mail: jasper.dingemanse@actelion.com).

Supported by Actelion Pharmaceuticals Ltd (J.T. and B.S.).

M. S. Mueller, K. Shakeri-Nejad, M. M. Gutierrez, A. Krause, and J. Dingemanse were full-time employees and shareholders of Actelion Pharmaceuticals Ltd at the time of study conduct; J. Täubel and B. Sanderson were full-time employees of Richmond Pharmacology Ltd and Chiltern (Early Phase) Ltd, respectively.

Received July 01, 2013

Accepted October 02, 2013

© 2014 by Lippincott Williams & Wilkins.