title: 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.
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.
authors.affiliation: *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.
authors.forename: Markus S
authors.initials: MS
authors.lastname: Mueller
authors.forename: Kasra
authors.initials: K
authors.lastname: Shakeri-Nejad
authors.forename: Marcelo M
authors.initials: MM
authors.lastname: Gutierrez
authors.forename: Andreas
authors.initials: A
authors.lastname: Krause
authors.forename: Jörg
authors.initials: J
authors.lastname: Täubel
authors.forename: Brian
authors.initials: B
authors.lastname: Sanderson
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D001562:Benzimidazoles; D001643:Bridged Bicyclo Compounds; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; C000592016:isobutyric acid 2-(2-((3-(4,7-dimethoxy-1H-benzoimidazol-2-yl)propyl)methylamino)ethyl)-5-phenylbicyclo(2.2.2)oct-5-en-2-yl ester