Tolerability and Pharmacokinetics of ACT-280778, a Novel Nondihydropyridine Dual L/T-type Calcium Channel Blocker

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.

Comparison of Digital 12‐Lead ECG and Digital 12‐Lead Holter ECG Recordings in Healthy Male Subjects: Results from a Randomized, Double‐Blinded, Placebo‐Controlled Clinical Trial

“…No serious adverse events were reported throughout the study and the novel nondihydropyridine dual L/T-type calcium channel blocker ACT-280778 was shown to be well tolerated. 10 Those subjects contributed with 413 ECGs recorded by Holter method and 406 ECGs by standard method.…”

“…This study used data collected from a Phase I, single-center, double-blinded, placebo-controlled, randomized, single-ascending oral dose and food interaction study to investigate the safety, tolerability and pharmacokinetics of ACT-280778 in healthy male subjects. 10 Each subject participated in one treatment period only (fasted), with the exception of subjects in the food effect group who participated in two treatment periods (fed/fasted).…”

The Case for an Unblinded Modeler in Early Clinical Development

“…Some models are readily available, including the efficacy‐safety tradeoff algorithm (supplementary material) or an adaptive design based on dose response that can be applied sequentially . In practice, any dose‐ or concentration‐response model can be utilized.…”

“…ACT‐280778 is a novel nondihydropyridine dual L/T‐type calcium channel blocker intended to be used in cardiovascular disease to lower blood pressure. The first‐in‐human study was conducted with groupwise dose selection based on modeling . The decision to have an unblinded modeler to guide dose escalation was driven by the large uncertainty around efficacy and safety of the compound and the optimum dose.…”