Safety and Tolerability of Dalcetrapib

Efficacy and safety data for dalcetrapib (RO4607381/JTT-705) are presented, following a report of increased mortality and cardiac events with another cholesteryl ester transfer protein inhibitor, torcetrapib, associated with off-target adverse effects (hypertension and the activation of the renin-an...

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Bibliographic Details
Published in:The American journal of cardiology 2009-07, Vol.104 (1), p.82-91
Main Authors: Stein, Evan A., MD, PhD, Stroes, Erik S.G., MD, PhD, Steiner, George, BA, MD, Buckley, Brendan M., DPhil, Capponi, Alessandro M., PhD, Burgess, Tracy, MSc, Niesor, Eric J., PhD, Kallend, David, MB BS Lon, Kastelein, John J.P., MD, PhD
Format: Article
Language:English
Subjects:
Anticholesteremic Agents - adverse effects
Anticholesteremic Agents - therapeutic use
Biological and medical sciences
Blood pressure
Cardiology. Vascular system
Cardiovascular
Cardiovascular disease
Cholesterol
Cholesterol Ester Transfer Proteins - antagonists & inhibitors
Clinical trials
Coronary Artery Disease - drug therapy
Double-Blind Method
Dyslipidemias - drug therapy
Female
Humans
Incidence
Inhibitor drugs
Male
Medical sciences
Middle Aged
Placebo effect
Quinolines - adverse effects
Quinolines - therapeutic use
Risk Assessment
Risk Factors
Safety
Sulfhydryl Compounds - adverse effects
Sulfhydryl Compounds - therapeutic use
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Summary:Efficacy and safety data for dalcetrapib (RO4607381/JTT-705) are presented, following a report of increased mortality and cardiac events with another cholesteryl ester transfer protein inhibitor, torcetrapib, associated with off-target adverse effects (hypertension and the activation of the renin-angiotensin-aldosterone system). The efficacy and clinical safety of dalcetrapib 300, 600, and 900 mg or placebo were assessed (n = 838) in 4 pooled 4-week phase IIa trials (1 monotherapy, n = 193; 3 statin combination, n = 353) and 1 12-week phase IIb trial (with pravastatin, n = 292). Nonclinical safety, assessed by the induction of aldosterone production and aldosterone synthase (cytochrome P450 11B2) messenger ribonucleic acid, was measured in human adrenocarcinoma (H295R) cells exposed to dalcetrapib or torcetrapib. Dalcetrapib increased high-density lipoprotein cholesterol by up to 36% and apolipoprotein A-I by up to 16%. The incidence of adverse events (AEs) was similar between placebo (42%) and dalcetrapib 300 mg (50%) and 600 mg (42%), with more events with dalcetrapib 900 mg (58%) (p
ISSN:0002-9149
1879-1913
DOI:10.1016/j.amjcard.2009.02.061