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-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 <0.05, pooled 4-week studies). Six serious AEs (3 with placebo, 1 with dalcetrapib 300 mg, and 2 with dalcetrapib 600 mg) were considered "unrelated" to treatment. Cardiovascular AEs were similar across treatment groups, with no dose-related trends and no clinically relevant changes in blood pressure or electrocardiographic results. Findings were similar in the 12-week study. In vitro, torcetrapib but not dalcetrapib increased aldosterone production and cytochrome P450 11B2 messenger ribonucleic acid levels. In conclusion, dalcetrapib alone or in combination with statins was effective at increasing high-density lipoprotein cholesterol and was well tolerated, without clinically relevant changes in blood pressure or cardiovascular AEs and no effects on aldosterone production as assessed nonclinically.
Stein
Evan A
EA
Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA. esteinmrl@aol.com
Stroes
Erik S G
ES
Steiner
George
G
Buckley
Brendan M
BM
Capponi
Alessandro M
AM
Burgess
Tracy
T
Niesor
Eric J
EJ
Kallend
David
D
Kastelein
John J P
JJ
D000577:Amides; D000924:Anticholesteremic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors; D003324:Coronary Artery Disease / Q000188:drug therapy*; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000188:drug therapy*; D004952:Esters; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use; D018570:Risk Assessment; D012307:Risk Factors; D013438:Sulfhydryl Compounds / Q000009:adverse effects* / Q000627:therapeutic use
D000577:Amides; D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D004952:Esters; D011804:Quinolines; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; C483909:torcetrapib