Lack of effect of dalcetrapib on QT interval in healthy subjects following multiple dosing.
OBJECTIVE
Evaluate dalcetrapib's potential to prolong QT intervals in healthy subjects.


METHODS
This was a single-center, randomized, active and placebo-controlled, six-sequence, three-period cross-over study. Participants [18-65 years; body mass index (BMI) 18-30 kg/m(2)] were randomized to daily doses of dalcetrapib 600 mg (therapeutic) or 3,900 mg (supratherapeutic) or to dalcetrapib-matched placebo for 7 days. On Day 8, subjects received single-dose moxifloxacin 400 mg (active control) or placebo, following the placebo or dalcetrapib, respectively. Electrocardiographic parameters were recorded on Days -1, 1, 7, and 8. The primary endpoint was the difference to placebo of time-matched change from baseline in the study-specific corrected QT interval (QTcS) at seven time-points within 24 h after dalcetrapib 3,900 mg on Day 7. An upper 95% confidence interval (CI) <10 ms confirmed the absence of a significant effect. Pharmacokinetic and lipid-related parameters were measured.


RESULTS
Subjects (n = 49) were predominantly male (71%), and all were white, with a mean age of 45 years and mean BMI of 25 kg/m(2). For the primary analysis, the upper 95% CI for dalcetrapib 3,900 mg was <10 ms at all time-points. Similar findings were obtained for dalcetrapib 600 mg. Following the administration of moxifloxacin, the QTcS increased by >5 ms. At Day 7, exposure for dalcetrapib 3,900 mg was approximately eightfold higher than that for dalcetrapib 600 mg [mean area under the plasma concentration-time curve between time 0 and 24 h 68,500 vs. 8,280 ng*h/mL; mean peak concentration 6,810 vs. 861 ng/mL]. Cholesteryl ester transfer protein activity was inhibited by 30%, and high-density lipoprotein cholesterol increased by 26% for dalcetrapib 600 mg. Dalcetrapib was well tolerated.


CONCLUSIONS
Dalcetrapib is not associated with QT interval prolongation, even at doses markedly greater than intended therapeutically.
F. Hoffmann-La Roche Ltd, Building 663, Office 2139, Basel 4070, Switzerland. michael.derks@roche.com
Michael
M
Derks
Markus
M
Abt
Anne
A
Mwangi
Georgina
G
Meneses-Lorente
D000284:Administration, Oral; D000328:Adult; D000577:Amides; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001372:Aza Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D015716:Electrocardiography, Ambulatory / Q000187:drug effects; D004952:Esters; D024841:Fluoroquinolones; D006321:Heart / Q000187:drug effects; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
D000577:Amides; D000924:Anticholesteremic Agents; D001372:Aza Compounds; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D024841:Fluoroquinolones; D011804:Quinolines; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D000077266:Moxifloxacin