Abstract
Purpose
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/m2] 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/m2. 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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR (2003) Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol 23:160–167
Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ (2004) Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol 24:490–497
de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ (2002) Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose response study. Circulation 105:2159–2165
Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B, ILLUMINATE Investigators (2007) Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357:2109–2122
Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, Shear CL, Duggan WT, Vicari RM, Grobbee DE, Kastelein JJ, RADIANCE 2 Investigators (2007) Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 370:153–160
Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML, RADIANCE 1 Investigators (2007) Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 356:1620–1630
Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM, ILLUSTRATE Investigators (2007) Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 356:1304–1316
Kuivenhoven JA, de Grooth GJ, Kawamura H, Klerkx AH, Wilhelm F, Trip MD, Kastelein JJ (2005) Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia. Am J Cardiol 95:1085–1088
Stein EA, Stroes ES, Steiner G, Buckley BM, Capponi AM, Burgess T, Niesor EJ, Kallend D, Kastelein JJ (2009) Safety and tolerability of dalcetrapib. Am J Cardiol 104:82–91
International Conference on Harmonisation (2005) E14 Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Available at: http://www.fda.gov/RegulatoryInformation/Guidances/ucm129335.htm. Accessed 6 Oct 2009
Lettieri J, Vargas R, Agarwal V, Liu P (2001) Effect of food on the pharmacokinetics of a single oral dose of moxifloxacin 400 mg in healthy male volunteers. Clin Pharmacokinet 40[Suppl 1]:19–25
Desai M, Li L, Desta Z, Malik M, Flockhart D (2003) Variability of heart rate correction methods for the QT interval. Br J Clin Pharmacol 55:511–517
Malik M, Camm AJ (2001) Evaluation of drug-induced QT interval prolongation: implications for drug approval and labelling. Drug Safety 24:323–351
Derks M, Fowler S, Kuhlmann O (2009) A single-center, open-label, one-sequence study of dalcetrapib coadministered with ketoconazole, and an in vitro study of the S-methyl metabolite of dalcetrapib. Clin Ther 31:586–599
Acknowledgments
Support for this study was provided by F. Hoffmann-La Roche Ltd. Editorial assistance was provided by Prime Medica Inc. during the preparation of this report, funded by F. Hoffmann-La Roche Ltd.
Disclosures
The authors are employees of F. Hoffmann-La Roche Ltd.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Derks, M., Abt, M., Mwangi, A. et al. Lack of effect of dalcetrapib on QT interval in healthy subjects following multiple dosing. Eur J Clin Pharmacol 66, 775–783 (2010). https://doi.org/10.1007/s00228-010-0841-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-010-0841-2