Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia.
Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D(2), which leads to poor patient compliance and suboptimal dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin D(2) receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)-induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n = 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n = 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients.
Paolini
John F
JF
Merck Research Laboratories, Rahway, NJ, USA. john_paolini@merck.com
Mitchel
Yale B
YB
Reyes
Robert
R
Kher
Uma
U
Lai
Eseng
E
Watson
Douglas J
DJ
Norquist
Josephine M
JM
Meehan
Alan G
AG
Bays
Harold E
HE
Davidson
Michael
M
Ballantyne
Christie M
CM
D000293:Adolescent; D000328:Adult; D000368:Aged; D003402:Creatine Kinase / Q000097:blood; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000188:drug therapy; D005260:Female; D005483:Flushing / Q000139:chemically induced* / Q000517:prevention & control*; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009525:Niacin / Q000008:administration & dosage / Q000009:adverse effects*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors
D003692:Delayed-Action Preparations; D000960:Hypolipidemic Agents; D007211:Indoles; C518174:MK-0524; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D009525:Niacin; D003402:Creatine Kinase; C036293:prostaglandin D2 receptor