Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D2 , which leads to poor patient compliance and suboptimal dosing. This phase ...II dose-ranging study was designed to assess whether the prostaglandin D2 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.
Background Development of niacin-like agents that favorably affect lipids with an improved flushing profile would be beneficial. Objective To evaluate a niacin receptor partial agonist, MK-0354, in ...Phase I and II studies. Methods The pharmacokinetic/pharmacodynamic effects of single and multiple doses (7 days) of MK-0354 (300–4000 mg) were evaluated in two Phase I studies conducted in healthy men. A Phase II study assessed the effects of MK-0354 2.5 g once daily on lipids during 4 weeks in 66 dyslipidemic patients. Results MK-0354 single doses up to 4000 mg and multiple doses (7 days) up to 3600 mg produced robust dose-related reductions in free fatty acid (FFA) over 5 hours. Single doses of MK-0354 300 mg and extended release-niacin (Niaspan) 1 g produced comparable reductions in FFA. Suppression of FFA following 7 daily doses of MK-0354 was similar to that after a single dose. In the Phase II study, MK-0354 2.5 g produced little flushing but no clinically meaningful effects on lipids (placebo-adjusted percent change: high-density lipoprotein cholesterol, 0.4%, 95% confidence interval −5.2 to 6.0; low-density lipoprotein cholesterol, −9.8%, 95% confidence interval −16.8 to −2.7; triglyceride, −5.8%, 95% confidence interval −22.6 to 11.9). Conclusion Treatment with MK-0354 for 7 days resulted in plasma FFA suppression with minimal cutaneous flushing. However, 4 weeks of treatment with MK-0354 failed to produce changes in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or triglycerides.
Background Prostaglandin D2 is a proinflammatory mediator believed to be important in asthma and allergic rhinitis (AR). Allelic variants in the prostaglandin D2 receptor type 1 (DP1) gene (PTGDR) ...have been suggested to be associated with asthma susceptibility. Objectives We sought to investigate the efficacy of the DP1 antagonist laropiprant (alone or with montelukast) in asthma and seasonal AR and explore whether sequence variations in PTGDR are associated with asthma severity. Methods For asthma, in a double-blind crossover study, 100 patients with persistent asthma were randomized to placebo or laropiprant, 300 mg/d for 3 weeks, followed by addition of montelukast, 10 mg/d for 2 weeks. PTGDR promoter haplotypes were categorized as high, medium, or low transcriptional efficiency. The primary efficacy end point was FEV1 . For AR, in a double-blind parallel-group study, 767 patients sensitized to a regionally prevalent fall allergen with symptomatic fall rhinitis were allocated to laropiprant, 25 mg/d or 100 mg/d; cetirizine, 10mg/d; or placebo for 2 weeks. The primary end point was the Daytime Nasal Symptoms Score. Results For asthma, no significant differences in FEV1 or asthma symptoms were noted for laropiprant versus placebo or laropiprant plus montelukast vs montelukast (differences between montelukast and placebo: P ≤ .001). No clear association was seen between haplotype pair (ie, diplotype) and asthma severity. For AR, although cetirizine (vs placebo) demonstrated an improvement in the Daytime Nasal Symptoms Score ( P < .001), laropiprant did not. Conclusion Laropiprant did not demonstrate efficacy in asthmatic patients or patients with AR. Variations in PTGDR did not appear related to baseline asthma severity or treatment response (NCT00533208; NCT00783601).
Treatment with niacin effectively improves multiple lipid parameters and cardiovascular outcomes. Widespread use of niacin, however, is limited by flushing, which is mediated primarily by ...prostaglandin D2 (PGD2). Laropiprant is a selective PGD2 receptor 1 (DP1) antagonist that reduces objective measures of niacin-induced flushing symptoms upon initiation of therapy and with more chronic use. Results from early dosing and formulation studies have culminated in the development of a combination extended-release (ER) niacin/laropiprant tablet aimed at providing the beneficial lipid-modifying effects of niacin, while reducing niacin-induced flushing. The improvement in the tolerability of niacin with ER niacin/laropiprant allows niacin dosing to initiate directly at 1 g and rapidly advance to a 2-g target dose. ER niacin/laropiprant generally is tolerated well and represents a new treatment option for dyslipidemia that offers the potential for more patients to receive the lipid-modifying and cardiovascular benefits of niacin.
