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: 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.
Authors: Zhaosha Li; Clara C Blad; Ronald J van der Sluis; Henk de Vries; Theo J C Van Berkel; Adriaan P Ijzerman; Menno Hoekstra Journal: Br J Pharmacol Date: 2012-10 Impact factor: 8.739
Authors: Robert W Walters; Arun K Shukla; Jeffrey J Kovacs; Jonathan D Violin; Scott M DeWire; Christopher M Lam; J Ruthie Chen; Michael J Muehlbauer; Erin J Whalen; Robert J Lefkowitz Journal: J Clin Invest Date: 2009-04-06 Impact factor: 14.808
Authors: John R Guyton; Sergio Fazio; Adeniyi J Adewale; Erin Jensen; Joanne E Tomassini; Arvind Shah; Andrew M Tershakovec Journal: Diabetes Care Date: 2012-02-14 Impact factor: 19.112