Safety, Tolerability and Pharmacokinetics of the Serotonin 5-HT6 Receptor Antagonist, SUVN-502, in Healthy Young Adults and Elderly Subjects.

Abstract

BACKGROUND AND OBJECTIVE:

SUVN-502, a selective 5-HT6 receptor antagonist, was found to be active in preclinical models of cognitive deterioration suggesting a potential role in the treatment of dementia related to Alzheimer's disease. The objective of this study was to characterize the safety, tolerability and pharmacokinetics of SUVN-502 in healthy young adults and elderly subjects following single and multiple oral doses.

METHODS:

Single doses (5, 15, 50, 100 and 200 mg SUVN-502) and multiple doses (50, 100 and 130 mg SUVN-502 once daily for 7 days) were evaluated in healthy young adults and multiple doses (50 and 100 mg SUVN-502 once daily for 14 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food, gender and age on SUVN-502 pharmacokinetics (100 mg single dose) was evaluated using an open-label, two-period, randomized, fed and fasted in a crossover design. SUVN-502 and M1 (major metabolite of SUVN-502) were monitored using validated analytical methods.

RESULTS:

SUVN-502 is safe and well tolerated up to the highest tested single dose of 200 mg in healthy young adults and multiple doses up to 130 mg for 7 days and 100 mg for 14 days in healthy young adults and elderly subjects, respectively. Exposures of SUVN-502 and M1 were more than dose-proportional over the evaluated dose range. Food and gender did not have a clinically meaningful effect on SUVN-502 exposure. The mean SUVN-502 total (AUC0-∞, and AUC0-last) and peak exposures (Cmax) were 2.9- and 2.2-fold higher, respectively, in elderly subjects compared to young subjects. Steady-state was achieved for SUVN-502 and M1 within 7 days after once-daily dosing of SUVN-502.

CONCLUSIONS:

SUVN-502 exhibited an acceptable safety, tolerability and pharmacokinetic profile in healthy young adults and elderly subjects. Based on the above results, 50 and 100 mg once-daily doses of SUVN-502 were advanced to Phase 2 evaluation in patients with moderate AD.

• Authors: Ramakrishna Nirogi, Koteshwara Mudigonda, Gopinadh Bhyrapuneni, Nageswara Rao Muddana, Vinod Kumar Goyal, Santosh Kumar Pandey, Raghava Choudary Palacharla
• Journal: Clinical drug investigation (Clin Drug Investig) Vol. 38 Issue 5 Pg. 401-415 (May 2018) ISSN: 1179-1918 [Electronic] New Zealand
• PMID: 29380267 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)

Chemical References

• Indoles
• Piperazines
• Receptors, Serotonin
• Serotonin Antagonists
• serotonin 6 receptor
• 1-((2-bromophenyl)sulfonyl)-5-methoxy-3-((4-methyl-1-piperazinyl)methyl)-1H-indole dimesylate monohydrate

Topics

• Administration, Oral
• Adult
• Aged
• Alzheimer Disease (drug therapy, metabolism)
• Area Under Curve
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Indoles (administration & dosage, pharmacokinetics)
• Male
• Piperazines (administration & dosage, pharmacokinetics)
• Receptors, Serotonin (metabolism)
• Serotonin Antagonists (administration & dosage, pharmacokinetics)
• Young Adult