Safety, Tolerability, and Pharmacokinetics of SUVN-G3031, a Novel Histamine-3 Receptor Inverse Agonist for the Treatment of Narcolepsy, in Healthy Human Subjects Following Single and Multiple Oral Doses.
Journal
Clinical drug investigation
ISSN: 1179-1918
Titre abrégé: Clin Drug Investig
Pays: New Zealand
ID NLM: 9504817
Informations de publication
Date de publication:
Jul 2020
Jul 2020
Historique:
pubmed:
14
5
2020
medline:
4
9
2020
entrez:
14
5
2020
Statut:
ppublish
Résumé
SUVN-G3031 is a novel, potent, and selective histamine-3 receptor (H A single ascending dose (SAD) and a multiple ascending dose (MAD) study for 14 days was conducted in healthy young adults using a randomized, double-blind study design. The effect of food, gender, and age on SUVN-G3031 pharmacokinetics (6 mg as a single dose) was evaluated using an open-label, two-period, randomized, crossover design in fed and fasted states. Pharmacokinetics and safety assessments were conducted throughout the study. Single doses of SUVN-G3031 up to 20 mg and multiple doses up to 6 mg once daily were found to be safe and well tolerated in healthy young adults. The most frequently reported adverse events were abnormal dreams, dyssomnia, and hot flushes. SUVN-G3031 exposure was dose proportional across the tested doses. Steady state was achieved on day 6 after once-daily dosing. Renal excretion (~ 60%) of unchanged SUVN-G3031 was the major route of elimination. Food, gender, and age did not have any clinically meaningful effect on SUVN-G3031 exposure. SUVN-G3031 was found to be safe and well tolerated in healthy human subjects without any effect of age, gender, and food on the pharmacokinetics and safety profile. Clinical Trials Registration (https://clinicaltrials.gov): NCT04072380 and NCT02342041.
Sections du résumé
BACKGROUND AND OBJECTIVE
OBJECTIVE
SUVN-G3031 is a novel, potent, and selective histamine-3 receptor (H
METHODS
METHODS
A single ascending dose (SAD) and a multiple ascending dose (MAD) study for 14 days was conducted in healthy young adults using a randomized, double-blind study design. The effect of food, gender, and age on SUVN-G3031 pharmacokinetics (6 mg as a single dose) was evaluated using an open-label, two-period, randomized, crossover design in fed and fasted states. Pharmacokinetics and safety assessments were conducted throughout the study.
RESULTS
RESULTS
Single doses of SUVN-G3031 up to 20 mg and multiple doses up to 6 mg once daily were found to be safe and well tolerated in healthy young adults. The most frequently reported adverse events were abnormal dreams, dyssomnia, and hot flushes. SUVN-G3031 exposure was dose proportional across the tested doses. Steady state was achieved on day 6 after once-daily dosing. Renal excretion (~ 60%) of unchanged SUVN-G3031 was the major route of elimination. Food, gender, and age did not have any clinically meaningful effect on SUVN-G3031 exposure.
CONCLUSION
CONCLUSIONS
SUVN-G3031 was found to be safe and well tolerated in healthy human subjects without any effect of age, gender, and food on the pharmacokinetics and safety profile. Clinical Trials Registration (https://clinicaltrials.gov): NCT04072380 and NCT02342041.
Identifiants
pubmed: 32399853
doi: 10.1007/s40261-020-00920-8
pii: 10.1007/s40261-020-00920-8
doi:
Substances chimiques
Morpholines
0
Piperidines
0
samelisant
65V47O9NOP
Histamine
820484N8I3
Banques de données
ClinicalTrials.gov
['NCT04072380', 'NCT02342041']
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
603-615Références
Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654–62.
doi: 10.1056/NEJMra1500587
Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007;369(9560):499–511.
doi: 10.1016/S0140-6736(07)60237-2
Jennum P, Ibsen R, Petersen ER, Knudsen S, Kjellberg J. Health, social, and economic consequences of narcolepsy: a controlled national study evaluating the societal effect on patients and their partners. Sleep Med. 2012;13(8):1086–93.
doi: 10.1016/j.sleep.2012.06.006
Black J, Reaven NL, Funk SE, McGaughey K, Ohayon M, Guilleminault C, Ruoff C, Mignot E. The Burden of Narcolepsy Disease (BOND) study: health-care utilization and cost findings. Sleep Med. 2014;15(5):522–9.
doi: 10.1016/j.sleep.2014.02.001
Leurs R, Bakker RA, Timmerman H, de Esch IJ. The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov. 2005;4(2):107–20.
doi: 10.1038/nrd1631
Leurs R, Blandina P, Tedford C, Timmerman H. Therapeutic potential of histamine H3 receptor agonists and antagonists. Trends Pharmacol Sci. 1998;19(5):177–83.
doi: 10.1016/S0165-6147(98)01201-2
Esbenshade TA, Browman KE, Bitner RS, Strakhova M, Cowart MD, Brioni JD. The histamine H3 receptor: an attractive target for the treatment of cognitive disorders. Br J Pharmacol. 2008;154(6):1166–81.
doi: 10.1038/bjp.2008.147
Parmentier R, Anaclet C, Guhennec C, Brousseau E, Bricout D, Giboulot T, Bozyczko-Coyne D, Spiegel K, Ohtsu H, Williams M, Lin JS. The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders. Biochem Pharmacol. 2007;73(8):1157–71.
doi: 10.1016/j.bcp.2007.01.002
Nirogi R, Shinde A, Mohammed AR, Badange RK, Reballi V, Bandyala TR, Saraf SK, Bojja K, Manchineella S, Achanta PK, Kandukuri KK, Subramanian R, Benade V, Palacharla RC, Jayarajan P, Pandey S, Jasti V. Discovery and development of n-[4-(1-cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide dihydrochloride (SUVN-G3031): a novel, potent, selective, and orally active histamine H3 receptor inverse agonist with robust wake-promoting activity. J Med Chem. 2019;62(3):1203–17.
doi: 10.1021/acs.jmedchem.8b01280
Bhayrapuneni G, Kamuju V, Gandipudi S, Jayarajan P, Abraham R, Bojja K, et al. SUVN-G3031, a novel, potent and selective histamine H3 receptor inverse agonist for the treatment of narcolepsy: preclinical characterization [abstract no. 0120]. Sleep. 2019;42(suppl 1):A50.
doi: 10.1093/sleep/zsz067.119
ICH Harmonized Tripartite Guideline, Guideline for Good clinical practice, E6 (R1), Current Step 4 version, dated 10 June 1996.
Nirogi R, Ajjala DR, Prakash Padala NS, Kalaikadiban I, Rayapati LP, Chunduru P, Shinde A. LC-MS/MS method for the quantification of SUVN-G3031, a novel H3 receptor inverse agonist for narcolepsy treatment. Bioanalysis. 2020. https://doi.org/10.4155/bio-2020-0020 .
doi: 10.4155/bio-2020-0020
pubmed: 32351118
US Food Drug Administration. Guidance for Industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Rockville, MD: Food and Drug Administration; 2005. Available from: http://www.fda.gov/downloads/drugs/guidances/ucm078932.pdf . Accessed 10 Apr 2020.
Kollb-Sielecka M, Demolis P, Emmerich J, Markey G, Salmonson T, Haas M. The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for Medicinal Products for Human Use. Sleep Med. 2017;33:125–9.
doi: 10.1016/j.sleep.2017.01.002