SpringerLink
Log in

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

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background and Objective

SUVN-G3031 is a novel, potent, and selective histamine-3 receptor (H3R) inverse agonist in development for the treatment of narcolepsy. Our objective was to characterize the safety, tolerability, and pharmacokinetics of SUVN-G3031 in healthy young adults after single and multiple doses, and to evaluate the effect of food, gender, and age on the pharmacokinetics.

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

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

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Scammell TE. Narcolepsy. N Engl J Med. 2015;373(27):2654–62.

    Article  CAS  Google Scholar 

  2. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007;369(9560):499–511.

    Article  Google Scholar 

  3. 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.

    Article  Google Scholar 

  4. 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.

    Article  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. 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.

    Article  CAS  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. ICH Harmonized Tripartite Guideline, Guideline for Good clinical practice, E6 (R1), Current Step 4 version, dated 10 June 1996.

  12. 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.

    Article  PubMed  Google Scholar 

  13. 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.

  14. 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.

    Article  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the principal investigators from Quintiles Phase One Services LLC for their support in the conduct of the studies reported in this article.

Author information

Authors and Affiliations

  1. Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road # 7, Banjara Hills, Hyderabad, 500 034, India

    Ramakrishna Nirogi, Koteshwara Mudigonda, Gopinadh Bhyrapuneni, Nageswara Rao Muddana, Anil Shinde, Vinod Kumar Goyal, Santosh Kumar Pandey, Abdul Rasheed Mohammed, Jyothsna Ravula, Satish Jetta & Veera Raghava Chowdary Palacharla

Authors
  1. Ramakrishna Nirogi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koteshwara Mudigonda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gopinadh Bhyrapuneni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nageswara Rao Muddana
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anil Shinde
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vinod Kumar Goyal
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Santosh Kumar Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Abdul Rasheed Mohammed
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jyothsna Ravula
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Satish Jetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Veera Raghava Chowdary Palacharla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramakrishna Nirogi.

Ethics declarations

Funding

This study was sponsored by Suven Life Sciences Ltd.

Conflict of interest

All authors are employees of Suven Life Sciences Ltd. The authors have no other conflicts of interest to declare.

Informed consent

All subjects provided written informed consent. The study was conducted at Quintiles Phase One Services LLC (Overland Park, KS, USA).

Ethics approval

The study was conducted in compliance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects, Good Clinical Practice Guidelines, and the Declaration of Helsinki. The protocols were reviewed and approved by the institutional review board, Midlands Independent Review Board (Overland Park, KS, USA).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nirogi, R., Mudigonda, K., Bhyrapuneni, G. et al. 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. Clin Drug Investig 40, 603–615 (2020). https://doi.org/10.1007/s40261-020-00920-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-020-00920-8

Search

Navigation