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First-in-Human Studies to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Novel 5-HT4 Partial Agonist, SUVN-D4010, in Healthy Adult and Elderly Subjects

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Abstract

Background and Objective

SUVN-D4010 is a novel, potent, highly selective 5-HT4 partial agonist intended for the treatment of cognitive disorders. The objective of the clinical study was to characterize the safety, tolerability, and pharmacokinetics of SUVN-D4010 in healthy adults after single and multiple doses, and to evaluate the effect of food, sex, and age on the pharmacokinetics.

Methods

Single-ascending dose and multiple-ascending dose studies for 14 days were conducted in healthy adults using a randomized, double-blind design. The effects of food, sex, and age on SUVN-D4010 pharmacokinetics (25 mg single dose) were evaluated using an open-label, two-period, randomized, fed and fasted, crossover design. Pharmacokinetics and safety assessments were conducted throughout the study.

Results

SUVN-D4010 at a single dose up to 45 mg and multiple doses up to 40 mg once daily was found to be safe and well tolerated in healthy adults. The most frequently reported adverse events were headache and nausea. SUVN-D4010 exposure was dose proportional across the tested doses. Steady state was achieved on day 2 after once-daily dosing for 14 days. Food had no significant effect on the exposures but an increase in median time to attain the maximum plasma concentration (tmax) from 2 h in a fasted state to 3.5 h in fed state was observed. The maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of SUVN-D4010 was 37% and 39%, respectively, lower in adult females compared to males following administration of a single 25 mg dose. In the elderly population, Cmax and AUC of SUVN-D4010 were 42% and 37%, respectively, lower compared to adult males following administration of a single 25 mg dose. SUVN-D4010 was well tolerated and safe in elderly subjects (≥ 65 years) following a single 25 mg dose.

Conclusion

SUVN-D4010 was found to be safe and well tolerated in healthy human subjects. SUVN-D4010 followed linear pharmacokinetics across the dose range. Accumulation was in the range of 1.3- to 1.4-fold after multiple dosing. Renal excretion is not the major route of elimination. Food had no effect on the exposures but increased the tmax of SUVN-D4010. Exposures were lower in females and elderly subjects suggesting sex and age effects on the pharmacokinetics of SUVN-D4010 and possible dose adjustment in these populations. SUVN-D4010 was well tolerated and safe in elderly subjects after a single dose.

Clinical trial identifiers: NCT02575482 and NCT03031574.

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Acknowledgements

The authors acknowledge the support received from Venkat Jasti, the CEO of Suven Life Sciences Ltd. The authors acknowledge the principal investigators from PRA services LLC for their support in the conduct of the studies reported in this manuscript.

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Authors and Affiliations

  1. Suven Life Sciences Ltd, Serene Chambers, Road 5, Avenue 7, Banjara Hills, Hyderabad, 500034, India

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

Authors
  1. Ramakrishna Nirogi
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  2. Gopinadh Bhyrapuneni
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  3. Nageswara Rao Muddana
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  4. Vinod Kumar Goyal
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  5. Santosh Kumar Pandey
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  6. Abdul Rasheed Mohammed
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  7. Jyothsna Ravula
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  8. Satish Jetta
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  9. Veera Raghava Chowdary Palacharla
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Corresponding author

Correspondence to Ramakrishna Nirogi.

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Funding

This study was sponsored by Suven Life Sciences Ltd.

Informed consent

All subjects provided written informed consent. The study was conducted at PRA Health Sciences – Early Development Services, Lenexa, KS, USA.

Conflict of interest

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

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).

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Not applicable.

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Authors’ contributions

All authors were involved in the study design, discussion, and interpretation of the results. All authors edited the manuscript and approved the final version.

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Nirogi, R., Bhyrapuneni, G., Muddana, N.R. et al. First-in-Human Studies to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Novel 5-HT4 Partial Agonist, SUVN-D4010, in Healthy Adult and Elderly Subjects. Clin Drug Investig 41, 469–482 (2021). https://doi.org/10.1007/s40261-021-01027-4

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  • DOI: https://doi.org/10.1007/s40261-021-01027-4

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