Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2021 Sep;21(3):295-304.
doi: 10.1007/s40268-021-00352-5. Epub 2021 Jun 23.

Safety and Pharmacokinetics of HTL0018318, a Novel M1 Receptor Agonist, Given in Combination with Donepezil at Steady State: A Randomized Trial in Healthy Elderly Subjects

Charlotte Bakker  1   2 , Jasper van der Aart  3 , Geert Labots  3 , Jan Liptrot  4 , David M Cross  5 , Erica S Klaassen  3 , Steve Dickinson  4 , Tim Tasker  4 , Geert Jan Groeneveld  3   6
Affiliations
Randomized Controlled Trial

Safety and Pharmacokinetics of HTL0018318, a Novel M1 Receptor Agonist, Given in Combination with Donepezil at Steady State: A Randomized Trial in Healthy Elderly Subjects

Charlotte Bakker et al. Drugs R D. 2021 Sep.

Abstract

Introduction: HTL0018318 is a selective muscarinic M1 receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer's disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g. donepezil).

Objective: We investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil.

Methods: This was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics.

Results: AEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] -3.1 to -0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI -3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5-5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other's pharmacokinetics.

Conclusion: HTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil.

Clinical trial registration: Netherlands Trial register identifier NL5915, registered on 28 October 2016.

PubMed Disclaimer

Conflict of interest statement

Jan Liptrot, Steve Dickinson and Tim Tasker are currently paid employees of Sosei Heptares and have owned stock in the company. David M. Cross is a paid independent consultant for Sosei Heptares.

Figures

Fig. 1
Fig. 1
Study design. CRU clinical research unit, Dpz donepezil, ss steady state
Fig. 2
Fig. 2
Timing of donepezil pharmacokinetic samples. Dpz donepezil, h hour, HTL HTL0018318
See this image and copyright information in PMC

References

    1. Overk CR, Masliah E. Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease. Biochem Pharmacol. 2014;88(4):508–516. doi: 10.1016/j.bcp.2014.01.015. - DOI - PMC - PubMed
    1. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30(4):572–580. doi: 10.1002/ana.410300410. - DOI - PubMed
    1. Bierer LM, Haroutunian V, Gabriel S, Knott PJ, Carlin LS, Purohit DP, et al. Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits. J Neurochem. 1995;64(2):749–760. doi: 10.1046/j.1471-4159.1995.64020749.x. - DOI - PubMed
    1. Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, et al. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;41(2):615–631. doi: 10.3233/jad-132690. - DOI - PubMed
    1. Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. CMAJ Can Med Assoc J (J Assoc Med Can) 2003;169(6):557–64. - PMC - PubMed

Publication types