PMID- 34164794
OWN - NLM
STAT- MEDLINE
DCOM- 20211025
LR  - 20211025
IS  - 1179-6901 (Electronic)
IS  - 1174-5886 (Print)
IS  - 1174-5886 (Linking)
VI  - 21
IP  - 3
DP  - 2021 Sep
TI  - Safety and Pharmacokinetics of HTL0018318, a Novel M(1) Receptor Agonist, Given 
      in Combination with Donepezil at Steady State: A Randomized Trial in Healthy 
      Elderly Subjects.
PG  - 295-304
LID - 10.1007/s40268-021-00352-5 [doi]
AB  - INTRODUCTION: HTL0018318 is a selective muscarinic M(1) 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.
CI  - (c) 2021. The Author(s).
FAU - Bakker, Charlotte
AU  - Bakker C
AUID- ORCID: 0000-0001-9822-2354
AD  - Centre for Human Drug Research (CDHR), Leiden, The Netherlands. cbakker@chdr.nl.
AD  - Leids Universitair Medisch Centrum, Leiden, The Netherlands. cbakker@chdr.nl.
FAU - van der Aart, Jasper
AU  - van der Aart J
AD  - Centre for Human Drug Research (CDHR), Leiden, The Netherlands.
FAU - Labots, Geert
AU  - Labots G
AD  - Centre for Human Drug Research (CDHR), Leiden, The Netherlands.
FAU - Liptrot, Jan
AU  - Liptrot J
AD  - Sosei Heptares, Cambridge, UK.
FAU - Cross, David M
AU  - Cross DM
AD  - Cross Pharma Consulting Ltd, Cambridge, UK.
FAU - Klaassen, Erica S
AU  - Klaassen ES
AD  - Centre for Human Drug Research (CDHR), Leiden, The Netherlands.
FAU - Dickinson, Steve
AU  - Dickinson S
AD  - Sosei Heptares, Cambridge, UK.
FAU - Tasker, Tim
AU  - Tasker T
AD  - Sosei Heptares, Cambridge, UK.
FAU - Groeneveld, Geert Jan
AU  - Groeneveld GJ
AD  - Centre for Human Drug Research (CDHR), Leiden, The Netherlands.
AD  - Leids Universitair Medisch Centrum, Leiden, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20210623
PL  - New Zealand
TA  - Drugs R D
JT  - Drugs in R&D
JID - 100883647
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Indans)
RN  - 0 (Piperidines)
RN  - 8SSC91326P (Donepezil)
SB  - IM
MH  - Aged
MH  - *Alzheimer Disease
MH  - Cholinesterase Inhibitors/adverse effects
MH  - Donepezil/adverse effects
MH  - Double-Blind Method
MH  - Humans
MH  - *Indans/adverse effects
MH  - Piperidines/adverse effects
PMC - PMC8363684
COIS- 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.
EDAT- 2021/06/25 06:00
MHDA- 2021/10/26 06:00
PMCR- 2021/06/23
CRDT- 2021/06/24 06:50
PHST- 2021/05/28 00:00 [accepted]
PHST- 2021/06/25 06:00 [pubmed]
PHST- 2021/10/26 06:00 [medline]
PHST- 2021/06/24 06:50 [entrez]
PHST- 2021/06/23 00:00 [pmc-release]
AID - 10.1007/s40268-021-00352-5 [pii]
AID - 352 [pii]
AID - 10.1007/s40268-021-00352-5 [doi]
PST - ppublish
SO  - Drugs R D. 2021 Sep;21(3):295-304. doi: 10.1007/s40268-021-00352-5. Epub 2021 Jun 
      23.