PMID- 33891333
OWN - NLM
STAT- MEDLINE
DCOM- 20211207
LR  - 20211214
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 87
IP  - 11
DP  - 2021 Nov
TI  - Safety, pharmacokinetics and pharmacodynamics of HTL0009936, a selective 
      muscarinic M(1) -acetylcholine receptor agonist: A randomized cross-over trial.
PG  - 4439-4449
LID - 10.1111/bcp.14872 [doi]
AB  - AIMS: HTL0009936 is a selective M(1) muscarinic receptor agonist in development 
      for cognitive dysfunction in Alzheimer's disease. Safety, tolerability and 
      pharmacokinetics and exploratory pharmacodynamic effects of HTL0009936 
      administered by continuous IV infusion at steady state were investigated in 
      elderly subjects with below average cognitive functioning (BACF). METHODS: Part A 
      was a four-treatment open label sequential study in healthy elderly investigating 
      10-83 mg HTL0009936 (IV) and a 24 mg HTL0009936 single oral dose. Part B was a 
      five-treatment randomized, double-blind, placebo and physostigmine controlled 
      cross-over study with IV HTL0009936 in elderly subjects with BACF. 
      Pharmacodynamic assessments were performed using neurocognitive and 
      electrophysiological tests. RESULTS: Pharmacokinetics of HTL0009936 showed 
      dose-proportional increases in exposure with a mean half-life of 2.4 hours. 
      HTL0009936 was well-tolerated with transient dose-related adverse events (AEs). 
      Small increases in mean systolic blood pressure of 7.12 mmHg (95% CI 
      [3.99-10.24]) and in diastolic of 5.32 mmHg (95% CI [3.18-7.47]) were noted at 
      the highest dose in part B. Overall, there was suggestive, but no definitive, 
      positive or negative pharmacodynamic effects. Statistically significant effects 
      were observed on P300 with HTL0009936 and adaptive tracking with physostigmine. 
      CONCLUSIONS: HTL0009936 showed well-characterized pharmacokinetics and single 
      doses were safe and generally well-tolerated in healthy elderly subjects. Due to 
      physostigmine tolerability issues and subject burden, the study design was 
      changed and some pharmacodynamic assessments (neurocognitive) were performed at 
      suboptimal drug exposures. Therefore no clear conclusions can be made on 
      pharmacodynamic effects of HTL0009936, although an effect on P300 is suggestive 
      of central target engagement.
CI  - (c) 2021 The Authors. British Journal of Clinical Pharmacology published by John 
      Wiley & Sons Ltd on behalf of British Pharmacological Society.
FAU - Bakker, Charlotte
AU  - Bakker C
AUID- ORCID: 0000-0001-9822-2354
AD  - Centre for Human Drug Research, Leiden, The Netherlands.
AD  - Leiden University Medical Center, Leiden, The Netherlands.
FAU - Prins, Samantha
AU  - Prins S
AD  - Centre for Human Drug Research, Leiden, The Netherlands.
AD  - Leiden University Medical Center, Leiden, The Netherlands.
FAU - Liptrot, Jan
AU  - Liptrot J
AD  - Sosei Heptares, Cambridge, UK.
FAU - Hart, Ellen P
AU  - Hart EP
AD  - Centre for Human Drug Research, Leiden, The Netherlands.
FAU - Klaassen, Erica S
AU  - Klaassen ES
AD  - Centre for Human Drug Research, Leiden, The Netherlands.
FAU - Brown, Giles A
AU  - Brown GA
AD  - Sosei Heptares, Cambridge, UK.
FAU - Brown, Alastair
AU  - Brown A
AD  - Sosei Heptares, Cambridge, UK.
FAU - Congreve, Miles
AU  - Congreve M
AD  - Sosei Heptares, Cambridge, UK.
FAU - Weir, Malcolm
AU  - Weir M
AD  - Sosei Heptares, Cambridge, UK.
FAU - Marshall, Fiona H
AU  - Marshall FH
AD  - Sosei Heptares, Cambridge, UK.
AD  - MSD Research Laboratories (Merck & Co), Kenilworth, New Jersey, USA.
FAU - Stevens, Jasper
AU  - Stevens J
AUID- ORCID: 0000-0003-1601-9008
AD  - Centre for Human Drug Research, Leiden, The Netherlands.
AD  - University of Groningen, University Medical Center Groningen, Groningen, The 
      Netherlands.
FAU - Cross, David M
AU  - Cross DM
AD  - Cross Pharma Consulting Ltd, Cambridge, UK.
FAU - Tasker, Tim
AU  - Tasker T
AD  - Sosei Heptares, Cambridge, UK.
FAU - Nathan, Pradeep J
AU  - Nathan PJ
AD  - Sosei Heptares, Cambridge, UK.
AD  - Department of Psychiatry, University of Cambridge, Cambridge, UK.
AD  - School of Psychological Sciences, Monash University, Australia.
FAU - Groeneveld, Geert Jan
AU  - Groeneveld GJ
AD  - Centre for Human Drug Research, Leiden, The Netherlands.
AD  - Leiden University Medical Center, Leiden, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20210508
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Cholinergic Agents)
RN  - 0 (Receptors, Cholinergic)
SB  - IM
MH  - Aged
MH  - Area Under Curve
MH  - *Cholinergic Agents
MH  - Cross-Over Studies
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Humans
MH  - *Receptors, Cholinergic
PMC - PMC8596821
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - M1 receptor
OT  - cholinergic system
OT  - elderly
OT  - muscarinic receptors
OT  - pharmacokinetics
OT  - safety
COIS- This study was sponsored by Sosei Heptares. J.L., G.A.B., A.B., M.C., M.W., 
      F.H.M., T.T. and P.J.N. are employees of Sosei Heptares and hold shares in the 
      company.
EDAT- 2021/04/24 06:00
MHDA- 2021/12/15 06:00
PMCR- 2021/05/08
CRDT- 2021/04/23 12:37
PHST- 2021/03/10 00:00 [revised]
PHST- 2020/05/11 00:00 [received]
PHST- 2021/03/16 00:00 [accepted]
PHST- 2021/04/24 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/04/23 12:37 [entrez]
PHST- 2021/05/08 00:00 [pmc-release]
AID - BCP14872 [pii]
AID - 10.1111/bcp.14872 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2021 Nov;87(11):4439-4449. doi: 10.1111/bcp.14872. Epub 2021 
      May 8.