PMID- 37036495
OWN - NLM
STAT- MEDLINE
DCOM- 20230417
LR  - 20230417
IS  - 1432-2072 (Electronic)
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 240
IP  - 5
DP  - 2023 May
TI  - Evidence of trospium's ability to mitigate cholinergic adverse events related to 
      xanomeline: phase 1 study results.
PG  - 1191-1198
LID - 10.1007/s00213-023-06362-2 [doi]
AB  - RATIONALE: The M(1)/M(4) preferring muscarinic receptor agonist xanomeline 
      demonstrated antipsychotic and procognitive effects in patients with Alzheimer's 
      disease or schizophrenia in prior studies, but further clinical development was 
      limited by cholinergic adverse events (AEs). KarXT combines xanomeline with the 
      peripherally restricted muscarinic receptor antagonist trospium with the goal of 
      improving tolerability and is in clinical development for schizophrenia and other 
      neuropsychiatric disorders. OBJECTIVE: Test the hypothesis that trospium can 
      mitigate cholinergic AEs associated with xanomeline. METHODS: Healthy volunteers 
      enrolled in this phase 1 (NCT02831231), single-site, 9-day, double-blind 
      comparison of xanomeline alone (n = 33) versus KarXT (n = 35). Rates of five 
      prespecified cholinergic AEs (nausea, vomiting, diarrhea, excessive sweating, 
      salivary hypersecretion) were compared between treatment arms. Vital signs, 
      electrocardiograms (ECGs), safety laboratory values, and pharmacokinetic (PK) 
      analyses were assessed. A self-administered visual analog scale (VAS) and 
      clinician-administered scales were employed. RESULTS: Compared with xanomeline 
      alone, KarXT reduced composite incidences of the five a priori selected 
      cholinergic AEs by 46% and each individual AE by >/= 29%. There were no episodes of 
      syncope in KarXT-treated subjects; two cases occurred in the xanomeline-alone 
      arm. The rate of postural dizziness was 11.4% in the KarXT arm versus 27.2% with 
      xanomeline alone. ECG, vital signs, and laboratory values were not meaningfully 
      different between treatment arms. The VAS and clinician-administered scales 
      tended to favor KarXT. PK analysis revealed that trospium did not affect 
      xanomeline's PK profile. CONCLUSIONS: Trospium was effective in mitigating 
      xanomeline-related cholinergic AEs. KarXT had an improved safety profile compared 
      with xanomeline alone.
CI  - (c) 2023. The Author(s).
FAU - Breier, Alan
AU  - Breier A
AD  - Department of Psychiatry, Indiana University School of Medicine, Indianapolis, 
      IN, USA.
AD  - Karuna Therapeutics, Boston, MA, USA.
FAU - Brannan, Stephen K
AU  - Brannan SK
AD  - Karuna Therapeutics, Boston, MA, USA.
FAU - Paul, Steven M
AU  - Paul SM
AD  - Karuna Therapeutics, Boston, MA, USA.
FAU - Miller, Andrew C
AU  - Miller AC
AUID- ORCID: 0000-0002-4330-320X
AD  - Karuna Therapeutics, Boston, MA, USA. amiller@karunatx.com.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20230410
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 9ORI6L73CJ (xanomeline)
RN  - 0 (Muscarinic Agonists)
RN  - 0 (Cholinergic Agents)
RN  - 0 (Pyridines)
RN  - 0 (Thiadiazoles)
RN  - 0 (Receptors, Muscarinic)
SB  - IM
MH  - Humans
MH  - *Muscarinic Agonists/therapeutic use
MH  - Cholinergic Agents
MH  - Pyridines
MH  - *Thiadiazoles
MH  - Receptors, Muscarinic
PMC - PMC10102054
OTO - NOTNLM
OT  - Healthy volunteers
OT  - KarXT
OT  - Muscarinic receptor agonist
OT  - Pharmacokinetics
OT  - Phase 1
OT  - Schizophrenia
OT  - Tolerability
OT  - Trospium
OT  - Xanomeline
COIS- The sponsor was involved in the design and conduct of the study; collection, 
      analysis, and interpretation of data; preparation, review, and approval of the 
      manuscript; and the decision to submit the manuscript for publication. Drs. 
      Brannan, Paul, and Miller are employees of and hold equity in Karuna 
      Therapeutics. Dr. Breier is a consultant to Karuna.
EDAT- 2023/04/11 06:00
MHDA- 2023/04/17 06:41
PMCR- 2023/04/10
CRDT- 2023/04/10 11:13
PHST- 2022/07/06 00:00 [received]
PHST- 2023/03/29 00:00 [accepted]
PHST- 2023/04/17 06:41 [medline]
PHST- 2023/04/11 06:00 [pubmed]
PHST- 2023/04/10 11:13 [entrez]
PHST- 2023/04/10 00:00 [pmc-release]
AID - 10.1007/s00213-023-06362-2 [pii]
AID - 6362 [pii]
AID - 10.1007/s00213-023-06362-2 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2023 May;240(5):1191-1198. doi: 
      10.1007/s00213-023-06362-2. Epub 2023 Apr 10.