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dc.contributor.authorBakker, Charlotte
dc.contributor.authorTasker, Tim
dc.contributor.authorLiptrot, Jan
dc.contributor.authorHart, Ellen P.
dc.contributor.authorKlaassen, Erica S.
dc.contributor.authorPrins, Samantha
dc.contributor.authorvan der Doef, Thalia F.
dc.contributor.authorBrown, Giles A.
dc.contributor.authorBrown, Alastair
dc.contributor.authorCongreve, Miles
dc.contributor.authorWeir, Malcolm
dc.contributor.authorMarshall, Fiona H.
dc.contributor.authorCross, David M.
dc.contributor.authorGroeneveld, Geert Jan
dc.contributor.authorNathan, Pradeep J.
dc.date.accessioned2021-06-29T07:33:56Z
dc.date.available2021-06-29T07:33:56Z
dc.date.issued2021-02-05
dc.date.submitted2020-09-16
dc.identifier.issn0306-5251
dc.identifier.issn1365-2125
dc.identifier.otherbcp14710
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/324549
dc.descriptionFunder: Sosei Heptares Therapeutics Ltd
dc.description.abstractAims: HTL0018318 is a selective M1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses. Methods: This randomized, double‐blind, placebo‐controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1–35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross‐over design in 14 healthy subjects. Results: Pharmacokinetics of HTL0018318 were well‐characterized showing dose proportional increases in exposure from 1–35 mg. Single doses of HTL0018318 were associated with mild dose‐related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2–16.3], 35‐mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9–18.9], 15‐mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance. Conclusion: HTL0018318 showed well‐characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias.
dc.languageen
dc.subjectORIGINAL ARTICLE
dc.subjectORIGINAL ARTICLES
dc.subjectAlzheimer's disease
dc.subjecthealthy subjects
dc.subjectmuscarinic
dc.subjectpharmacokinetics
dc.subjectsafety
dc.titleFirst‐in‐man study to investigate safety, pharmacokinetics and exploratory pharmacodynamics of HTL0018318, a novel M 1 ‐receptor partial agonist for the treatment of dementias
dc.typeArticle
dc.date.updated2021-06-29T07:33:55Z
prism.endingPage2955
prism.issueIdentifier7
prism.publicationNameBritish Journal of Clinical Pharmacology
prism.startingPage2945
prism.volume87
dc.identifier.doi10.17863/CAM.72002
dcterms.dateAccepted2020-12-16
rioxxterms.versionofrecord10.1111/bcp.14710
rioxxterms.versionAO
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.contributor.orcidBakker, Charlotte [0000-0001-9822-2354]


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