Abstract
Background
The cholinergic system and M
1
receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M
1
receptor partial agonist HTL0018318 is ...under development for the symptomatic treatment of Dementia’s including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects.
Methods
This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15–35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (
n
= 36; 3 cohorts) and elderly (
n
= 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions.
Results
HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15–35 mg. Maximum plasma concentrations were achieved after 1–2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (
n
-back) and learning (Milner maze) with moderate to large effect sizes.
Conclusion
Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB.
Trial registration
Netherlands Trial Register identifier
NTR5781
. Registered on 22 March 2016.
Introduction
This study examined the safety and pharmacodynamic effects of selective muscarinic M1 receptor orthosteric agonist HTL0018318 in 60 patients with mild‐to‐moderate Alzheimer's disease ...(AD) on background donepezil 10 mg/day.
Methods
A randomized, double‐blind, placebo‐controlled 4‐week safety study of HTL0018318 with up‐titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition.
Results
Treatment‐emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7–21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post‐dose, HTL0018318‐related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up‐titration but not maintenance. Postive effects of HTL0018318 were found on specific attention and memory endpoints.
Discussion
HTL0018318 was well tolerated in mild‐to‐moderate AD patients and showed positive effects on attention and episodic memory on top of therapeutic doses of donepezil.
Cholinergic dysfunction is involved in a range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease (LBD), leading to widespread use of cholinergic ...therapies. However, such drugs have focused on increasing the availability of acetylcholine (ACh) generally, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders. We discuss how the selectivity of cholinergic system dysfunction suggests that targeted cholinergic therapeutics to the muscarinic receptor subtypes will be vital in treating several disorders associated with cognitive dysfunction and behavioural and psychological symptoms.
•The cholinergic system degenerates in many neuropsychiatric disorders.•Cholinergic drugs typically increase all cholinergic activity.•Targeting M1 and M4 receptors may more effectively treat the ...disorders discussed.
Cholinergic dysfunction is involved in a range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease (LBD), leading to widespread use of cholinergic therapies. However, such drugs have focused on increasing the availability of acetylcholine (ACh) generally, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders. We discuss how the selectivity of cholinergic system dysfunction suggests that targeted cholinergic therapeutics to the muscarinic receptor subtypes will be vital in treating several disorders associated with cognitive dysfunction and behavioural and psychological symptoms.
Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however ...have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.
The relationship between the selective serotonin reuptake inhibitor paroxetine and the sparteine oxidation polymorphism was investigated in a combined single‐dose (30 mg) and steady‐state (30 mg/day ...for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of sparteine. The median area under the plasma concentration‐time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol · hr/L), whereas at steady state the median AUCsst interphenotype difference was only twofold (4410 versus 2550 nmol · hr/L). Plasma half‐life and steady‐state plasma concentration were significantly longer and higher, respectively, in poor metabolizers than in extensive metabolizers (41 versus 16 hours and 151 versus 81 nmol/L). Paroxetine pharmacokinetics were linear in poor metabolizers and nonlinear only in extensive metabolizers. Sparteine metabolic ratio (MR = 12 hour urinary ratio of sparteine/de‐hydrosparteine), increased during treatment with paroxetine in subjects who were extensive metabolizers, and after 14 days treatment two extensive metabolizers were phenotyped as poor metabolizers and the remaining extensive metabolizers were changed into extremely slow extensive metabolizers with sparteine MRs of 5.7 to 16.5. The inhibition of sparteine metabolism was rapidly reversed after cessation of paroxetine administration. In the poor metabolizers there were no significant changes in MRs during the study. It is concluded that paroxetine and sparteine metabolism cosegregates, but the interphenotype difference in metabolism was less prominent at steady state than after a single dose, presumably because of saturation of the sparteine oxygenase (CYP2D6) in subjects who were extensive metabolizers. Paroxetine is a potent inhibitor of sparteine oxidation by CYP2D6 in vivo.
Clinical Pharmacology and Therapeutics (1992) 51, 278–287; doi:10.1038/clpt.1992.23
HTL0018318 is a selective M
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.
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.
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.
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.
Aims
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.
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