First‐in‐man study to investigate safety, pharmacokinetics and exploratory pharmacodynamics of HTL0018318, a novel M₁‐receptor partial agonist for the treatment of dementias

Abstract

HTL0018318 is a selective M 1 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. TheseThe authors confirm that the PI for this paper is Geert Jan Groeneveld and that he had direct clinical responsibility for patients.

Safety and Pharmacokinetics of HTL0018318, a Novel M1 Receptor Agonist, Given in Combination with Donepezil at Steady State: A Randomized Trial in Healthy Elderly Subjects

“…The pharmacokinetics of HTL0018318 were well-characterized in plasma and urine. The characteristics were comparable to the pharmacokinetic data observed in previous studies [12,14]. Median t max (1.74-2.5 h) and mean halflife following the fifth dose (10.5-13.7 h) did not appear to change with respect to HTL0018318 dose level and co-dosing with donepezil.…”

“…The side effect profile observed in this study was comparable to that observed in the single ascending dose (SAD) and multiple ascending dose (MAD) studies with HTL0018318 [12,14]. Only nausea and vomiting were reported more frequently than in the SAD and MAD study.…”

“…To mask the difference in taste between HTL0018318 and placebo, a peppermint strip (Listerine) was administered 1 minute before and after the administration of the oral solution. In humans, the time to maximum observed plasma concentration (t max ) of HTL0018318 was 1-2 h, and the half-life was approximately 16 h, which permits once-daily dosing [12,14]. Steady state was reached after two or three daily doses [12].…”

Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M1 receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study

“…We previously reported the safety and tolerability of HTL0018318 following ascending doses in healthy subjects [21]. In this study, we report the safety and tolerability of HTL0018318 following multiple ascending dosing over 10 days in healthy younger adult and elderly subjects.…”

“…Pre-clinical studies have shown HTL0018318 to reverse scopolamine-induced deficits in passive avoidance learning in rats consistent with procognitive effects reported with other M 1 agonists on tests of learning and memory. The single ascending dose (SAD) study with HTL0018318 has shown that single doses of HTL0018318 up to 35 mg were relatively welltolerated in healthy younger adult and elderly subjects [21]. HTL0018318 was absorbed rapidly, peak plasma concentration was typically reached 1-2 h post-dose and the average elimination half-life was 12-16 h. Approximately 30% of the plasma unbound concentration entered the cerebral spinal fluid.…”