Concentration of donepezil in the cerebrospinal fluid of AD patients: Evaluation of dosage sufficiency in standard treatment strategy

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

“…HTL0018318 was found to distribute into CSF with a CSF:plasma ratio of about 30% based on C max and AUC (16–82% in CSF as fraction of unbound plasma HTL0018318 concentration, from 2–9 h, respectively). The CSF to unbound plasma ratio for HTL0018318 is comparable or higher than the equivalent ratio for drugs approved for symptomatic treatment described in literature 44–47 . The concentration of donepezil in CSF achieved 11.25% 12 hours postadministration and 25.97% 24 hours postadministration, compared with plasma concentrations 44 while approximately 30–40% of rivastigmine plasma concentrations were detected in the CSF 45 .…”

“…The CSF to unbound plasma ratio for HTL0018318 is comparable or higher than the equivalent ratio for drugs approved for symptomatic treatment described in literature. [44][45][46][47] The concentration of donepezil in CSF achieved 11.25% 12 hours postadministration and 25.97% 24 hours postadministration, compared with plasma concentrations 44 while approximately 30-40% of rivastigmine plasma concentrations were detected in the CSF. 45 S2 and S3; however, these effects were fairly isolated and inconsistent with regard to the dose of HTL0018318, cognitive domains modulated, the EEG frequency band affected including the electrode position and the cohort type.…”

The New Acetylcholinesterase Inhibitors PC‐37 and PC‐48 (7‐Methoxytacrine‐Donepezil‐Like Compounds): Characterization of Their Metabolites in Human Liver Microsomes, Pharmacokinetics and In Vivo Formation of the Major Metabolites in Rats

“…Both compounds are able to target the CNS. Based on our results, the compounds may penetrate the blood-brain barrier via an active transport system such as in the case of donepezil [22]. The brain concentration exceeds the plasmatic concentration relatively quickly, PC-37 in the 15th minute and PC-48 in the 30th minute after i.m.…”

“…Donepezil is a structurally different AChE inhibitor that was approved by the FDA in 1996 [20]. Donepezil is a relatively low-toxicity commonly used anti-AD drug that has shown beneficial effects on cognitive function, daily living activities and some neuropsychiatric symptoms in AD patients [21,22]. Donepezil may also play some role in mitigation of oxidative stress and in the improvement of cerebral blood flow [23,24].…”