No synergistic effect of subtherapeutic doses of donepezil and EVP-6124 in healthy elderly subjects in a scopolamine challenge model

Introduction: Donepezil is a widely used cholinesterase inhibitor in the management of Alzheimer's disease. Despite large-scaled evidence for its efficacy, elevated peripheral ACh levels often lead to side effects and are dose limiting. The present exploratory study is designed to determine the potentiation of the effects of donepezil by cotreatment with EVP-6124, an alpha-7 nicotinic agonist, to reduce scopolamine-induced cognitive deficits in healthy elderly subjects. Secondary objectives are to explore safety and pharmacokinetic and pharmacodynamics effects of EVP-6124 alone and in combination with donepezil compared to placebo. Methods: A phase I randomized, single-center, placebo-controlled, double-blind, five-way, partial crossover study was performed with donepezil 2.5, 5 mg or placebo combined with EVP-6124 0.3, 1, 2, 4 mg or placebo in three cohorts of healthy elderly subjects in a scopolamine (0.3 mg i.v.) challenge test. Safety, pharmacokinetic, and pharmacodynamics outcomes were assessed. Results: A total of 36 subjects completed the study. Donepezil pharmacokinetic parameters were similar with and without EVP-6124. Effective dose combinations were donepezil/EVP-6124(5/2 mg) and donepezil/EVP-6124 (5/0.3 mg) and showed improvements of the delayed recall of the Visual Verbal Learning Test (1.2; CI = 0.1–2.3) and reaction time during the two-back condition of the N-back (−42; CI = −77, −8), respectively. Overall, no marked reversal of scopolamine effects was observed. Discussion: This study shows no synergistic effect of subtherapeutic doses of donepezil and EVP-6124 in a scopolamine challenge model in healthy elderly subjects. Dosing of scopolamine and the combination of donepezil and EVP-6124 requires further study

Pharmacokinetics and pharmacodynamics of oral mecamylamine - Development of a nicotinic acetylcholine receptor antagonist cognitive challenge test using modelling and simulation

A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects. A one-compartment linear kinetic model best described the plasma concentrations of mecamylamine. Mecamylamine's estimated clearance was 0.28 ± 0.015 L min-1. The peripheral volume of distribution (291 ± 5.15 L) was directly related to total body weight. Mecamylamine impaired the accuracy and increased the reaction time in tests evaluating short term working memory with a steep increase in the concentration-effect relationship at plasma concentrations below 100 μg L-1. On the other hand, mecamylamine induced a decrease in performance of tests evaluating visual and fine motor coordination at higher plasma concentrations (EC50 97 μg L-1). Systolic and diastolic blood pressure decreased exponentially after a plasma mecamylamine concentration of 80 μg L-1, a known effect previously poorly studied in healthy subjects. The developed mecamylamine PKPD model was used to quantify the effects of nicotinic blockade in a set of neurophysiological tests in humans with the goal to provide insight into the physiology and pharmacology of the nicotinic system in humans and the possibility to optimize future trials that use mecamylamine as a pharmacological challenge

Effects on Spasticity and Neuropathic Pain of an Oral Formulation of δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis

Purpose: The aim of the present study was to evaluate the efficacy of an oral formulation of δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS). Methods: This accelerated proof-of-concept study consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4-week, parallel, randomized, placebo-controlled treatment phase. Twenty-four patients with progressive MS and moderate spasticity were enrolled. During the treatment phase, biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment. Serum samples were collected to determine pharmacokinetic properties and perform population modeling. Safety and tolerability profiles were assessed based on adverse events and safety measurements. Findings: Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo.Implications. This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile

Acute response to cholinergic challenge predicts long-term response to galantamine treatment in patients with Alzheimer's disease

Aims: Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20–40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long-term treatment response. Methods: This study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double-blind, placebo-controlled cross-over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open-label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non-responder based on their minimental state examination (MMSE), neuropsychiatric inventory (NPI) and disability assessment in dementia (DAD) scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non-responders. Results: A single dose of galantamine significantly reduced saccadic reaction time (−0.0099; 95% CI = −0.0195, −0.0003; P =.0430), absolute frontal EEG parameters in alpha (−14.9; 95% CI = −21.0, −8.3; P =.0002), beta (−12.6; 95% CI = −19.4, −5.3; P =.0019) and theta (−17.9; 95% CI = −25.0, −10.0; P =.0001) frequencies. Relative frontal (−1.669; 95% CI = −2.999, −0.339; P =.0156) and occipital (−1.856; 95% CI = −3.339, −0.372; P =.0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95% CI = 0.158, 2.475; P =.0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (−20.4; 95% CI = −31.6, −7.47; P =.0046), beta (−15.7; 95% CI = −28.3, −0.93; P =.0390) and theta (−25.9; 95% CI = −38.4, −10.9; P =.0024) EEG parameters and of relative frontal theta power (−3.27%; 95% CI = −5.96, −0.58; P =.0187) on EEG significantly distinguished responders (n = 11) from non-responders (n = 32) after 6 months. Conclusions: This study demonstrates that acute PD effects after single dose of galantamine are correlated with long-term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment