Galantamine Pharmacokinetics, Safety, and Tolerability Profiles Are Similar in Healthy Caucasian and Japanese Subjects

Abstract

The aim of this study was to compare the pharmacokinetics of galantamine in healthy Japanese and Caucasian subjects and assess the safety and tolerability of galantamine in both ethnic groups. Parallel groups of healthy Japanese (n = 13; 6 males and 7 females)and Caucasian (n = 12; 6 males and 6 females) subjects matched for weight and age received single oral doses of galantamine 4 mg, or galantamine 8 mg, or placebo in a double-blind, three-way crossover trial according to a randomized dosing schedule. Concentrations of galantamine and norgalantamine were determined in plasma and urine samples taken up to 48 and 24 hours after dosing, respectively. Safety and tolerability were monitored throughout the trial by recording adverse events, laboratory tests, and cardiovascular parameters. The mean plasma concentration-time profiles of galantamine were very similar after single doses of galantamine (4 and 8 mg), and there was an approximate dose proportionality of galantamine pharmacokinetic parameters in both Caucasian and Japanese ethnic groups. The mean (+/- SD) pharmacokinetic parameters in the two ethnic groups did not show any clinically relevant differences. The ratios for the area under the plasma-concentration curve from time zero to infinity (AUC)0-infinity) in Japanese:Caucasian subjects with 4 and 8 mg doses were 103% (90% confidence interval [CII = 92-116) and 107% (90% CI = 94-121), respectively. Ratios for maximum plasma concentration (Cmax) values were 107% (90% CI= 90-127) and 108% (90% CI= 95-123), respectively. These ratios and associated 90% CIs were within the 80% to 125% range limit of bioequivalence. Analysis of variance (ANOVA) showed that these ratio values demonstrated no statistically significant difference between the two ethnic groups. There was no overt difference in the adverse event profile in Japanese subjects compared with Caucasian subjects. There were no serious adverse events, and no subjects discontinued from the study because of adverse events. No consistent or clinically relevant pattern of blood chemistry, hematology, or cardiovascular changes was seen. These results suggest that the pharmacokinetic profiles of galantamine after single-dose administration are not statistically significantly different between Caucasian and Japanese groups. Galantamine was well tolerated. The safety and tolerability of galantamine were very similar in the two ethnic groups.

Chapter 3 Chemical and Biological Aspects of Narcissus Alkaloids

“…Owing to the relative lack of alternative treatment, galanthamine (75) is a reasonable approximation of the ideal concept of symptomatic Alzheimer's disease therapy (523,535). Galanthamine is effective and well tolerated, resulting in short-term improvements in cognition, func tion, and daily life activities in patients with mild to moderate symptoms (530,541,542). Galanthamine is effective and well tolerated, resulting in short-term improvements in cognition, func tion, and daily life activities in patients with mild to moderate symptoms (530,541,542).…”

Pharmacogenetic Aspects of Therapy with Cholinesterase Inhibitors: The Role of CYP2D6 in Alzheimers Disease Pharmacogenetics

“…Of particular interest are the potential interactions of cholinesterase inhibitors with other drugs of current use in patients with AD, such as antidepressants, neuroleptics, antiarrhythmics, analgesics, and antiemetics which are metabolized by the cytochrome P450 CYP2D6 enzyme [108]( Table 2). Although most studies predict the safety of donepezil [121] and galantamine [119,122], as the two principal cholinesterase inhibitors metabolized by CYP2D6-related enzymes [120,123], no pharmacogenetic studies have been performed so far on an individual basis to personalize the treatment, and most studies reporting safety issues are the result of pooling together pharmacological and clinical information obtained with conventional procedures [104,[124][125][126]. In certain cases, genetic polymorphism in the expression of CYP2D6 is not expected to affect the pharmacodynamics of some cholinesterase inhibitors because major metabolic pathways are glucuronidation, O-demethylation, N-demethylation, N-oxidation, and epimerization.…”

Galantamine inhibits β-amyloid aggregation and cytotoxicity

“…Our data imply that sub-stochiometric concentrations of galantamine can influence Aβ aggregation, since 500 nM galantamine exerted a significant inhibitory effect on the aggregation of 50 µM Aβ . Physiological concentrations of galantamine have been reported to reach 115 nM in human plasma following a single, oral 8 mg dose [51] and in animal studies the galantamine brain to plasma ratios in rats, mice and rabbits are increased with values of up to 6.6:1 [43]. This suggests that the lower experimental levels of galantamine used in our aggregation studies are potentially achievable in patients, especially at the customary clinical 24 mg dosage, and so could have a significant effect on Aβ oligomer formation in vivo.…”