Pharmacokinetics and Safety of Galantamine in Subjects with Hepatic Impairment and Healthy Volunteers

Abstract

The objective of this study was to compare the pharmacokinetics and safety of galantamine in subjects with hepatic impairment with those in healthy subjects. This was an open-label study in which a single oral 4-mg dose of galantamine was administered to volunteers with mild (Child-Pugh score of 5-6, n = 8), moderate (Child-Pugh score of 7-9, n = 8), or severe hepatic impairment (Child-Pugh score of 10-15, n = 1) and to healthy, matched control subjects (n = 8). Galantamine pharmacokinetics and safety (adverse events, laboratory test results, electrocardiograms, vital signs, and cardiac events) were assessed over 6 days after administration of galantamine. The pharmacokinetic parameters of galantamine were similar in subjects with mild hepatic impairment compared with healthy controls. Compared with the healthy control group, subjects with moderate hepatic impairment showed relative increases in the area under the plasma-concentration curve from zero to infinity (AUC0-infinity) (+33%) and terminal half-life (t1/2) (+30%) (p = 0.051 and p = 0.003, respectively), a 23% relative decrease in total plasma clearance (p = 0.061), and a small but significant relative increase in the fraction of free plasma galantamine (p = 0.009). Galantamine was well tolerated by all subjects. There were no serious adverse events (AEs) or premature withdrawals from the study because of AEs. Reported AEs were headache (three cases), nausea (one case), and paresthesia (one case). There were no clinically relevant changes in clinical laboratory findings, vital signs, and electrocardiograms. Low patient recruitment (n = 1) precluded statistical analysis of galantamine pharmacokinetics and safety in severe hepatic impairment. It was concluded that the pharmacokinetics of galantamine in subjects with mild hepatic impairment was similarto those in healthy subjects. In subjects with moderate hepatic impairment, galantamine clearance was decreased by approximately 23% compared with normal volunteers. Galantamine was also well tolerated and appeared to be safe in subjects with mild ormoderate hepatic impairment. Based on the study results, it appears that it would not be necessary to adjust doses of galantamine during administration to subjects with mild hepatic impairment. In subjects with moderately impaired hepatic function, dose titration should proceed cautiously. Unfortunately, difficulties with patient recruitment did not allow adequate assessment of the safety of galantamine in subjects with severe hepatic impairment in this study. Therefore, the use of galantamine in subjects with severe hepatic impairment is not recommended.

Beyond Cholinesterase Inhibition: Anti-Inflammatory Role and Pharmacological Profile of Current Drug Therapy for Alzheimer's Disease

“…When galantamine is administered together to other CYP3A4 and CYP2D6 inhibitors, dose reduction may be required. Evidence suggests caution in the use of galantamine in patients with moderate impairment of hepatic function, and galantamine is not recommended in severe hepatic dysfunction [78].…”

Alzheimers Disease and Neural Transplantation as Prospective Cell Therapy

“…These drugs bring also risks of side effects. For instance, tacrine is associated with high hepatotoxicity [96], donepezil is selective for AchE but has peripheral side effects, rivastigmine is unspecific for AchE or BuChE and causes nausea, vomiting, intestinal problems, abdominal pain and dyspepsia [98], and galantamine has similar side effects to rivastigmine [99].…”

Quantification of Galantamine in Human Plasma by Validated Liquid Chromatography-Tandem Mass Spectrometry using Glimepride as an Internal Standard: Application to Bioavailability Studies in 32 Healthy Korean Subjects

“…Cytochrome P450 (CYP) 2D6 and 3A4 are the major isozymes involved in the hepatic metabolism. CYP2D6 is responsible for the O-desmethylgalantamine, and CYP3A4 is involved in the production of galantamine N-oxide (3,15). Galantamine demonstrates biexponential elimination, with a mean plasma terminal elimination half-life of 5.26 h (16) to 5.68 h (17) in healthy subjects (18).…”

“…Sample preparation consisted of protein precipitation followed by liquid -liquid extraction, either one-step or using back-extraction and re-extraction (22,27). In other methods, an HPLC method with fluorescence detection was used to quantify the galantamine in plasma throughout the preclinical and the earlier clinical trials (14,15). Codeine was used as IS and samples were extracted by one-step liquid -liquid extraction of galantamine into toluene (14,23), or by a precipitation processes with trichloracetic acid followed by alkalization of the sample and by liquid -liquid extraction into chloroform (22).…”