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.

An LC-MS/MS method for the simultaneous determination of lycorine and galanthamine in rat plasma and its application to pharmacokinetic study of Lycoris radiata extract in rats

“…Currently, the most widely employed biological sample preparation methodologies included protein precipitation (PPT), liquid-liquid extraction (LLE), and solid phase extraction (SPE). Several analytical methods for determining galanthamine in biological fluids have been reported [13,14,20] . Nirogi et al extracted galanthamine from plasma samples using toluene as the extraction solvent in the LC-MS/MS method [13] , and Verhaeghe et al reported that adding 0.1 mol/L sodium hydroxide and a saturated potassium chloride solution can extract galanthamine from plasma samples using toluene in the LC-MS/MS method [14] .…”

Galanthamine from snowdrop—the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge

“…Thus, it is important to assess any effects of reduced hepatic function on the pharmacokinetic profile of the drug. The issue is highlighted in a clinical trial by Zhao et al (2002). For patients with moderate hepatic impairment, the pharmacokinetic parameters were very similar to those in healthy patients.…”

High-performance liquid chromatographic method with UV photodiode-array, fluorescence and mass spectrometric detection for simultaneous determination of galantamine and its phase I metabolites in biological samples

“…Cytochrome P450 (CYP) 2D6 and 3A4 are the major CYP isoenzymes involved in the hepatic metabolism of this drug. CYP2D6 is responsible for the formation of O-desmethyl-galantamine, and CYP3A4 is involved in the production of galantamine N-oxide [13,14].…”