title: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, LLC, Titusville, New Jersey 08560-0200, USA.
authors.forename: Qinying
authors.initials: Q
authors.lastname: Zhao
authors.forename: Ganesh R
authors.initials: GR
authors.lastname: Iyer
authors.forename: Tom
authors.initials: T
authors.lastname: Verhaeghe
authors.forename: Luc
authors.initials: L
authors.lastname: Truyen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000704:Analysis of Variance; D019540:Area Under Curve; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005702:Galantamine / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000502:physiology; D018709:Statistics, Nonparametric
chemical_list: D002800:Cholinesterase Inhibitors; D005702:Galantamine