Galantamine population pharmacokinetics in patients with Alzheimer's disease: modeling and simulations

Galantamine is a reversible, competitive inhibitor of acetylcholinesterase and an allosteric modulator of nicotinic acetylcholine receptors. It is cleared by renal and hepatic mechanisms, including metabolism by the CYP 450 2D6 and 3A4 isoenzymes. The authors estimated the population pharmacokinetics of galantamine using nonlinear mixed-effects modeling as implemented in NONMEM software. Data from 15 clinical studies (1089 individuals, 7480 concentration measurements in total) were used to examine the effect of body size, demographic characteristics, and concomitant disease status on galantamine pharmacokinetic parameters. Galantamine clearance was shown to decrease with age and increase with body weight and creatinine clearance of individuals. Median clearance in male and female patients with Alzheimer's disease (AD) was 14.8 and 12.4 L/h, respectively. The dissimilarity was related to the body weight difference, not to the real gender effect. Metabolic clearance was reduced by 60% in patients with moderate or severe hepatic dysfunction (Pugh score 7 or higher). Simulations were performed to assess the impact of hepatic impairment and renal insufficiency on peak plasma concentration of galantamine. Simulations confirmed the need for slower dose titration in patients with hepatic impairment: 4 mg daily during 1 week followed by 4, 8, and 12 mg bid, with each dose level during 1 week compared to the standard titration scheme 4-8-12-16 mg bid. However, no significant differences between plasma levels in AD patients with and without severe renal insufficiency were found. CYP 450 2D6 genotype also influenced galantamine clearance but not to the extent that dose adjustment is required.