Comparison of the Pharmacokinetics of E2020, A New Compound for Alzheimer's Disease, in Healthy Young and Elderly Subjects

Abstract

E2020, a central-acting cholinesterase inhibitor, is now under clinical development as a potential therapeutic agent for senile dementia of Alzheimer type. In the current study, the authors compared the pharmacokinetics of this drug after single oral administration in 12 healthy young volunteers (20-27 years of age) and 6 elderly volunteers (65-82 years of age). The subjects received a single 2-mg oral dose of E2020 after a meal. Blood samples for determination of the drug level were collected over 168 hours after drug administration and were measured by specific high-pressure liquid chromatography methods with ultraviolet detection. E2020 was generally well tolerated by all subjects of both groups. The plasma elimination half-life of the beta-phase (t 1/2 beta) and time to maximum peak plasma concentration (tmax) were significantly longer in the elderly than in the young: t 1/2 beta, 103.8 +/- 40.6 versus 59.7 +/- 16.1 hours; and tmax, 5.2 +/- 2.8 versus 3.4 +/- 1.5 hours, respectively. There were no statistically significant differences in maximum peak plasma concentration and area under the curve between the two groups. The mean (+/- standard deviation) oral clearance (Cl/F) in the elderly (9.1 +/- 2.4 L/h) was similar to that in the young (10.6 +/- 2.7 L/h). The volume of distribution in the steady state (Vdss/F) was significantly larger in the elderly than that in the young: 1217.2 +/- 223.2 versus 852.5 +/- 147.7 L, respectively. These results suggested that the drug was absorbed more slowly and distributed more widely and thoroughly, but that its clearance from the body is essentially unaffected by age.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioequivalence study of Donepezil hydrochloride in healthy Korean volunteers

“…Previous pharmacokinetic studies have shown that the elimination half-life of donepezil in elderly patients is almost twice as long as that in young healthy volunteers. [8,9] However, the exposure of the drug including C max , CL/F and AUC measured during therapeutic drug monitoring of elderly patients with Alzheimer's disease are comparable to those observed in young healthy volunteers. The difference of the half-life between the two age groups is probably due to a large distribution volume in the elderly.…”

Donepezil: A Review of Pharmacological Characteristics and Role in the Management of Alzheimer Disease

“…14,15 Age, however, does increase the t max , which is attributed to decreased gastrointestinal absorption. 16 There exists a linear relationship between donepezil dose and AUC in dose range of 1 to 10 mg/ day. 17 In the clinical trials, mean trough plasma concentration (C min ) was reported as 25.9 ± 0.7 and 50.6 ± 1.9 µg/L with doses of 5 and 10 mg, respectively.…”

Donepezil for Alzheimer's Disease: Pharmacodynamic, Pharmacokinetic, and Clinical Profiles

“…After oral administration of donepezil, the maximal plasma concentration of the drug is reached at 2.4 to 4.4 h (47,51,62,89). The absorption of donepezil is not affected by food and does not vary with the time of the day (47).…”

“…Plasma levels of donepezil reached steady state at 14 to 21 days during repeated administration of the drug, at 5 or 10 mg/day for 21 or 28 days (47,56,90). Donepezil is metabolized largely by the hepatic enzymes, CYP2D6 and CYP3A4, although after single or repeated administration of the drug a fraction of the dose (11 to 17%) is recovered in the urine unchanged (47,51,89). The following metabolites were recovered in significant amounts: 6-O-desmethyl donepezil, which has similar acyivity to that of the parent drug; donepezil-cis-N-oxide; 5-O-desmethyl donepezil; and the glucuronide conjugate of 5-O-desmethyl donepezil.…”

“…The following metabolites were recovered in significant amounts: 6-O-desmethyl donepezil, which has similar acyivity to that of the parent drug; donepezil-cis-N-oxide; 5-O-desmethyl donepezil; and the glucuronide conjugate of 5-O-desmethyl donepezil. While various unidentified metabolites were present, more of the dose was recovered in the urine (23 to 57%) (47,51,89) than in the feces (9 to 15%) (7,89). Donepezil and its metabolites are eliminated largely by the kidney (89).…”