PHARMACOKINETICS OF E2020, A NEW COMPOUND FOR ALZHEIMERS-DISEASE, IN HEALTHY MALE-VOLUNTEERS

E2020 is a new cholinesterase inhibitor with a novel chemical structur e, which is under clinical investigation for use in Alzheimer's diseas e in Japan and the USA. Three separate studies were conducted to evalu ate the safety and to establish the pharmacokinetic profile of E2020 a fter oral administration to healthy male subjects. E2020 was administe red as: (1) single oral doses (0.3 mg, 1 mg, 2 mg, 5 mg, 8 mg and 10 m g) in a fasting condition, (2) a single oral dose (2 mg) after a meal and (3) repeated oral doses (2 mg once daily for 21 days). The concent rations of E2020 and its metabolites in plasma, serum, urine and feces were determined by HPLC methods with UV detection. E2020 was generall y well tolerated by all subjects. In the single-dose study, there was a linear relationship between dose and mean AUC. The mean plasma half- life was about 50 hours and was dose-independent. The total clearance and renal clearance of E2020 were also dose-independent and the mean v alues after 10 mg dosing were 9.7 l/hour and 0.86 l/hour, respectively . The cumulative total urinary and fecal excretion of the sum of uncha nged E2020 and its metabolites at 264 hours after the administration o f the single 10-mg-dose was 36.1% and 8.6% of the dose, respectively. The mean serum protein binding was 92.6%. No effect of food intake on the pharmacokinetics was observed. Evaluation of the mean trough level s and AUC0-24 of E2020 indicated that a steady-state was achieved afte r approximately 2 weeks of daily dosing.