RELATIONSHIP BETWEEN PHARMACOKINETICS AND PHARMACODYNAMICS OF EPTASTIGMINE IN YOUNG HEALTHY-VOLUNTEERS

Eptastigmine is a long-lasting acetyl-cholinesterase inhibitor, curren tly being developed for the symptomatic treatment of Alzheimer's disea se. In the present study, we investigated the relationship between pha rmacokinetics and pharmacodynamics of eptastigmine in young healthy vo lunteers. Eight male subjects received single oral doses of 10, 20, an d 30 mg of eptastigmine and placebo according to a double-blind, rando mized, crossover design. Blood was collected before and 0.5, 1, 1.5, 2 , 3, 4, 6, and 24 hours after drug administration. Cholinesterase acti vity was measured using a potentiometric method in both plasma (butyry l-cholinesterase) and in red blood cells (acetyl-cholinesterase). Epta stigmine plasma levels were measured by a very sensitive high-performa nce liquid chromatography method (limit of quantitation 0.2 ng/mL). Ep tastigmine plasma concentrations increased proportionally with the dos e (mean +/- SEM AUC(0-24) was 0.74 +/- 0.58, 3.61 +/- 1.15, and 6.25 /- 1.51 ng . h/mL with 10, 20, and 30 mg, respectively) and were undet ectable at 24 hours. The inhibition of acetyl-cholinesterase was dose- dependent (peak inhibition was 15 +/- 2%, 30 +/- 4%, and 36 +/- 6% wit h 10, 20, and 30 mg, respectively) and long-lasting, with a residual i nhibition of 8 to 11% at 24 hours. Acetyl-cholinesterase inhibition an d drug plasma levels were related over time with a counterclockwise hy steresis curve, suggesting the formation of active metabolites and/or a slow association to and dissociation from the enzyme in red blood ce lls. Butyryl-cholinesterase inhibition was weak and not dose-dependent (peak inhibition was 12 +/- 4%, 13 +/- 3%, and 12 +/- 2% with 10, 20, and 30 mg, respectively). The drug was well tolerated by all subjects . These results indicate that after oral administration, eptastigmine is absorbed linearly and produces a dose-dependent, long-lasting inhib ition of acetyl-cholinesterase.