First in human study with a prodrug of galantamine: Improved benefit‐risk ratio?

Abstract Introduction Gln‐1062 (Memogain) is a pharmacologically inactive prodrug of galantamine. Owing to its lipophilic nature, it preferentially enters the brain, where it is cleaved into active galantamine. Gln‐1062 is expected to have fewer peripheral side effects than other cholinesterase inhibitors, with improved effectiveness. Methods This was a double‐blind, comparator and placebo‐controlled, sequential cohort, single ascending dose study in 58 healthy subjects with Gln‐1062 in doses of 5.5, 11, 22, 33, and 44 mg, compared with oral galantamine 16 mg and donepezil 10 mg. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed. Results Gln‐1062 doses up to 33 mg were well tolerated and induced a dose‐dependent increase in the plasma concentrations of Gln‐1062 and galantamine. Gln‐1062 had a dose‐dependent positive effect on verbal memory and attention, mainly in the first hours after drug administration. Discussion Gln‐1062 was better tolerated than galantamine in doses with the same molarity and led to improved effects in cognitive tests. This is most likely caused by the more favorable distribution ratio between peripheral and central cholinesterase inhibition. These results give reason for further exploration of this compound.