The effect of food and time of administration on the pharmacokinetic and pharmacodynamic profile of metrifonate

Objective: Metrifonate - via its pharmacologically active metabolite DDVP i s an inhibitor of cholinesterase effective in the treatment of Alzheimer's disease. Two separate studies were performed to investigate the influence o f food and time of administration, respectively, on the concentration vs. t ime profiles of metrifonate and DDVP and cholinesterase inhibition. Methods: In study I, a single dose of metrifonate 50 mg tablet was administ ered either in the fasting condition or within 5 min after completion of an American breakfast. In study II, a single dose of metrifonate 80 mg tablet was given either at 8:00 a.m. after overnight fasting, 7:00 p.m. (7 h afte r lunch) or 10:00 p.m. (4 h after dinner). Both studies were performed in a non-blind, randomized, single-centre, cross-over design in healthy Caucasi an volunteers. AUC and C-max of metrifonate and DDVP as primary parameters were compared between treatments by ANOVA and acetylcholinesterase (AChE) a nd butyrylcholinesterase (BChE) inhibition vs. time profiles were assessed. Results: In study I a high-fat/high-calorie breakfast had no effect on the AUC of DDVP, while its C-max was decreased to 56% and t(max) was prolonged, compared to the fasting condition. The effects on metrifonate were similar . In study II bioequivalence was shown for AUC and C-max of DDVP when compa ring administration of metrifonate at 8:00 a.m. and 7:00 p.m. Administratio n at 10:00 p.m. also had no effect on AUC of DDVP while a reduction in rate of absorption was observed. In both studies the equivalence in AUC of DDVP was paralleled by equivalent effects on BChE inhibition. Following single metrifonate administration little inhibition of AChE was observed. Metrifon ate was well tolerated. Conclusions: Delayed gastric emptying is likely to cause the reduced rate o f absorption of metrifonate with food. In view of unchanged bioavailability of its active metabolite, this food effect is considered to be without cli nical relevance and metrifonate can be administered with or without food. T he decrease in rate of absorption following administration of the drug at 1 0:00 p.m. is either a protracted food effect or an effect of time. As the b ioavailability of DDVP as well as pharmacodynamic profiles were independent of the time of administration it is concluded that metrifonate can be take n in the morning or evening without compromising its safety or efficacy.