Effects of a magnesium aluminium hydroxide containing antacid, cimetidine or ranitidine on the pharmacokinetics of metrifonate and its metabolite DDVP

Objective: Metrifonate - via its pharmacologically active metabolite 2,2-dichlorovinyl dimethylphosphate (DDVP) - is an inhibitor of acetylcholinesterase effective in the treatment of Alzheimer's disease. Two studies were performed to investigate the influence of potentially frequent co-medications on the pharmacokinetics of metrifonate and DDVP. Design: In study I, a single dose of metrifonate 50mg was administered either alone, in combination (within 5 minutes) with magnesium/aluminium hydroxide-containing antacid, or 90 minutes before the antacid. In study II, a single dose of metrifonate 50mg was given either alone or after pretreatment/in combination with cimetidine and ranitidine, respectively. Both studies were performed in a non-blind, randomised, single-centre, three-fold crossover design. Participants: Healthy Caucasian volunteers allocated as follows: study I - 18 participants (12 female/6 male), aged 55 to 75 years (mean age 62 years); study II - 16 participants (6 female/10 male), aged 45 to 58 years (mean age 50 years). Target Parameters: Area under the curve (AUC) and maximum concentration (C-max) of metrifonate and DDVP as primary parameters were compared between treatments by analysis of variance. Results: The ratios and 90% confidence intervals (metrifonate + co-medication/ metrifonate alone) of AUC and Cmax of both analytes fulfilled the criteria defined for showing lack of relevant interaction for all treatment comparisons in both studies. Metrifonate was well tolerated. Conclusion: In View of their widespread over-the-counter or prescription use, magnesium/aluminium hydroxide-containing antacids, cimetidine or ranitidine are likely co-medications that have led to clinically relevant interactions with a number of drugs. These drugs do not affect the pharmacokinetics of metrifonate and DDVP and may be combined with metrifonate without compromising its tolerability or efficacy. In light of the fact that cytochrome P450 enzymes are not involved in the metabolism of metrifonate, its propensity for pharmacokinetic drug-drug interactions is low.