Disposition of a single dose of warfarin in healthy individuals after pretreatment with metrifonate

Objective: Metrifonate, through its active metabolite dichlorvos, is an ace tylcholinesterase inhibitor effective in the treatment of Alzheimer's disea se (AD). Patients with AD often require treatment with warfarin, which has a narrow therapeutic index. In view of the many reported interactions of wa rfarin, it was essential to ascertain whether the combined administration o f metrifonate and warfarin altered the anticoagulant actions of warfarin. T his study was therefore designed to determine the effects of pretreatment w ith multiple doses of metrifonate or placebo on the pharmacokinetic and pha rmacodynamic properties of a single dose of warfarin in healthy persons. Design: This was a double-blind, placebo-controlled, two-treatment, two-per iod, crossover study. The participants received metrifonate 50mg once daily or matching placebo for two periods of 8 days each, separated by a 21-day period. On the morning of the fourth day of each 8-day period, every partic ipant received 25mg of racemic warfarin (5 x 5mg oral tablets). Study Participants: Fourteen healthy Caucasians (12 men and two women), age d 18 to 45 years, were included. Target Parameters: The effects of pretreatment with metrifonate or placebo on the pharmacokinetic and pharmacodynamic characteristics of warfarin were evaluated, as assessed by plasma concentrations of (R)- and (S)-warfarin, prothrombin time and factor VII activity. The safety and tolerability of bo th treatments was recorded. Results: The 90% confidence intervals for the true mean ratios of warfarin plus metrifonate to warfarin alone were within the range of 0.80 to 1.25 fo r the primary test parameters, area under the curve (AUC) of prothrombin ti me versus time and maximum prothrombin time, as well as for the AUC of plas ma concentration versus time and the maximum plasma concentration for both warfarin enantiomers. The two treatments were equivalent with regard to the se parameters. The study drugs were generally well tolerated. Conclusion: Pretreatment with a therapeutic dose of metrifonate does not si gnificantly influence the pharmacokinetic or pharmacodynamic characteristic s of a single dose of warfarin in healthy volunteers. Based on the similari ty in pharmacokinetics of metrifonate in volunteers and patients with AD, t his study also predicts the absence of an effect of metrifonate on warfarin in the target population of the drug.