Pharmacokinetics, pharmacodynamics, and safety of metrifonate in patients with Alzheimer's disease

L. Creed Pettigrew, Florian Bieber, John Lettieri, Daniel P. Wermeling, Frederick A. Schmitt, Alex J. Tikhtman, J. Wesson Ashford, Charles D. Smith, David R. Wekstein, William R. Markesbery, John Orazem, Bianca B. Ruzicka, Janice Mas, Barbara Gulanski

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


Metrifonate is converted nonenzymatically to 2,2, dimethyl dichlorovinyl phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21-day, randomized, double-blind, placebo-controlled trial of metrifonate in patients with Alzheimer's disease (n = 27) evaluated four doses, each administered orally once daily. All patients received a loading dose (LD) for 6 days followed by a maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5 mg/kg (75-135 mg), MD = 0.25 mg/kg (12.5-25 mg); panel 2, LD = 2.5 mg/kg (125-225 mg), MD = 0.40 mg/kg (20-35 mg); panel 3, LD = 4.0 mg/kg (200-335 mg), MD = 0.65 mg/kg (30-60 mg); and panel 4, LD = 4.0 mg/kg (200-335 mg), MD = 1.0 mg/kg (50-90 mg). All metrifonate doses were well tolerated. Most adverse events were mild to moderate in intensity, gastrointestinal in nature, and transient. Mean area under the concentration- time curve (AUC) and maximum concentration (C(max)) for both metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had similar, largely dose-independent mean values for time to C(max) (t(max)) and half-life (t( 1/4 )). There was little or no accumulation of either metrifonate or DDVP with long-term administration. After 21 days of treatment, mean percent erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and panels 1 through 4, respectively. Cognitive improvement was observed with the two highest metrifonate doses. These results reflect favorable safety and pharmacokinetic profiles for the use of metrifonate in the treatment of Alzheimer's disease.

Original languageEnglish
Pages (from-to)236-245
Number of pages10
JournalJournal of Clinical Pharmacology
Issue number3
StatePublished - Mar 1998

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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