Safety and tolerability of metrifonate in patients with alzheimer's disease: Results of a maximum tolerated dose study

Metrifonate, a pro-drug that is transformed non-enzymatically into a potent inhibitor of acetylcholinesterase (AChE), has been used in the tropics for over 30 years for the treatment of schistosomiasis. A pilot study, and Phase I and Phase II studies of metrifonate in Alzheimer's disease (AD) p...

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Published in:Life sciences (1973) 1998-03, Vol.62 (16), p.1433-1441
Main Authors: Cutler, Neal R, Jhee, Stanford S, Cyrus, Pamela, Bieber, Florian, TanPiengco, Paul, Sramek, John J, Gulanski, Barbara
Format: Article
Language:English
Subjects:
acetylcholinesterase inhibitor
Aged
Aged, 80 and over
Alzheimer ' s disease
Alzheimer Disease - drug therapy
bridging studies
Cholinesterase Inhibitors - adverse effects
Cholinesterase Inhibitors - pharmacokinetics
Cohort Studies
Dose-Response Relationship, Drug
Female
Follow-Up Studies
Humans
Male
maximum tolerated dose
metrifonate
Middle Aged
Prodrugs - adverse effects
Prodrugs - pharmacokinetics
Prodrugs - therapeutic use
Trichlorfon - adverse effects
Trichlorfon - pharmacokinetics
Trichlorfon - urine
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Summary:Metrifonate, a pro-drug that is transformed non-enzymatically into a potent inhibitor of acetylcholinesterase (AChE), has been used in the tropics for over 30 years for the treatment of schistosomiasis. A pilot study, and Phase I and Phase II studies of metrifonate in Alzheimer's disease (AD) patients conducted prior to the current study showed benign, dose-dependent adverse event profiles consisting primarily of gastrointestinal events, optimal daily dosing with a loading phase (in the absence of a loading dose phase, 6–8 weeks were required to attain steady-state AChE inhibition levels), and an improvement in Alzheimer's Disease Assessment Scale (ADAS) scores. The current open-label study was designed to evaluate the safety and tolerability of relatively high loading doses, followed by lower maintenance doses of metrifonate in the same patient population, and to determine the maximum tolerated dose (MTD) of metrifonate. Accordingly, the first cohort of 8 probable AD patients (per National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria) were administered once-daily loading doses of 2.5 mg/kg (125–225 mg) for 14 days, followed by 4.0 mg/kg (200–360 mg) for an additional 3 days. These patients were maintained on once-daily doses of 2.0 mg/kg (100–180 mg) for 14 days. AChE inhibition for this cohort ranged from 88% to 94%. On Day 28 of 31, this cohort was discontinued due to moderate to severe side effects in 6 patients; consequently, the second cohort of 8 probable AD patients received a once-daily loading dose of 2.5 mg/kg (125–225 mg) for 14 days followed by a once-daily maintenance dose of 1.5 mg/kg (75–135 mg) for 35 days. This maintenance dose yielded an AChE inhibition level ranging from 89% to 91%. In spite of an AChE inhibition level comparable to that achieved with the higher dose, the reduced dose was associated with a more favorable adverse event profile which was mainly gastrointestinal and musculoskeletal in nature. The maximum tolerated dose was established at 1.5 mg/kg/day (75–135 mg/day) for maintenance dosing in AD patients.
ISSN:0024-3205
1879-0631
DOI:10.1016/S0024-3205(98)00082-4