SAFETY AND TOLERABILITY OF METRIFONATE IN PATIENTS WITH ALZHEIMERS-DISEASE - RESULTS OF A MAXIMUM TOLERATED DOSE STUDY

Metrifonate, a pro-drug that is transformed non-enzymatically into a p otent inhibitor of acetylcholinesterase (AChE), has been used in the t ropics 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 ben ign, dose-dependent adverse event profiles consisting primarily of gas trointestinal events, optimal daily dosing with a loading phase (in th e absence of a loading dose phase, 6-8 weeks were required to attain s teady-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 hig h loading doses, followed by lower maintenance doses of metrifonate in the same patient population, and to determine the maximum tolerated d ose (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 Associa tion [NINCDS-ADRDA] criteria) were administered once-daily loading dos es of 2.5 mg/kg (125-225 mg) for 14 days, followed by 4.0 mg/kg (200-3 60 mg) for an additional 3 days. These patients were maintained on onc e-daily doses of 2.0 mg/kg (100-180 mg) for 14 days. AChE inhibition f or this cohort ranged from 88% to 94%. On Day 28 of 31, this cohort wa s discontinued due to moderate to severe side effects in 6 patients; c onsequently, the second cohort of 8 probable AD patients received a on ce-daily loading dose of 2.5 mg/kg (125-225 mg) for 14 days followed b y 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 achi eved 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 patient s.