A multicenter, randomized, placebo controlled, multiple-dose, safety and pharmacokinetic study of AIT-082 (Neotrofin™) in mild Alzheimer's disease patients

• Published in: Life sciences (1973) Vol. 73; no. 5; pp. 539 - 553
• Main Authors: Grundman, M, Capparelli, E, Kim, H.T, Morris, J.C, Farlow, M, Rubin, E.H, Heidebrink, J, Hake, A, Ho, G, Schultz, A.N, Schafer, K, Houston, W, Thomas, R, Thal, L.J
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 20-06-2003
• Subjects: Administration, Oral; Aged; AIT-082; Alzheimer Disease - drug therapy; Alzheimer Disease - psychology; Alzheimer's disease; Area Under Curve; Clinical trial; Cognition - drug effects; Female; Humans; Male; Neotrofin; Neuropsychological Tests; Nootropic Agents - administration & dosage; Nootropic Agents - adverse effects; Nootropic Agents - blood; Pharmacokinetics; Severity of Illness Index; United States; United States; Clinical trial; Neotrofin; AIT-082; Pharmacokinetics; Alzheimer's disease
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(03)00320-5

A phase 1, randomized, double-blind, placebo-controlled, dose escalation study of the purine derivative, AIT-082 (Neotrofin™, NeoTherapeutics) was conducted in mild Alzheimer's disease (AD) patients to evaluate multiple-dose safety, tolerability, and pharmacokinetics. Possible short-term effects of AIT-082 on cognition and memory were preliminarily investigated. AIT-082 is currently being developed as a potential treatment for Alzheimer's disease and other neurological disorders. Pre-clinical studies indicate that AIT-082 has memory enhancing properties, stimulates neuritogenesis and the production of neurotrophic factors. Patients received an oral dose of AIT-082 or placebo daily for one week. Thirty-six AD patients were divided into three dose cohorts; each dose cohort consisted of twelve patients with 8 patients randomized to AIT-082 and 4 to placebo. The 3 doses of AIT-082 evaluated in this study were 100 mg/day, 500 mg/day, and 2,000 mg/day. There were no serious adverse events at any dose and the drug was well tolerated without significant side effects. AIT-082 was orally and rapidly absorbed, resulting in peak serum concentrations within 2 hours with an elimination half-life of approximately 20 hours. Higher doses resulted in corresponding increases in peak concentrations and areas under the curve (AUC). There was an approximate 2-fold accumulation in AIT-082 with daily dosing (as reflected by the AUC) at steady state. There were no significant differences by treatment arm on the clinical or neuropsychological evaluations. AIT-082 was rapidly absorbed by the oral route with a half-life suitable for dosing once or twice daily. No problems with tolerability or safety were found. AIT-082 appears suitable for testing in larger clinical trials for the treatment of AD and other neurologic disorders.