Single Dose Safety, Tolerance, and Pharmacokinetics of HP 029 in Healthy Young Men: A Potential Alzheimer Agent

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Abstract
1,2,3,4‐tetrahydro‐9‐aminoacridin‐1‐ol maleate (HP 029) is a new cholinergic compound that has been shown to enhance memory in animals and therefore may be potentially effective in humans for the treatment of Alzheimer's disease (AD). The initial safety, tolerance, and pharmacokinetics of HP 029 after single oral doses were assessed in a randomized, double‐blind, placebo controlled study in 70 healthy young men (eight dose groups). The test doses ranged from 5 to 200 mg. There were 9 subjects per dose group, 6 on HP 029 and 3 on placebo. The 5 and 100 mg dose groups had only 8 subjects. Plasma and urine samples were analyzed for nonconjugated HP 029 using an HPLC assay with a detection limit of 1 ng/ml. HP 029 was rapidly absorbed after oral dosing with mean peak plasma levels occurring between 0.75 and 1.2 hours. The mean peak levels ranged from 12.7 and 234.7 ng/ml after the 10 and 200 mg doses, respectively. There were dose related increases in peak plasma levels, AUCs, and the amounts of drug excreted in the urine. The mean plasma half‐life was about 2.0 hours and was not affected by dose. About 6 to 11% of the dose was eliminated in the urine. HP 029 was renally cleared at a high rate and independent of dose. There were no clinically important or drug‐related changes in any of the physical examinations, audiograms, or ophthalmologic examinations. There were only minor within‐subject fluctuations in vital signs, ECGs, and laboratory values, none of which were clinically meaingful or drug related after any of the doses of HP 029. After the 75 mg dose one subject reported mild dizziness, diarrhea and vomiting, and a moderate headache. These side effects were considered to be possibly/probably drug related and none required treatment. Two subjects in the 200 mg dose group experienced a moderate to severe headache that was not considered drug‐related. Based upon the results of this single dose safety study in young men, testing of the safety, tolerance and pharmacokinetics of multiple oral doses of HP 029 is indicated.