P4–368: The prolonged action of the acetylcholinesterase inhibitor ZT–1 after subcutaneous injections of sustained release implants in healthy volunteers

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ZT–1 –a huperzine A derivative– is a very potent and selective acetylcholinesterase inhibitor. It produces a marked increase in cerebral acetylcholine level making it a candidate for symptomatic Alzheimer's disease (AD) treatment. In addition, ZT–1 shows neuroprotective effects in in vitro and in vivo models. The problems linked to the oral route of administration in AD patients is the variability in drug exposure, the compliance and, therefore, a potentially less pronounced treatment effect. The aim of this study was to assess the plasma concentration–time profile of ZT–1 and its active metabolite huperzine A (Hup A), the tolerance and safety of a subcutaneous (s.c.) sustained release implant formulation of ZT–1 administered to young healthy volunteers. Implants of ZT–1 were administered s.c. to 4 cohorts of 3 males each. Cohorts 1 and 2 received a single dose of 3mg and 6mg, respectively; Cohorts 3 and 4 received two injections (separated by 28 days) of 6mg and 9mg, respectively. Tolerance and safety were assessed on standard parameters. Concentration–time profiles of ZT–1 and Hup A were followed up to 85 days after first implantation. A prolonged release of huperzine A up to four weeks was observed after single or repeated injections of ZT–1 implants. ZT–1 plasma levels were very low and often below the limit of quantification (LOQ=0.2 nM), while Hup A levels ranged from the LOQ (1 nM) up to 10 nM. No tolerance or safety concerns were observed. The only relevant observed adverse events were mild headache (n=4) and severe migraine (n=1). Results of this study indicate that, after administration of ZT–1 implants, sustained levels of Hup A can be achieved over several weeks and tolerance is excellent. This new route of administration may be useful to treat AD patients as compliance can be improved and thereby efficacy probably increased.