A systematic evaluation of the preclinical pharmacokinetic/pharmacodynamic relationship of Alzheimer's disease gold standard drugs in the rat: An in vitro, ex vivo and in vivo comparison

There are only four drugs (donepezil, (Aricept), galantamine (Reminyl ®), rivastigmine (Exelon ®) and memantine (Namenda ®)) clinically-approved for the treatment of Alzheimer's disease (AD). Considering the widespread use of these drugs as pre-clinical 'AD gold standards', very few preclinical studies have systematically characterised the four drugs side-by-side and related their pharmacodynamic (PD) efficacy to pharmacokinetic (PK) activity. The present studies systematically evaluated the PK/PD relationship of each drug in order to recommend clinically-relevant, translational doses for future preclinical studies within the IMI PharmaCog consortium. Male Lister hooded rats were pre-treated with 3 active doses of each drug (n =27 per dose; donepezil 0.3–1–3; galantamine 0.63–2.5–5; rivastigmine 0.3–1–3 or memantine 1–10–30; all mg/kg; i.p.) were used throughout. Brain and plasma samples were taken at variable intervals up to 24 hr later. For donepezil, galantamine and rivastigmine, an optimized Ellman method (1961) was used to determine acetylcholinesterase (AChE) activity. For memantine, brain NMDA receptor occupancy was assessed using an ex vivo [3 H]MK-801 binding assay. Open-field locomotor activity (LMA) was measured automatically (EthoVisonXT 8) for 90 min after dosing (n =12 per dose) and samples taken at 95 min. Donepezil was the most potent drug in vitro followed by galantamine and rivastigmine (IC 50 plasma = 0.009 < 0.77 < 14.2 μM, brain = 0.01 < 1.5 < 7.6μM). Rivastigmine was the most potent drug ex vivo followed by donepezil and galantamine (IC 50 plasma = 0.001 < 0.11 < 3.92 μM; brain IC 50 = 0.003 < 0.0076μM). Differences in activity at butyrylcholinesterase (BuChE), time-dependency of action and reversibility were also seen in vitro and ex vivo. Memantine occupied brain NMDA receptors in a dose-dependant manner with an IC 50 = 6μM. Significant impairments in LMA were seen following 3mg/kg donepezil, 2.5 - 5mg/kg galantamine and 3mg/kg rivastigmine. Memantine increased LMA at 1 but decreased at 3mg/kg. Systematic characterisation of each AChE inhibitor revealed multiple differences in their preclinical in vitro and ex vivo mechanism of action. Donepezil, whilst not the most potent, was deemed the most robust AChE inhibitor with the biggest efficacy vs. side-effect margin at optimal doses of 1mg/kg. Memantine demonstrated considerable, clinically-relevant activity and exposure at 1mg/kg.