Predicting cerebral acetylcholine dynamics with huperzine A pharmacokinetics in blood via mPBPK-PD modeling

Huperzine A (HupA) is a highly selective, reversible acetylcholinesterase (AChE) inhibitor that exhibits neuroprotective effects and is clinically used to manage benign memory decline. However, the specific relationship between the pharmacokinetic (PK) profile of HupA and cerebral acetylcholine (ACh) dynamics remains poorly characterized. Here, we characterize the PK-pharmacodynamic (PD) properties of HupA in rats under both physiological and pathological conditions. Following a single intramuscular injection, HupA exhibits a short half-life but rapid brain penetration, while multiple dosing significantly enhances its brain exposure. In a middle cerebral artery occlusion (MCAO) rat model, HupA demonstrates increased brain distribution. Furthermore, HupA elevates ACh concentrations across multiple brain regions, concurrently modulating several monoamine neurotransmitters. Using a minimal physiologically based pharmacokinetic-pharmacodynamic (mPBPK-PD) modeling approach, cerebral ACh dynamics were accurately predicted based on the pharmacokinetics of HupA in systemic circulation. The developed mPBPK-PD model exhibits robust predictive performance and holds potential for guiding the optimization of clinical dosing regimens and improving the therapeutic efficacy of HupA.