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

Huperzine A (HupA) is a highly selective and reversible acetylcholinesterase (AChE) inhibitor that has shown neuroprotective effects and is clinically used for benign memory decline. The specific relationship between HupA pharmacokinetic profile and acetylcholine (ACh) dynamics in the brain has not been studied in depth. Here we depict the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of HupA in rat under physiological and pathological conditions. The results demonstrate that HupA has short half-life but rapid brain penetration after single intramuscular injection to rats, and multiple dosing remarkably enhances the brain exposure of HupA. In a middle cerebral artery occlusion (MCAO) rat model, HupA shows increased brain distribution. HupA increases the concentration of ACh in multiple brain areas, accompanied by simultaneous change of several monoamine neurotransmitters. Using minimal physiologically based pharmacokinetic-pharmacodynamic (mPBPK-PD) analysis, the cerebral ACh dynamics could be reliably predicted by HupA pharmacokinetics in blood. Our mPBPK-PD model has predictive ability to optimize clinical dosing regimen and efficacy of HupA.