Pharmacokinetic/Pharmacodynamic Models of an Alzheimer's Drug, Donepezil, in Rats

Abstract

To investigate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of donepezil (Don), simultaneous examination of the PK of Don and the change in acetylcholine (ACh) in the cerebral hippocampus was analyzed using microdialysis in rats. Don plasma concentrations reached their maximum at the end of a 30-minute infusion. The maximum plasma concentrations (C_maxs) of the major active metabolite, 6-O-desmethyl donepezil, were 9.38 and 13.3 ng/ml at 60 minutes after starting infusions at 1.25 and 2.5 mg/kg doses, respectively. The amount of ACh in the brain increased shortly after the start of the infusion and reached the maximum value at about 30 to 45 minutes, then decreased to the baseline with a slight delay from the transition of the Don concentration in plasma at a 2.5 mg/kg dose. However, the 1.25 mg/kg group showed little increase in ACh in the brain. The PK/PD models of Don, which were constructed using a general 2-compartment PK model with/without Michaelis-Menten metabolism and the suppressive effect of conversion of ACh to choline using an ordinary indirect response model, were able to effectively simulate Don's plasma and ACh profiles. The ACh profile in the cerebral hippocampus at a 1.25 mg/kg dose was effectively simulated using both constructed PK/PD models and parameters obtained at a 2.5 mg/kg dose by the PK/PD models and indicated that Don largely had no effect on ACh. When these models were used to simulate at 5 mg/kg, the Don PK were nearly linear, whereas the ACh transition had a different profile to lower doses. SIGNIFICANCE STATEMENT: Efficacy/safety of a drug and its pharmacokinetics (PK) are closely correlated. Therefore, it is important to understand the relationship between the drug's PK and its pharmacodynamics (PD). A quantitative procedure of achieving these goals is the PK/PD analysis. We constructed the PK/PD models of donepezil in rats. These models can predict the acetylcholine-time profiles from the PK. The modeling technique is a potential therapeutic application to predict the effect when changes in the PK are caused by pathological condition and co-administered drugs.