Population Pharmacokinetics Of Levodopa And Clinical Evaluation Of Dopamine Agonists As An Adjunct To Levodopa And Benserazide In Parkinson's Disease

Objective:1. To evaluate the population pharmacokinetics(PPK) of Chinese out-patients with parkinson's disease and healthy volunteers taking Levodopa.2. To evaluate the efficacy, safety and tolerability of dopamine agonists (pramipexole or piribedil) in the treatment of patients with parkinson'disease(PD) as an adjunctive therapy to levodopa and benserazide.Methods:1. Steady state plasma concentration datas( n=124 ) , and dense plasma concentration datas ( n=153 ) , were respectively collected from 117 PD out-patients and 13 healthy volunteers, during their routine clinical care. The plasma concentrations of levodopa(LD) was determined by HPLC-ECD method.The influence of the fixed effects on clearance of LD was investigated using NONlinear mixed effects model( NONMEM ) .2. The 40 patients with PD were enrolled in a open-label, parapell-group trial. The patients received pramipexole or piribedil as an adjunct to levodopa and benserazide for 12-weeks, when levodopa started to become less effective or when patient's symptoms fluctuated. The efficacy of dopamine agoist were assessed by using the UPDRS score . The safety and tolerability was assessed on the basis of adverse events and blood pressure.Results:1. The final regression model of LD was:AGECL L h CLAGE. It is found that age significantly influences the clearance of levodopa.2. After the two groups received pramipexole and piribedil respectively, the UPDRS I-IV scores were significantly reduced. The averaged UPDRS-I and UPDRS-â…£score had decreased to 1.65 and 1.35 in pramipexole respectively , 0.95 and 1.0 in piribedil group, as compared with 12-weeks and base-line, which showed that prameipexole was superior to piribedil in these part. The total clinical effectiveness was 80% for prameipexole group and 75% for piribedil group, the difference between two groups was insignificant. No significant difference in terms of the frequencies of adverse event between pramipexole and piribedil group.Conclusion:1. According to the population pharmacokinetics model of Levodopa in Chinese out-patients with Parkinson's disease, was set up in this study, with patient's dose and age, we can evaluate the clearance of patients and establish individualized dosing regimens.2. Pramipexole or piribedil are effective and well-tolerated in the treatment of patients with parkinson'disease as an adjunct to levodopa and benserazide at least with short-term use.