Clinicians recognize levodopa has a short-duration response (measured in hr) and a long-duration response (measured in days) in Parkinson's disease. In addition there is a diurnal pattern of motor function with better function in the morning. Previous pharmacokinetic-pharmacodynamic modeling has quantified only the short-duration response. We have developed a pharmacokinetic-pharmacodynamic model for the short- and long-duration responses to exogenous levodopa and the effects of residual endogenous levodopa synthesis in patients with Parkinson's disease. Thirteen previously untreated (de novo) patients with Parkinson's disease and twelve patients who had received levodopa orally for 9.7+/-4.0 years (chronic) were investigated. A 2 hr IV infusion of levodopa with concomitant oral carbidopa was given on two occasions separated by 3 days with no levodopa in between. A two compartment pharmacokinetic model was used to fit plasma levodopa concentrations. A sigmoid Emax model was used to relate concentrations from endogenous and exogenous sources to tapping rate (a measure of motor response). A model incorporating three effect compartments (fast equilibration (half life, Teqf). slow equilibration (Teqs) and dopa synthesis (Teqd)), yielded the most descriptive model for levodopa pharmacokinetics and pharmacodynamics. Baseline tapping rate reflected endogenous levodopa synthesis and the long-duration response. Partial loss of the long-duration response during the 3 days without levodopa in the chronic group lowered baseline tapping (36+/-7%, mean+/-SEM) and increased maximum levodopa induced response above baseline (112+/-31%). The maximum levodopa induced response after the drug holiday is a result of lowered baseline tapping due to the loss of long-duration response and not due to a change in levodopa pharmacokinetics or pharmacodynamics.

中文翻译：

---

对帕金森氏病中外源左旋多巴和内源性左旋多巴产生的短期和长期响应进行建模。

临床医生认识到左旋多巴对帕金森氏病有短期反应（以小时为单位）和长期反应（以天为单位）。此外，早晨有运动功能的昼夜模式，功能更好。先前的药代动力学-药效学建模仅量化了短期反应。我们针对帕金森氏病患者对外源左旋多巴的短期和长期反应以及残余内源性左旋多巴合成的影响建立了药代动力学-药效学模型。研究了13名先前未接受治疗（从头开始）的帕金森氏病患者和12名口服左旋多巴达9.7 +/- 4。0年（慢性）的患者。两次将左旋多巴与口服卡比多巴同时静脉输注2小时，两次间隔3天，中间没有左旋多巴。使用两室药代动力学模型拟合血浆左旋多巴浓度。使用S形Emax模型，将内源性和外源性浓度与振实速率（运动反应的量度）相关联。包含三个效应区室的模型（快速平衡（半衰期，Teqf），缓慢平衡（Teqs）和多巴合成（Teqd））产生了左旋多巴药代动力学和药效学最具描述性的模型。基线攻牙率反映了内源性左旋多巴的合成和长期反应。慢性组在3天内无左旋多巴的长期反应部分丧失，降低了基线攻牙率（36 +/- 7％，平均值±SEM）和最大左旋多巴诱发的基线以上反应增加（112 +/- 31％）。药物休假后最大左旋多巴诱发的反应是基线敲击降低的结果，这是由于长期反应的丧失而不是左旋多巴药代动力学或药效学的变化所致。