Othman Ahmed A, Dutta Sandeep
Clinical Pharmacology and Pharmacometrics, AbbVie, North Chicago, IL, USA; Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Br J Clin Pharmacol. 2014 Jul;78(1):94-105. doi: 10.1111/bcp.12324.
Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa-carbidopa delivery through intrajejunal infusion. This study characterized the population pharmacokinetics of levodopa following a 16 h jejunal infusion of LCIG or frequent oral administration of levodopa-carbidopa tablets (LC-oral) in subjects with advanced Parkinson's disease (PD).
A non-linear mixed-effects model of levodopa pharmacokinetics was developed using serial plasma concentrations from an LCIG phase 1 study and a phase 3 double-blind, double-dummy study of the efficacy and safety of LCIG compared with LC-oral in advanced PD patients (n = 68 for model development; 45 on LCIG and 23 on LC-oral). The final model was internally evaluated using stochastic simulations and bootstrap and externally evaluated using sparse pharmacokinetic data from 311 subjects treated in a long term safety study of LCIG.
The final model was a two compartment model with a transit compartment for absorption, first order elimination, bioavailability for LCIG (97%; confidence interval = 95% to 98%) relative to LC-oral, different first order transit absorption rate constants (LCIG = 9.2 h(-1) vs. LC-oral = 2.4 h(-1) ; corresponding mean absorption time of 7 min for LCIG vs. 25 min for LC-oral) and different residual (intra-subject) variability for LCIG (15% proportional error, 0.3 μg ml(-1) additive error) vs. LC-oral (29% proportional error, 0.59 μg ml(-1) additive error). Estimated oral clearance and steady-state volume of distribution for levodopa were 24.8 l h(-1) and 131 l, respectively.
LCIG administration results in faster absorption, comparable levodopa bioavailability and significantly reduced intra-subject variability in levodopa concentrations relative to LC-oral administration.
左旋多巴-卡比多巴肠凝胶（LCIG）通过空肠内输注实现左旋多巴-卡比多巴的持续给药。本研究对晚期帕金森病（PD）患者进行16小时空肠输注LCIG或频繁口服左旋多巴-卡比多巴片（LC-口服）后左旋多巴的群体药代动力学特征进行了描述。
利用来自LCIG 1期研究的系列血浆浓度以及一项LCIG与LC-口服在晚期PD患者中疗效和安全性比较的3期双盲、双模拟研究（模型开发中n = 68；45例接受LCIG治疗，23例接受LC-口服治疗）建立左旋多巴药代动力学的非线性混合效应模型。最终模型通过随机模拟和自助法进行内部评估，并利用来自LCIG长期安全性研究中接受治疗的311名受试者的稀疏药代动力学数据进行外部评估。
最终模型为二室模型，有一个用于吸收的转运室、一级消除，相对于LC-口服，LCIG的生物利用度为97%（置信区间 = 95%至98%），不同的一级转运吸收速率常数（LCIG = 9.2 h⁻¹ 对比 LC-口服 = 2.4 h⁻¹ ；LCIG相应的平均吸收时间为7分钟，而LC-口服为25分钟）以及LCIG不同的残差（受试者内）变异性（15%比例误差，0.3 μg/ml加性误差）对比LC-口服（29%比例误差，0.59 μg/ml加性误差）。左旋多巴的估计口服清除率和稳态分布容积分别为24.8 l/h和131 l。
与LC-口服给药相比，LCIG给药导致吸收更快、左旋多巴生物利用度相当且左旋多巴浓度的受试者内变异性显著降低。
