White Martin, Kenny Gavin N C, Schraag Stefan
Department of Anaesthesiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Clin Pharmacokinet. 2008;47(2):119-27. doi: 10.2165/00003088-200847020-00005.
Attempts to describe the variability of propofol pharmacokinetics in adults and to derive population covariates have been sparse and limited mainly to experiments based on bolus doses or infusions in healthy volunteers. This study aimed to identify age and gender covariates for propofol when given as an infusion in anaesthetized patients.
One hundred and thirteen patients (American Society of Anesthesiologists class I or II and aged 14-92 years) were anaesthetized for elective surgical procedures with propofol using a target controlled infusion (TCI) system and with alfentanil as a baseline analgesic infusion. Frequent venous blood samples were obtained for measurement of propofol plasma concentrations. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Pharmacokinetic accuracy was determined by the percentage prediction error, bias and precision, as were wobble and divergence. The clearance of propofol from the central compartment was determined for each patient using the computerized record of the infusion profile delivered to each patient, together with relevant blood propofol concentration estimations. For each patient, the nonlinear mixed-effects modelling (NONMEM) objective function was employed to determine the goodness of fit.
The population distribution of propofol clearance was subsequently found to have a Gaussian distribution only in the log domain (mean value equivalent to 26.1 mL/kg/min). The distribution in the normal domain was consequently asymmetric, with a slight predominance of patients with high values of clearance (5% and 95% confidence limits 17.7 and 42.1 mL/kg/min, respectively). Using regression analysis, gender and age covariates were derived that optimized the performance of the target controlled infusion system. The clearance (CL) of propofol in male patients changed little with age (CL [mL/kg/min]=26.88-0.029xAge; r2=0.006) whereas that in female patients had a higher initial value but decreased progressively with age (CL [mL/kg/min]=37.87-0.198xAge; r2=0.246).
We achieved a relatively simple and practical covariate model in which the variability of pharmacokinetics within the study population could be ascribed principally to variability in clearance from the central compartment. Pharmacokinetic simulation predicted an improved performance of the TCI system when employing the derived covariates model, especially in elderly female patients.
描述成年患者丙泊酚药代动力学变异性并推导群体协变量的研究较为稀少,且主要局限于在健康志愿者中基于单次推注剂量或输注进行的实验。本研究旨在确定在麻醉患者中输注丙泊酚时的年龄和性别协变量。
113例患者(美国麻醉医师协会分级为I或II级,年龄14 - 92岁)接受择期手术,使用靶控输注(TCI)系统以丙泊酚麻醉,并以阿芬太尼作为基线镇痛输注。频繁采集静脉血样以测定丙泊酚血浆浓度。
药代动力学准确性通过预测误差百分比、偏差和精密度以及摆动和离散度来确定。利用输送给每位患者的输注曲线的计算机记录以及相关的血液丙泊酚浓度估计值,为每位患者确定丙泊酚从中央室的清除率。对于每位患者,采用非线性混合效应建模(NONMEM)目标函数来确定拟合优度。
随后发现丙泊酚清除率的群体分布仅在对数域呈高斯分布(平均值相当于26.1 mL/kg/min)。因此,在正常域中的分布不对称,清除率高值的患者略占优势(5%和95%置信限分别为17.7和42.1 mL/kg/min)。通过回归分析,推导了优化靶控输注系统性能的性别和年龄协变量。男性患者丙泊酚的清除率随年龄变化不大(清除率[mL/kg/min]=26.88 - 0.029×年龄;r² = 0.006),而女性患者的清除率初始值较高,但随年龄逐渐降低(清除率[mL/kg/min]=37.87 - 0.198×年龄;r² = 0.246)。
我们建立了一个相对简单实用的协变量模型,研究人群中药代动力学的变异性主要可归因于中央室清除率的变异性。药代动力学模拟预测,采用推导的协变量模型时,TCI系统的性能会有所改善,尤其是在老年女性患者中。