Department of Anesthesiology, Leiden University Medical Center, P5-Q, 2300 RC Leiden, The Netherlands.
Anesth Analg. 2010 Sep;111(3):626-32. doi: 10.1213/ANE.0b013e3181e5e8af. Epub 2010 Jun 14.
In pharmacokinetic-pharmacodynamic modeling studies, venous plasma samples are sometimes used to derive pharmacodynamic model parameters. In the current study the extent of arteriovenous concentration differences of morphine-6-glucuronide (M6G) was quantified. We used simulation studies to estimate possible biases in pharmacodynamic model parameters when linking venous versus arterial concentrations to effect.
Seventeen healthy volunteers received an IV 90-second infusion of 0.3 mg/kg morphine-6-glucuronide (M6G). Arterial and venous blood samples, from the radial artery and cubital vein, respectively, were obtained. An extended pharmacokinetic model was constructed linking arterial and venous compartments. The extent of bias in pharmacodynamic model parameter estimates was explored in simulation studies with NONMEM, simulating M6G effect using first-order effect-compartment-inhibitory sigmoid E(MAX) models. M6G effect was simulated at various values for the arterial blood-effect-site equilibration half-lifes (t(1/2)k(E0)), ranging from 5 to 240 minutes.
Arteriovenous concentration differences were apparent, with higher arterial plasma concentrations just after infusion, whereas at later times (>60 minutes) venous M6G concentrations exceeded arterial concentrations. The extended pharmacokinetic model adequately described the data and consisted of 3 arterial compartments, 1 central venous compartment, and 1 peripheral venous compartment. The simulation studies revealed large biases in model parameters derived from venous concentration data. The biases were dependent on the value of t(1/2)k(E0). Assuming that the true values of M6G t(1/2)k(E0) range from 120 to 240 minutes (depending on the end point measured), we would have underestimated t(1/2)k(E0) by 30%, whereas the potency parameter would have been overestimated by about 40%, when using venous plasma samples.
Because of large arteriovenous differences in M6G plasma, concentration biases in pharmacodynamic model parameters will occur when linking venous concentration to effect, using a traditional effect-compartment model.
在药代动力学-药效动力学建模研究中，有时会使用静脉血浆样本来推导药效动力学模型参数。本研究旨在定量研究吗啡-6-葡萄糖醛酸（M6G）的动静脉浓度差异程度。我们通过模拟研究来估计将静脉与动脉浓度与效应相关联时，对药效动力学模型参数可能产生的偏差。
17 名健康志愿者接受了 0.3mg/kg 吗啡-6-葡萄糖醛酸（M6G）的静脉 90 秒输注。分别从桡动脉和肘静脉采集动脉和静脉血样。建立了一个扩展的药代动力学模型，将动脉和静脉室联系起来。通过 NONMEM 进行模拟研究，探索药效动力学模型参数估计中的偏差程度，使用一阶效应室抑制 sigmoid E（MAX）模型模拟 M6G 效应。模拟了不同动脉血-效应部位平衡半衰期（t（1/2）k（E0））值下的 M6G 效应，范围从 5 分钟到 240 分钟。
动静脉浓度差异明显，输注后即刻动脉血浆浓度较高，而在稍后时间（>60 分钟）静脉 M6G 浓度超过动脉浓度。扩展的药代动力学模型很好地描述了数据，由 3 个动脉室、1 个中央静脉室和 1 个外周静脉室组成。模拟研究表明，从静脉浓度数据推导的模型参数存在较大偏差。偏差取决于 t（1/2）k（E0）的值。假设 M6G t（1/2）k（E0）的真实值范围为 120 至 240 分钟（取决于测量的终点），当使用静脉血浆样本时，我们将低估 t（1/2）k（E0）约 30%，而效力参数将高估约 40%。
由于 M6G 血浆中的动静脉差异较大，当使用传统的效应室模型将静脉浓度与效应相关联时，药效动力学模型参数会出现浓度偏差。
