Mohanty Utkala, Dixit Narendra M
Department of Chemical Engineering, Indian Institute of Science, Bangalore 560012, India.
J Theor Biol. 2008 Apr 7;251(3):541-51. doi: 10.1016/j.jtbi.2007.12.017. Epub 2007 Dec 28.
We present a model of the pharmacokinetics of enfuvirtide, a potent inhibitor of the fusion of human immunodeficiency virus type 1 (HIV-1) with target cells. We assume that subcutaneously administered enfuvirtide accumulates in the injection region, diffuses locally, and gets absorbed into blood, where it reversibly associates with lipidic cell membranes and is eventually eliminated. We develop mathematical descriptions of each of these processes and predict the time-evolution of the concentration of enfuvirtide in plasma, C(p). We find, interestingly, that diffusion of enfuvirtide in the subcutaneous region is decoupled from absorption, which enables deduction of analytical expressions for C(p) following single dose administration and ordinary differential equations following multiple dose administration and renders our model amenable to data analysis. Model predictions provide excellent fits to observed plasma concentration-time profiles of enfuvirtide following the intravenous and subcutaneous administration of a single dose and without any adjustable parameters capture quantitatively concentration-time profiles following the administration of multiple doses. Our model thus presents a robust description of the pharmacokinetics of enfuvirtide and may be applied in conjunction with models of viral dynamics to assess responses of HIV-1 patients to alternative enfuvirtide-based therapies. Further, our model reveals that key pharmacokinetic characteristics of enfuvirtide, viz., steady state values of peak and trough concentrations and area under the concentration-time curve, vary nearly linearly with dosage over a broad range of dosages and for different dosing regimens, which enables a priori estimation of enfuvirtide exposure levels for different treatment protocols and may serve to establish guidelines for therapy optimization.
我们提出了一种恩夫韦肽的药代动力学模型，恩夫韦肽是一种有效的人类免疫缺陷病毒1型（HIV-1）与靶细胞融合抑制剂。我们假设皮下注射的恩夫韦肽在注射部位蓄积，在局部扩散，并被吸收进入血液，在血液中它与脂质细胞膜可逆性结合，最终被消除。我们对这些过程分别进行了数学描述，并预测了血浆中恩夫韦肽浓度C(p)随时间的变化。有趣的是，我们发现恩夫韦肽在皮下区域的扩散与吸收是解耦的，这使得我们能够推导单剂量给药后C(p)的解析表达式以及多剂量给药后的常微分方程，并且使我们的模型适用于数据分析。模型预测与单次静脉注射和皮下注射后观察到的恩夫韦肽血浆浓度-时间曲线拟合良好，并且在没有任何可调参数的情况下定量捕捉了多剂量给药后的浓度-时间曲线。因此，我们的模型对恩夫韦肽的药代动力学进行了稳健的描述，可与病毒动力学模型结合应用，以评估HIV-1患者对基于恩夫韦肽的替代疗法的反应。此外，我们的模型表明，在广泛的剂量范围和不同的给药方案下，恩夫韦肽的关键药代动力学特征，即峰浓度和谷浓度的稳态值以及浓度-时间曲线下面积，随剂量几乎呈线性变化，这使得能够对不同治疗方案的恩夫韦肽暴露水平进行先验估计，并可能有助于建立治疗优化指南。
