Plontke Stefan K, Siedow Norbert, Wegener Raimund, Zenner Hans-Peter, Salt Alec N
Department of Otorhinolaryngology, Head and Neck Surgery, Tübingen Hearing Research Center (THRC), University of Tübingen, Tübingen, Germany.
Audiol Neurootol. 2007;12(1):37-48. doi: 10.1159/000097246. Epub 2006 Nov 17.
Cochlear fluid pharmacokinetics can be better represented by three-dimensional (3D) finite-element simulations of drug dispersal.
Local drug deliveries to the round window membrane are increasingly being used to treat inner ear disorders. Crucial to the development of safe therapies is knowledge of drug distribution in the inner ear with different delivery methods. Computer simulations allow application protocols and drug delivery systems to be evaluated, and may permit animal studies to be extrapolated to the larger cochlea of the human.
A finite-element 3D model of the cochlea was constructed based on geometric dimensions of the guinea pig cochlea. Drug propagation along and between compartments was described by passive diffusion. To demonstrate the potential value of the model, methylprednisolone distribution in the cochlea was calculated for two clinically relevant application protocols using pharmacokinetic parameters derived from a prior one-dimensional (1D) model. In addition, a simplified geometry was used to compare results from 3D with 1D simulations.
For the simplified geometry, calculated concentration profiles with distance were in excellent agreement between the 1D and the 3D models. Different drug delivery strategies produce very different concentration time courses, peak concentrations and basal-apical concentration gradients of drug. In addition, 3D computations demonstrate the existence of substantial gradients across the scalae in the basal turn.
The 3D model clearly shows the presence of drug gradients across the basal scalae of guinea pigs, demonstrating the necessity of a 3D approach to predict drug movements across and between scalae with larger cross-sectional areas, such as the human, with accuracy. This is the first model to incorporate the volume of the spiral ligament and to calculate diffusion through this structure. Further development of the 3D model will have to incorporate a more accurate geometry of the entire inner ear and incorporate more of the specific processes that contribute to drug removal from the inner ear fluids. Appropriate computer models may assist in both drug and drug delivery system design and can thus accelerate the development of a rationale-based local drug delivery to the inner ear and its successful establishment in clinical practice.
药物扩散的三维（3D）有限元模拟能够更好地体现耳蜗内的流体药代动力学。
经圆窗膜进行局部药物递送越来越多地用于治疗内耳疾病。了解不同给药方式下药物在内耳中的分布情况对于安全疗法的开发至关重要。计算机模拟能够评估应用方案和药物递送系统，还可能使动物研究结果外推至人类更大的耳蜗。
基于豚鼠耳蜗的几何尺寸构建了耳蜗的有限元三维模型。药物在各腔室之间及内部的扩散通过被动扩散来描述。为证明该模型的潜在价值，利用先前一维（1D）模型得出的药代动力学参数，针对两种临床相关的应用方案计算了耳蜗内甲基强的松龙的分布情况。此外，还采用了简化几何结构来比较三维模拟与一维模拟的结果。
对于简化几何结构，一维模型和三维模型计算得出的随距离变化的浓度曲线高度吻合。不同的药物递送策略会产生截然不同的药物浓度-时间过程、峰值浓度以及基底-顶端浓度梯度。此外，三维计算结果表明，在蜗底的各个阶之间存在显著的梯度。
三维模型清楚地显示了豚鼠蜗底各阶存在药物梯度，这表明有必要采用三维方法来准确预测药物在具有更大横截面积的阶之间及内部的移动情况，比如人类的耳蜗。这是首个纳入螺旋韧带体积并计算通过该结构扩散情况的模型。三维模型的进一步开发必须纳入更精确的整个内耳几何结构，并纳入更多有助于从内耳液中清除药物的具体过程。合适的计算机模型可能有助于药物及药物递送系统的设计，从而加速基于合理依据的内耳局部药物递送的开发及其在临床实践中的成功应用。
