Plontke Stefan K R, Salt Alec N
Tübingen Hearing Research Center and Department of Otorhinolaryngology, Head and Neck Surgery, University of Tübingen, D-72076 Tübingen, Germany.
Hear Res. 2003 Aug;182(1-2):34-42. doi: 10.1016/s0378-5955(03)00138-2.
The delivery of drugs to the inner ear by applying them directly onto the round window membrane is a promising way to treat human inner ear disorders. To further develop this strategy, and to design controlled clinical trials, additional preclinical studies are necessary. It is especially important to derive the time course and total dose for the various target regions within the inner ear. Since direct pharmacokinetic measurements in the human cochlea are not possible, simulations provide a valuable tool for the interpretation and planning of animal studies, for evaluating changes of application protocols and drug delivery systems, and for extrapolating the results from animal studies to the human. The present study has analyzed two previously published data sets in which concentration time courses of corticosteroids in the cochlear fluids were reported. Drug movements were simulated with a finite element computer model of the inner ear fluids. The time course of corticosteroid pharmacokinetics could be approximated for each study by consideration of the specific experimental paradigm. Although the experimental studies reported considerably different drug levels in the fluid samples taken from the cochlea, these differences were largely explained by considering the experimental design of the respective studies. After correction for experimental differences, the calculated perilymph levels of drug were within a factor of two of each other. The simulations demonstrated that an important factor controlling the drug level achieved is the time the drug solution remains in the middle ear. It can be concluded that small differences in delivery protocols may cause large variations in the drug levels achieved in the inner ear fluids.
将药物直接应用于圆窗膜从而递送至内耳是治疗人类内耳疾病的一种很有前景的方法。为了进一步发展这一策略并设计对照临床试验，还需要进行额外的临床前研究。确定内耳内各个靶区域的时间进程和总剂量尤为重要。由于无法在人类耳蜗中进行直接的药代动力学测量，模拟为解释和规划动物研究、评估给药方案和药物递送系统的变化以及将动物研究结果外推至人类提供了一个有价值的工具。本研究分析了两个先前发表的数据集，其中报告了耳蜗液中皮质类固醇的浓度-时间进程。利用内耳液的有限元计算机模型模拟了药物的移动。通过考虑特定的实验范式，可以对每项研究的皮质类固醇药代动力学时间进程进行近似。尽管实验研究报告的取自耳蜗的液体样本中的药物水平有很大差异，但通过考虑各自研究的实验设计，这些差异在很大程度上得到了解释。在对实验差异进行校正后，计算得出的外淋巴液药物水平彼此相差不超过两倍。模拟结果表明，控制所达到的药物水平的一个重要因素是药物溶液留在中耳的时间。可以得出结论，给药方案的微小差异可能会导致内耳液中所达到的药物水平有很大差异。
