Otorhinolaryngology Department, University of Navarra Clinic, Pamplona, Spain.
Otorhinolaryngology Department, University of Navarra Clinic, Pamplona, Spain.
Hear Res. 2021 May;404:108228. doi: 10.1016/j.heares.2021.108228. Epub 2021 Mar 19.
The method of drug delivery directly into the cochlea with an implantable pump connected to a CI electrode array ensures long-term delivery and effective dose control, and also provides the possibility to use different drugs. The objective is to develop a model of inner ear pharmacokinetics of an implanted cochlea, with the delivery of FITC-Dextran, in the non-human primate model.
A preclinical cochlear electrode array (CI Electrode Array HL14DD, manufactured by Cochlear Ltd.) attached to an implantable peristaltic pump filled with FITC-Dextran was implanted unilaterally in a total of 15 Macaca fascicularis (Mf). Three groups were created (5 Mf in each group), according to three different drug delivery times: 2 hours, 24 hours and 7 days. Perilymph (10 samples, 1μL each) was sampled from the apex of the cochlea and measured immediately after extraction with a spectrofluorometer. After scarifying the specimens, x-Rays and histological analysis were performed.
Surgery, sampling and histological analysis were performed successfully in all specimens. FITC-Dextran quantification showed different patterns, depending on the delivery group. In the 2 hours injection experiment, an increase in FITC-Dextran concentrations over the sample collection time was seen, reaching maximum concentration peaks (420-964µM) between samples 5 and 7, decreasing in successive samples, without returning to baseline. The 24-hours and 7-days injection experiments showed even behaviour throughout the 10 samples obtained, reaching a plateau with mean concentrations ranging from 2144 to 2564 µM and from 1409 to 2502µM, respectively. Statistically significant differences between the 2 hours and 24 hours groups (p = 0.001) and between the 2 hours and 7 days groups (p = 0.037) were observed, while between the 24 hours and 7 days groups no statistical differences were found.
This experimental study shows that a model of drug delivery and pharmacokinetics using an active pump connected to an electrode array is feasible in Mf. An infusion time ranging from 2 to 24 hours is required to reach a maximum concentration peak at the apex. It establishes then an even concentration profile from base to apex that is maintained throughout the infusion time in Mf. Flow mechanisms during injection and during sampling that may explain such findings may involve cochlear aqueduct flow as well as the possible existence of substance exchange from scala tympani to extracellular spaces, such as the modiolar space or the endolymphatic sinus, acting as a substance reservoir to maintain a relatively flat concentration profile from base to apex during sampling. Leveraging the learnings achieved by experimentation in rodent models, we can move to experiment in non-human primate with the aim of achieving a useful model that provides transferrable data to human pharmacokinetics. Thus, it may broaden clinical and therapeutic approaches to inner ear diseases.
将药物直接输送到植入式泵连接到 CI 电极阵列的耳蜗中的方法可确保长期输送和有效剂量控制，并且还提供了使用不同药物的可能性。目的是在非人类灵长类动物模型中开发一种植入耳蜗的内耳药代动力学模型，用于输送 FITC-Dextran。
总共将 15 只猕猴（Mf）中的每只单侧植入带有可植入蠕动泵的预临床耳蜗电极阵列（CI 电极阵列 HL14DD，由 Cochlear Ltd. 制造），该泵充满 FITC-Dextran。根据三种不同的药物输送时间创建了三组（每组 5 只 Mf）：2 小时、24 小时和 7 天。在提取后立即使用分光荧光计从耳蜗顶点采集 10 个（每个 1μL）的外淋巴液样本进行测量。在对标本进行划伤后，进行 X 射线和组织学分析。
所有标本均成功进行了手术、取样和组织学分析。FITC-Dextran 定量显示出不同的模式，具体取决于输送组。在 2 小时注射实验中，在样品采集时间内观察到 FITC-Dextran 浓度的增加，在第 5 和第 7 个样品之间达到最大浓度峰值（420-964µM），在随后的样品中逐渐降低，而未恢复到基线。在 24 小时和 7 天注射实验中，在获得的 10 个样本中均表现出均匀的行为，达到平均浓度范围为 2144 至 2564µM 和 1409 至 2502µM 的平台。在 2 小时和 24 小时组之间（p=0.001）以及在 2 小时和 7 天组之间（p=0.037）观察到统计学上的显著差异，而在 24 小时和 7 天组之间未发现统计学差异。
这项实验研究表明，使用连接到电极阵列的主动泵进行药物输送和药代动力学的模型在猕猴中是可行的。需要 2 到 24 小时的输注时间才能在顶点处达到最大浓度峰值。然后，在猕猴中建立了从基部到顶点的均匀浓度分布，并且在整个输注时间内都保持不变。在注射和采样过程中可能涉及耳蜗导水管流以及从鼓阶到细胞外空间（例如蜗轴空间或内淋巴窦）的物质交换的流动机制，作为物质储库，以维持从基部到顶点的相对平坦的浓度分布在采样过程中。利用在啮齿动物模型中进行实验所获得的经验教训，我们可以在非人类灵长类动物中进行实验，目的是建立一个有用的模型，为人类药代动力学提供可转移的数据。因此，它可以拓宽针对内耳疾病的临床和治疗方法。
