Surgical procedure of intratympanic injection and inner ear pharmacokinetics simulation in domestic pigs

被引:5
|
作者
Moatti, Adele [1 ,2 ]
Connard, Shannon [2 ,3 ]
De Britto, Novietta [1 ,2 ]
Dunn, William A. [4 ]
Rastogi, Srishti [1 ]
Rai, Mani [1 ,2 ]
Schnabel, Lauren V. [2 ,3 ]
Ligler, Frances S. [5 ]
Hutson, Kendall A. [4 ]
Fitzpatrick, Douglas C. [4 ]
Salt, Alec [6 ]
Zdanski, Carlton J. [4 ]
Greenbaum, Alon [1 ,2 ]
机构
[1] North Carolina State Univ, Univ North Carolina Chapel Hill, Joint Dept Biomed Engn, Raleigh, NC 27599 USA
[2] North Carolina State Univ, Comparat Med Inst, Raleigh, NC 27599 USA
[3] North Carolina State Univ, Dept Clin Sci, Raleigh, NC USA
[4] Univ North Carolina Chapel Hill, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC USA
[5] Texas A&M Univ, Dept Biomed Engn, College Stn, TX USA
[6] Tuner Sci, Jacksonville, IL USA
基金
美国国家卫生研究院;
关键词
intratympanic; inner ear; fluid simulation; round window membrane; pigs; swine; pharmacokinetics; ROUND-WINDOW MEMBRANE; DEXAMETHASONE SODIUM-PHOSPHATE; BRAIN-STEM RESPONSE; INTRAVENOUS DELIVERY; DRUG-DELIVERY; COCHLEAR; PERMEABILITY; DIMENSIONS; LATENCY;
D O I
10.3389/fphar.2024.1348172
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Introduction: One major obstacle in validating drugs for the treatment or prevention of hearing loss is the limited data available on the distribution and concentration of drugs in the human inner ear. Although small animal models offer some insights into inner ear pharmacokinetics, their smaller organ size and different barrier (round window membrane) permeabilities compared to humans can complicate study interpretation. Therefore, developing a reliable large animal model for inner ear drug delivery is crucial. The inner and middle ear anatomy of domestic pigs closely resembles that of humans, making them promising candidates for studying inner ear pharmacokinetics. However, unlike humans, the anatomical orientation and tortuosity of the porcine external ear canal frustrates local drug delivery to the inner ear.Methods: In this study, we developed a surgical technique to access the tympanic membrane of pigs. To assess hearing pre- and post-surgery, auditory brainstem responses to click and pure tones were measured. Additionally, we performed 3D segmentation of the porcine inner ear images and used this data to simulate the diffusion of dexamethasone within the inner ear through fluid simulation software (FluidSim).Results: We have successfully delivered dexamethasone and dexamethasone sodium phosphate to the porcine inner ear via the intratympanic injection. The recorded auditory brainstem measurements revealed no adverse effects on hearing thresholds attributable to the surgery. We have also simulated the diffusion rates for dexamethasone and dexamethasone sodium phosphate into the porcine inner ear and confirmed the accuracy of the simulations using in-vivo data.Discussion: We have developed and characterized a method for conducting pharmacokinetic studies of the inner ear using pigs. This animal model closely mirrors the size of the human cochlea and the thickness of its barriers. The diffusion time and drug concentrations we reported align closely with the limited data available from human studies. Therefore, we have demonstrated the potential of using pigs as a large animal model for studying inner ear pharmacokinetics.
引用
收藏
页数:13
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