Pharmacokinetics of sodium thiosulfate in Guinea pig perilymph following middle ear application

Abstract

Hypothesis: To determine the pharmacokinetics of sodium thiosulfate in the inner ear perilymph following middle ear application in Guinea pigs. Background: Cisplatin chemotherapy is often associated with a dose-dependent high frequency sensorineural hearing loss. Sodium thiosulfate has been shown to reduce cisplatin-induced ototoxicity when given intravenously, but this may limit the tumoricidal effects of the chemotherapy. Recent animal studies looking at middle ear application of sodium thiosulfate have shown prevention of outer hair cell and hearing loss, but the perilymph pharmacokinetics have not yet been established. Methods: Twenty Guinea pig ears were split into two groups and administered sodium thiosulfate to the middle ear at either a concentration of 250 mg/mL or 50 mg/mL for 30 min. Perilymph samples were then obtained serially through the round window over 6 h. Sodium thiosulfate concentrations were obtained using high-pressure liquid chromatography. Results: The 250 mg/mL group had a maximum perilymph concentration of 7.27 mg/mL (±0.83) that decreased to 0.94 mg/mL (±0.03) over 6 h. The 50 mg/mL group had an initial concentration of 1.63 mg/mL (±0.17) and was undetectable after 1 h. The half-life of sodium thiosulfate within perilymph was 0.74 h. Conclusions: and Relevance: The results of this study show that sodium thiosulfate is capable of diffusing through round window and into the inner ear perilymph. Peak levels decline over several hours after exposure. This has a potential application as a localized therapy in the prevention of cisplatin induced ototoxicity. Keywords: Sodium thiosulfate, Pharmacokinetics, Perilymph, Cisplatin, Ototoxicity