Methods of otoprotection against platinum-based antineoplastic agents
Disclosed herein are methods for otoprotection against platinum-based antineoplastic agents by administering a thiosulfate salt to a subject in need thereof. Typically, the thiosulfate salt is administered to the subject scheduled to be administered a platinum-based antineoplastic agent within 4 hours. Alternatively, the thiosulfate salt is administered within 7 hours after the administration of a platinum-based neoplastic agent.
1 . A method of mitigating platinum-induced hearing loss in a human subject in need thereof, the method comprising (i) administering to the subject by intratympanically or transtympanically injecting an effective amount of a hypertonic composition having a calculated osmolarity of 3,000-7,000 mOsm/L and comprising 0.5M-1.0M of a thiosulfate salt, wherein the calculated osmolarity is calculated based on the thiosulfate salt and an optional tonicity agent, if present, and (ii) intravenously administering platinum-based antineoplastic agent to the subject 1 to 3 hours following step (i).
2 . The method of claim 1 , wherein the thiosulfate salt is an alkaline thiosulfate salt, ammonium thiosulfate salt, or a solvate thereof.
3 . The method of claim 1 , wherein the thiosulfate salt is sodium thiosulfate.
4 . The method of claim 1 , wherein the hypertonic composition comprises 1.0M of the thiosulfate salt.
5 . The method of claim 1 , wherein the hypertonic composition additionally comprises 1%-2% (w/v) of hyaluronan.
6 . The method of claim 5 , wherein the hypertonic composition comprises 1% (w/v) of hyaluronan.
7 . The method of claim 1 , wherein 200-1,000 μL of the hypertonic pharmaceutical composition are administered to a round window of the human subject.
8 . The method of claim 1 , wherein the effective amount is an amount that produces a plasma thiosulfate concentration that is 30 UM or less at the time the platinum-based antineoplastic agent is administered.
9 . The method of claim 1 , wherein the effective amount is an amount that produces a maximum thiosulfate concentration of 0.6-10 mmol/L by 1 hour post administration.
10 . The method of claim 1 , wherein the effective amount is an amount that produces a thiosulfate concentration of 0.1-2 mmol/L by 7 hours post administration in the subject's cochlea.
11 . The method of claim 1 , wherein the hypertonic composition produces a cochlear thiosulfate C max that is at least 30 times greater than a cochlear C max of the platinum-based antineoplastic agent, wherein the cochlear C max concentrations are modeled by a pharmacokinetic simulation of intravenous infusion in a two compartment model.
12 . The method of claim 1 , wherein the hypertonic composition is administered transtympanically.
13 . The method of claim 12 , wherein the transtympanic administration is by injection directly through a tympanic membrane.
14 . The method of claim 13 , wherein prior to injection a separate ventilation hole in the tympanic membrane is created to allow air to escape the middle ear space.
15 . The method of claim 1 , wherein the thiosulfate salt is sodium thiosulfate, wherein the hypertonic composition comprises 1.0M of the thiosulfate salt, and wherein the hypertonic composition additionally comprises 1% (w/v) of hyaluronan.
16 . A hypertonic pharmaceutical composition having a calculated osmolarity of 400-1,500 mOsm/L and comprising 0.1 to 0.5M of an anti-platinum chemoprotectant agent, a liquid solvent, 5% to 20% (w/v) of a gelling agent relative to the liquid solvent, and an optional tonicity agent, wherein the calculated osmolarity is calculated based on the chemoprotectant agent and the tonicity agent, if present.
17 . A method for determining a treatment window for intratympanic or transtympanic administration of a hypertonic composition comprising 0.5M-1.0M of a thiosulfate salt, the method comprising:
a) providing a subject administered a hypertonic pharmaceutical composition comprising a thiosulfate salt by transtympanic or intratympanic injection;
b) obtaining a perilymph sample from the subject;
c) quantifying the concentration of thiosulfate salt in the perilymph sample using liquid chromatography with tandem mass spectrometry (LC-MS/MS);
d) intravenously administering a platinum-based antineoplastic agent to the subject;
e) repeating steps b) and c) one or more times; and
f) calculating the half-life of thiosulfate in the perilymph.