Methods for preventing toxicity of platinum drugs

Abstract

Methods for reducing platinum drug-induced toxicity in a cell expressing Organic Cation Transporter 2 (OCT2), methods for reducing platinum drug-induced toxicity in a subject, methods for treating cancer, methods for increasing efficacy of platinum drug treatment in a subject, and pharmaceutical compositions are described. The described methods and compositions include an OCT2 inhibitor where the OCT2 inhibitor is buflomedil or a salt thereof, dolutegravir or a salt thereof, contains an imidazole, or is miconazole or a salt thereof.

1 - 109 . (canceled) 
     
     
         110 . A method for reducing platinum drug-induced toxicity in a human subject in need thereof comprising:
 administering a platinum drug that is cisplatin to the subject in need thereof; and   administering an effective dose of a selective Organic Cation Transporter 2 (OCT2) inhibitor to the subject in need thereof,   wherein the OCT2 inhibitor is selected from the group consisting of buflomedil, a buflomedil salt, dolutegravir, and a dolutegravir salt.   wherein the toxicity is nephrotoxicity or ototoxicity.   
     
     
         111 . The method of  claim 110 , wherein the method is for increasing patient compliance for treating cancer in the subject, whereby said subject completes treatment with a cumulative dose of the platinum drug of at least 100 mg/m 2 . 
     
     
         112 . The method of  claim 110 , wherein the selective OCT2 inhibitor results in its plasma level during the period of platinum administration at least 0.43 mg/L, 0.86 mg/L, 1.29 mg/L, 1.72 mg/L or 2.15 mg/L. 
     
     
         113 . The method of  claim 110 , wherein the selective OCT2 inhibitor does not reduce the efficacy of cisplatin. 
     
     
         114 . The method of  claim 110 , wherein the subject in need has cancer, and wherein the cancer expresses at least one of Organic Cation Transporter 1 (OCT1) or Organic Cation Transporter 3 (OCT3). 
     
     
         115 . The method of  claim 114 , wherein the cancer is selected from the group consisting of colorectal cancer, liver cancer, gastric carcinoma, pancreatic adenocarcinoma, esophageal or esophagogastric junction carcinoma, lung cancer, head and neck cancer, and lymphoma. 
     
     
         116 . The method of  claim 110 , wherein the selective OCT2 inhibitor is administered enterally, intravenously, intramuscularly, intraperitoneally, orally, or parenterally. 
     
     
         117 . The method of  claim 110 , wherein the selective OCT2 inhibitor is buflomedil or a buflomedil salt. 
     
     
         118 . The method of  claim 110 , wherein the selective OCT2 inhibitor is dolutegravir and a dolutegravir salt. 
     
     
         119 . The method of  claim 110 , wherein the subject in need thereof has liver cancer. 
     
     
         120 . The method of  claim 110 , wherein the subject in need thereof has gastric carcinoma. 
     
     
         121 . The method of  claim 110 , wherein the subject in need thereof has pancreatic adenocarcinoma. 
     
     
         122 . The method of  claim 110 , wherein the subject in need thereof has esophagogastric junction carcinoma. 
     
     
         123 . The method of  claim 110 , wherein the subject in need thereof has lung cancer. 
     
     
         124 . The method of  claim 110 , wherein the subject in need thereof has head and neck cancer. 
     
     
         125 . The method of  claim 110 , wherein the subject in need thereof has lymphoma. 
     
     
         126 . A method for reducing platinum drug-induced nephrotoxicity in a human subject in need thereof comprising:
 administering a platinum drug that is cisplatin to the subject in need thereof; and   administering an effective dose of a selective Organic Cation Transporter 2 (OCT2) inhibitor selected from the group consisting of buflomedil, a buflomedil salt, dolutegravir, and a dolutegravir salt to the subject in need thereof,   wherein the subject in need thereof has cancer, and   wherein the cancer expresses at least one of Organic Cation Transporter 1 (OCT1) and Organic Cation Transporter 3 (OCT3)   
     
     
         127 . A method for reducing platinum drug-induced ototoxicity in a human subject in need thereof comprising:
 administering a platinum drug that is cisplatin to the subject in need thereof; and   administering an effective dose of a selective Organic Cation Transporter 2 (OCT2) inhibitor selected from the group consisting of buflomedil, a buflomedil salt, dolutegravir, and a dolutegravir salt to the subject in need thereof,   wherein the subject in need thereof has cancer, and   wherein the cancer expresses at least one of Organic Cation Transporter 1 (OCT1) and Organic Cation Transporter 3 (OCT3).   
     
     
         128 . A pharmaceutical composition for reducing platinum drug-induced nephrotoxicity or ototoxicity, formulated for intravenous administration comprising
 a platinum drug that is cisplatin,   a selective OCT2 inhibitor selected from the group consisting of buflomedil, a buflomedil salt, dolutegravir, and a dolutegravir salt, and   a pharmaceutically acceptable carrier.   
     
     
         129 . A kit comprising a selective OCT2 inhibitor that is buflomedil or a buflomedil salt, or dolutegravir or a dolutegravir salt; for use in reducing cisplatin-induced toxicity wherein the toxicity is nephrotoxicity or ototoxicity in a subject having cancer in a subject; and instructions for use.