Methods of Administering 3,4-Diaminopyridine

Abstract

Provided herein are methods of determining NAT acetylation status of a subject with a 3,4-DAP-sensitive disease, methods of selecting a dose of 3,4-DAP or a pharmaceutically acceptable salt thereof adjusted to a subject's acetylation status, methods of administering 3,4-diaminopyridine or a pharmaceutically acceptable salt thereof to a patient in need thereof, and methods of treating 3,4-DAP sensitive diseases.

What is claimed is: 
     
         1 . A method of treating a human patient diagnosed with Lambert-Eaton myasthenic syndrome (LEMS) in need of treatment thereof comprising administering a dose of 3,4-diaminopyridine (3,4-DAP), or an equivalent amount of a pharmaceutically acceptable salt thereof, based on the patient's N-acetyl transferase 2 (NAT2) acetylation status. 
     
     
         2 . The method of  claim 1 , wherein the patient's NAT2 aceytlation status is determined from the patient's NAT2 genotype for a NAT2 allele *5, *6, *7, or *14 single nucleotide polymorphism (SNP), and wherein a patient who is a carrier of at least one normal function NAT2 allele is a fast acetylator and a patient who is a carrier of two reduced function NAT2 alleles is a slow acetylator. 
     
     
         3 . The method of  claim 2 , wherein the fast acetylator is a carrier of two normal function NAT2 alleles. 
     
     
         4 . The method of  claim 2 , wherein the normal function NAT2 allele is a wild-type allele. 
     
     
         5 . The method of  claim 2 , wherein the two reduced function NAT2 alleles each comprise a mutation at one or more of amino acid positions 191, 282, 341, 434, 481, 590, 813, 845, or 857. 
     
     
         6 . The method of  claim 5 , wherein the two reduced function NAT2 alleles each comprise one or more of a 282T, 341C, 191A, 481T, 590A, or 857A mutation. 
     
     
         7 . The method of  claim 6 , wherein the two reduced function NAT2 alleles each comprise a 282T and/or 341C mutation. 
     
     
         8 . The method of  claim 1 , wherein the patient's NAT2 aceytlation status is determined from the patient's metabolic phenotype for caffeine, and wherein a patient who is a slow or fast metabolizer of caffeine is a slow or fast NAT2 acetylator, respectively. 
     
     
         9 . The method of  claim 1 , wherein the patient's NAT2 aceytlation status is determined from the patient's metabolic phenotype for 3,4-DAP, and wherein a patient who is a slow or fast metabolizer of 3,4-DAP is a slow or fast NAT2 acetylator, respectively. 
     
     
         10 . The method of  claim 1 , wherein the patient is a NAT2 fast acetylator and the dose is a total daily dose of about 30 mg to about 240 mg of 3,4-DAP, or an equivalent amount of a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 10 , wherein the about 30 mg to about 240 mg of 3,4-DAP is provided via an equivalent amount of 3,4-DAP phosphate salt. 
     
     
         12 . The method of  claim 10 , wherein the total daily dose is about 30 mg to about 100 mg of 3,4-DAP, or an equivalent amount of a pharmaceutically acceptable salt thereof 
     
     
         13 . The method of  claim 12 , wherein the total daily dose is provided via up to 5 divided doses per day. 
     
     
         14 . The method of  claim 13 , wherein the total daily dose is provided via 3 to 4 divided doses per day or 2 to 3 divided doses per day. 
     
     
         15 . The method of  claim 13 , wherein the divided dose is about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of 3,4-DAP, or the equivalent amount of a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 12 , wherein the total daily dose is about 30 mg, about 50 mg, about 60 mg, about 80 mg, or about 100 mg of 3,4-DAP, or the equivalent amount of a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 1 , wherein the patient is a NAT2 slow acetylator and the dose is a total daily dose of about 7.5 mg to about 40 mg of 3,4-DAP, or an equivalent amount of a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 17 , wherein the about 7.5 mg to about 40 mg of 3,4-DAP is provided via an equivalent amount of 3,4-DAP phosphate salt. 
     
     
         19 . The method of  claim 17 , wherein the total daily dose is about 15 mg to about 30 mg of 3,4-DAP, or the equivalent amount of a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 19 , wherein the total daily dose is provided via 3 to 4 divided doses per day or 2 to 3 divided doses per day. 
     
     
         21 . The method of  claim 19 , wherein the total daily dose is about 15 mg or about 30 mg of 3,4-DAP, or the equivalent amount of a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 17 , wherein the total daily dose is about 7.5 mg to about 15 mg of 3,4-DAP, or the equivalent amount of a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 22 , wherein the total daily dose is provided via 2 to 3 divided doses per day. 
     
     
         24 . The method of  claim 22 , wherein the total daily dose is about 7.5 mg of 3,4-DAP, or the equivalent amount of a pharmaceutically acceptable salt thereof. 
     
     
         25 . A method of treating a human patient diagnosed with LEMS in need of treatment thereof comprising administering a total daily dose of 3,4-DAP, or an equivalent amount of a pharmaceutically acceptable salt thereof, based on the patient's genotype for a NAT2 allele *5,*6, *7, or *14 SNP,
 wherein the total daily dose is about 30 mg to about 240 mg of 3,4-DAP, or an equivalent amount of a pharmaceutically acceptable salt thereof, for a patient who is a carrier of at least one normal function NAT2 allele, or   wherein the total daily dose is about 7.5 mg to about 40 mg of 3,4-DAP, or an equivalent amount of a pharmaceutically acceptable salt thereof, for a patient who is a carrier of two reduced function NAT2 alleles.   
     
     
         26 . The method of  claim 25 , wherein the patient is a carrier of two normal function NAT2 alleles. 
     
     
         27 . The method of  claim 25 , wherein the normal function NAT2 allele is a wild-type allele. 
     
     
         28 . The method of  claim 25 , wherein the two reduced function NAT2 alleles each comprise a mutation at one or more of amino acid positions 191, 282, 341, 434, 481, 590, 813, 845, or 857. 
     
     
         29 . The method of  claim 28 , wherein the two reduced function NAT2 alleles each comprise one or more of a 282T, 341C, 191A, 481T, 590A, or 857A mutation. 
     
     
         30 . The method of  claim 29 , wherein the two reduced function NAT2 alleles each comprise a 282T and/or 341C mutation.