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 pharmaceuticaliy 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.

1 . A method of determining whether a subject who has a 3,4-DAP-sensitive disease is a slow or fast acetylator of 3,4-DAP, comprising determining the subject's NAT polymorphism phenotype or genotype. 
     
     
         2 . The method of  claim 1 , wherein the 3,4-DAP-sensitive disease is LEMS, myasthenia gravis, or congenital myasthenia. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the subject's phenotype is determined by administering caffeine to the subject, taking a urine sample, and measuring the metabolites of caffeine in the urine 
     
     
         6 - 7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the subject is determined to be a slow or fast acetylator by taking a sample of the subject's genomic DNA and determining the subject's genotype. 
     
     
         9 - 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the subject is determined to be a slow or fast acetylator by administering 3,4-DAP, or a pharmaceutically acceptable salt thereof, to the subject and measuring the amount of 3,4-DAP and N-(4-aminopyridin-3-yl)acetamide wherein the fast acetylator has an AUC 0-inf  ratio of N-(4-aminopyridin-3-yl)acetamide/3,4-DAP of greater than about 30 and a slow acetylator has an AUC 0-inf  ratio of N-(4-aminopyridin-3-yl)acetamide/3,4-DAP of less than about 10. 
     
     
         14 . The method of  claim 1 , further comprising selecting a dose of 3,4-DAP or a pharmaceutically acceptable salt thereof in an amount that is adjusted to the subject's acetylator status. 
     
     
         15 - 21 . (canceled) 
     
     
         22 . The method of  claim 14 , further comprising administering the dose of 3,4-DAP or a pharmaceutically acceptable salt thereof. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the pharmaceutically acceptable salt is phosphate. 
     
     
         26 - 36 . (canceled) 
     
     
         37 . A method of treating a subject with a 3,4-DAP-sensitive disease comprising:
 determining whether the subject is a slow acetylator or fast acetylator;   selecting a dose of 3,4-DAP or a pharmaceutically acceptable salt thereof based on the subject's acetylator status; and   administering the dose of 3,4-DAP to the subject in need thereof.   
     
     
         38 . A method of treating a subject with a 3,4-DAP-sensitive disease comprising:
 selecting a dose of 3,4-DAP or a pharmaceutically acceptable salt thereof in an amount adjusted to the subject's acetylator status; and   administering the dose of 3,4-DAP to the subject in need thereof.   
     
     
         39 . A method of treating a subject with a 3,4-DAP-sensitive disease comprising administering a dose of 3,4-DAP or a pharmaceutically acceptable salt thereof to the subject in need thereof in an amount adjusted to the subject's acetylator status. 
     
     
         40 . The method of  claim 39 , wherein the disease is LEMS, myasthenia gravis, or congenital myasthenia. 
     
     
         41 - 50 . (canceled) 
     
     
         51 . The method of  claim 39 , wherein the subject has two N-acetyltransferase 2 (NAT2) slow alleles. 
     
     
         52 . The method of  claim 51 , wherein each NAT2 slow allele is a NAT2*5, *6, *7, or *14 allele. 
     
     
         53 . The method of  claim 51 , wherein each NAT2 slow allele comprises one or more of a 282T, 341C, 191A, 481T, 590A, or 857A mutation. 
     
     
         54 . The method of  claim 53 , wherein each NAT2 slow allele comprises a 282T mutation, a 341C mutation, or a 282T and a 341C mutation. 
     
     
         55 . The method of  claim 39 , wherein the subject has one or two NAT2 fast alleles. 
     
     
         56 . The method of  claim 55 , wherein the NAT2 fast allele is a wild-type allele. 
     
     
         57 . A method of treating a human patient diagnosed with a 3,4-DAP-sensitive disease in need of treatment thereof comprising:
 (a) administering 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 to a human patient with a 3,4-DAP sensitive disease who is a slow acetylator of caffeine and/or a slow acetylator of 3,4-DAP; or   (b) administering 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 to a human patient with a 3,4-DAP sensitive disease who is a fast acetylator of caffeine and/or a fast acetylator of 3,4-DAP.