Methods of therapeutic monitoring of phenylacetic acid prodrugs

Abstract

The present disclosure provides methods for adjusting the dosage of PAA prodrugs (e.g., HPN-100, PBA) based on measurement of PAA and PAGN in plasma and calculating the PAA:PAGN ratio so as to determine whether PAA to PAGN conversion is saturated.

1 - 22 . (canceled) 
     
     
         23 . A method of treating a urea cycle disorder (UCD) in a subject in need thereof who is 2 months of age and older, the method comprising:
 a) administering a first dosage of glyceryl tri-[4-phenylbutyrate] to the subject, wherein the first dosage results in a ratio of plasma phenylacetic acid (PAA) to phenylacetylglutamine (PAGN) greater than 2 in the subject; and   b) administering a second dosage of glyceryl tri-[4-phenylbutyrate] to the subject, wherein the second dosage is less than the first dosage.   
     
     
         24 . The method of  claim 23 , further comprising measuring the PAA level and the PAGN level in the subject after administering the first dosage and reaching a steady state of glyceryl tri-[4-phenylbutyrate] in the subject. 
     
     
         25 . The method of  claim 23 , further comprising measuring the PAA level and the PAGN level in the subject about 48 hours to about one week after the first dosage is administered to the subject. 
     
     
         26 . A method of treating a urea cycle disorder (UCD) in a subject in need thereof who is 2 months of age and older, the method comprising:
 a) administering a first dosage of glyceryl tri-[4-phenylbutyrate] to the subject, wherein the first dosage results in a ratio of plasma phenylacetic acid (PAA) to phenylacetylglutamine (PAGN) greater than 2.5 in the subject; and   b) administering a second dosage of glyceryl tri-[4-phenylbutyrate] to the subject, wherein the second dosage is less than the first dosage.   
     
     
         27 . The method of  claim 26 , further comprising measuring the PAA level and the PAGN level in the subject after administering the first dosage and reaching a steady state of glyceryl tri-[4-phenylbutyrate] in the subject. 
     
     
         28 . The method of  claim 26 , further comprising measuring the PAA level and the PAGN level in the subject about 48 hours to about one week after the first dosage is administered to the subject. 
     
     
         29 . A method of treating a urea cycle disorder in a subject in need thereof who is 2 months of age and older, the method comprising:
 a) administering a first dosage of glyceryl tri-[4-phenylbutyrate] to the subject, wherein the first dosage results in a ratio of plasma phenylacetic acid (PAA) to phenylacetylglutamine (PAGN) less than 1 in the subject; and   b) administering a second dosage of glyceryl tri-[4-phenylbutyrate] to the subject, wherein the second dosage is greater than the first dosage.   
     
     
         30 . The method of  claim 29 , further comprising measuring the PAA level and the PAGN level in the subject after administering the first dosage and reaching a steady state of glyceryl tri-[4-phenylbutyrate] in the subject. 
     
     
         31 . The method of  claim 29 , further comprising measuring the PAA level and the PAGN level in the subject about 48 hours to about one week after the first dosage is administered to the subject.