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 - 13 . (canceled) 
     
     
         14 . A method of treating a urea cycle disorder in a subject in need thereof, comprising:
 administering to the subject glyceryl tri-[4-phenylbutyrate] (HPN-100) at a first dosage;   determining the subject's plasma PAA to PAGN ratio;   adjusting the dosage of the glyceryl tri-[4-phenylbutyrate] (HPN-100) based on the subject's plasma PAA to PAGN ratio; and   administering to the subject glyceryl tri-[4-phenylbutyrate] (HPN-100) at the adjusted dosage.   
     
     
         15 . The method of  claim 14 , wherein if the plasma PAA to PAGN ratio is less than 1, the adjusted dosage is greater than the first dosage. 
     
     
         16 . The method of  claim 14 , wherein if the plasma PAA to PAGN ratio is greater than 2.5, the adjusted dosage is less than the first dosage. 
     
     
         17 . The method of  claim 14 , wherein the glyceryl tri-[4-phenylbutyrate] is administered orally. 
     
     
         18 . A method for treating a urea cycle disorder in a subject in need thereof while minimizing the risk of the subject suffering an adverse event related to PAA accumulation, comprising:
 administering to the subject glycerol triphenylbutyrate;   determining the ratio of plasma PAA:PAGN following said administration; and   comparing said ratio to a predetermined target level,   wherein, when said ratio exceeds said target level, said subject is determined to have an enhanced risk of suffering an adverse event related to PAA accumulation and the method further comprises: administering to the subject a decreased amount of glycerol triphenylbutyrate.   
     
     
         19 . The method of  claim 18 , wherein the predetermined target level is 2.5. 
     
     
         20 . The method of  claim 18 , wherein the glyceryl tri-[4-phenylbutyrate] is administered orally. 
     
     
         21 . The method of  claim 18 , wherein PAA accumulation comprises a plasma PAA value equal or exceeding 400 μg/mL. 
     
     
         22 . The method of  claim 18 , wherein PAA accumulation comprises a plasma PAA value equal or exceeding 500 μg/mL. 
     
     
         23 . The method of  claim 18 , wherein adverse event related to PAA accumulation comprises symptoms of emesis, nausea, headache, somnolence or confusion in the patient. 
     
     
         24 . A method of treating a urea cycle disorder in a subject in need thereof wherein the subject is at increased risk of PAA accumulation due to inadequate levels of PAA conjugating enzyme, comprising:
 administering to the subject glyceryl tri-[4-phenylbutyrate] (HPN-100);   determining the subject's plasma PAA to PAGN ratio;   adjusting the dosage of the glyceryl tri-[4-phenylbutyrate] (HPN-100) based on the subject's plasma PAA to PAGN ratio; and   administering to the subject glyceryl tri-[4-phenylbutyrate] (HPN-100) at the adjusted dosage.   
     
     
         25 . The method of  claim 24 , wherein the subject has hepatic impairment. 
     
     
         26 . The method of  claim 25 , wherein the subject has moderate or severe hepatic impairment.