METHODS OF TREATMENT USING AMMONIA-SCAVENGING DRUGS
The invention provides a method for determining a dose and schedule and making dose adjustments of PBA prodrugs used to treat nitrogen retention states, or ammonia accumulation disorders, by measuring urinary excretion of phenylacetylglutamine and/or total urinary nitrogen. The invention provides methods to select an appropriate dosage of a PBA prodrug based on the patient's dietary protein intake, or based on previous treatments administered to the patient. The methods are applicable to selecting or modifying a dosing regimen for a subject receiving an orally administered ammonia scavenging drug.
1 . A method of treating a subject having a nitrogen retention disorder comprising (a) determining a target urinary phenylacetyl glutamine (PAGN) output based on a target nitrogen output; (b) calculating an effective initial dosage of a phenylacetic acid (PAA) prodrug selected from glyceryl tri-[4-phenylbutyrate] (HPN-100) and phenylbutyric acid (PBA) or a pharmaceutically acceptable salt of PBA, wherein the effective dosage of PAA prodrug is calculated based on a mean conversion of PAA prodrug to urinary PAGN of 60% to 75%; and (c) administering the effective initial dosage of PAA prodrug to the patient.
2 . A method of administering a phenylacetic acid (PAA) prodrug selected from glyceryl tri-[4-phenylbutyrate] (HPN-100) and phenylbutyric acid (PBA) or a pharmaceutically acceptable salt of PBA to a subject having a nitrogen retention disorder comprising (a) administering a first dosage of the PAA prodrug; (b) determining urinary phenylacetyl glutamine (PAGN) excretion following administration of the first dosage of the PAA prodrug; (c) calculating an effective dosage of the PAA prodrug based on the urinary PAGN excretion, wherein the effective dosage is based on a mean conversion of PAA prodrug to urinary PAGN of 60% to 75%; and (d) administering the effective dosage to the patient.
3 . The method of claim 1 or 2 , wherein the PAA prodrug is HPN-100.
4 . The method of claim 1 or 2 , wherein the pharmaceutically acceptable salt of PBA is sodium PBA.
5 . The method of claim 1 or 2 where administration of the calculated dosage of PAA prodrug results in a normal plasma ammonia level in the subject.
6 . The method of claim 1 or 2 , wherein the target urinary PAGN output is determined as a ratio of the concentration of urinary PAGN to urinary creatinine.
7 . The method of claim 1 or 2 , wherein the target urinary PAGN output takes into account the patient's dietary protein intake.
8 . The method of claim 1 or 2 , wherein the target urinary PAGN output takes into account the patient's residual urea synthesis capacity.