METHODS FOR TREATING UREA CYCLE DISORDERS
Provided are methods of administering glycerol phenylbutyrate to a patient in need thereof, wherein said patient is also being treated with a CYP3A4 substrate having a narrow therapeutic index, midazolam or a pharmaceutically acceptable salt thereof, or celecoxib.
1 - 5 . (canceled)
6 . The method of claim 18 , wherein the patient is 2 years of age or older.
7 . The method of claim 6 , wherein the glycerol phenylbutyrate is administered daily in three equally divided dosages.
8 . The method of claim 18 , wherein the patient is between 2 months of age to less than 2 years of age.
9 . The method of claim 8 , wherein the glycerol phenylbutyrate is administered daily in three or more equally divided dosages.
10 . The method of claim 18 , further comprising restricting the patient's dietary protein.
11 . The method of claim 18 , wherein the therapeutically effective amount of the glycerol phenylbutyrate is 4.5 to 11.2 mL/m 2 /day (5 to 12.4 g/m 2 /day).
12 . The method of claim 18 , further comprising monitoring the patient's plasma ammonia levels to determine the need for dosage titration of the glycerol phenylbutyrate.
13 . The method of claim 12 , wherein the patient is 6 years and older with an elevated plasma ammonia and the method further comprises increasing the glycerol phenylbutyrate dosage to reduce the fasting ammonia level to less than half the upper limit of normal.
14 . The method of claim 12 , wherein the patient is an infant or pediatric and the method further comprises adjusting the glycerol phenylbutyrate dosage to keep the first ammonia of the morning below the upper limit of normal.
15 . The method of claim 18 , further comprising obtaining measurements of plasma phenylacetate (PAA) concentrations and the ratio of plasma PAA to phenylacetylglutamine (PAGN).
16 . The method of claim 18 , further comprising obtaining measurements of urinary phenylacetylglutamine (U-PAGN).
17 . The method of claim 16 , wherein if the U-PAGN excretion is insufficient to cover daily dietary protein intake and/or the fasting ammonia is greater than half the upper limit of normal, the method further comprises increasing the glycerol phenylbutyrate dosage.
18 . A method of administering glycerol phenylbutyrate to a patient in need thereof, wherein said patient is also being treated with midazolam or a pharmaceutically acceptable salt thereof, comprising
administering to the patient a therapeutically effective amount of the glycerol phenylbutyrate,
informing the patient that the efficacy of the midazolam or a pharmaceutically acceptable salt thereof may be reduced; and
monitoring the therapeutic effect of the midazolam or a pharmaceutically acceptable salt thereof.
19 . (canceled)
20 . The method of claim 18 , further comprising administering an increased dosage of the midazolam or a pharmaceutically acceptable salt thereof.