Dosages and uses of ornithine phenylacetate for treating hyperammonemia
Embodiments of the present disclosure relate to doses of ornithine phenylacetate for treating or ameliorating hyperammonemia and the methods of administrating the same in a patient with a chronic liver disease, for example, cirrhosis. In some embodiments, the patient also has hepatic encephalopathy as a complication of the liver disease.
1 . A method of treating or ameliorating hyperammonemia in a patient with liver disease, comprising:
administering a first amount of ornithine phenylacetate to the patient during a first period of time; and
administering a second amount of ornithine phenylacetate to the patient during a second period of time;
wherein the first amount of ornithine phenylacetate is between about 10 g to about 30 g, and the second amount of ornithine phenylacetate is less than the first amount.
2 . The method of claim 1 , wherein the first period of time is from about 1 hour to about 10 hours, the second period of time is longer than the first period of time, and a total of the first period of time and the second period of time is from about 18 hours to 36 hours.
3 . The method of claim 1 , wherein the first amount of ornithine phenylacetate is about 20 g, and wherein the first period of time is about 6 hours.
4 . The method of claim 1 , wherein the second amount of ornithine phenylacetate is about 15 g, and wherein the second period of time is about 18 hours.
5 . The method of claim 1 , wherein the second amount of ornithine phenylacetate is administered immediately after the completion of the administration of the first amount of ornithine phenylacetate.
6 . The method of claim 1 , wherein the first amount or the second amount of ornithine phenylacetate is administered by intravenous infusion.
7 . The method of claim 1 , further comprising administering a third amount of ornithine phenylacetate immediately following the completion of the administration of the second amount of ornithine phenylacetate during a third period of time, wherein the third period of time is from about 2 days to about 10 days.
8 . The method of claim 7 , wherein the third period of time is about 4 days.
9 . The method of claim 7 , wherein the third amount of ornithine phenylacetate administered per day (24 hours) is the same or less than the second amount of ornithine phenylacetate.
10 . The method of claim 9 , wherein the third amount of ornithine phenylacetate administered per day is about 15 g, and wherein the third amount of ornithine phenylacetate is administered by intravenous infusion.
11 . The method of claim 1 , wherein the patient is also receiving standard of care.
12 . A method of treating or ameliorating hyperammonemia in a patient with liver disease, comprising:
selecting a patient with liver disease in need of treatment of hyperammonemia who is suffering from impaired renal function, wherein said patient has estimated glomerular filtration rate (eGFR) between 15 mL/min/1.73 m 2 and 29 mL/min/1.73 m 2 ;
administering a first amount of ornithine phenylacetate to the patient during a first period of time; and
administering a second amount of ornithine phenylacetate to the patient during a second period of time;
wherein the first amount of ornithine phenylacetate is between about 5 g to about 20 g, and the second amount of ornithine phenylacetate is less than the first amount.
13 . A method of treating or ameliorating hyperammonemia in a patient with liver disease, comprising:
determining the renal function or receiving information on the renal function of a patient with liver disease who is in need of treatment of hyperammonemia; and
administering a first amount of ornithine phenylacetate to the patient during a first period of time; wherein the first amount is from about 10 g to about 30 g when the patient's estimated creatinine clearance is greater than 35 mL/min; or
administering a first amount of ornithine phenylacetate to the patient during a first period of time; wherein the first amount is from about 5 g to about 15 g when the patient's estimated creatinine clearance is equal to or less than 35 mL/min.
14 . A method of treating or ameliorating hyperammonemia in a patient with liver disease, comprising:
determining the body weight or body size or receiving information on the body weight or body size of a patient with liver disease who is in need of treatment of hyperammonemia;
administering a first amount of ornithine phenylacetate administered to the patient during a first period of time;
monitoring plasma concentration of phenylacetic acid in the patient; and
adjusting the amount of ornithine phenylacetate administered to the patient during a second period of time based on the plasma concentration of phenylacetic acid.
15 . A method of treating or ameliorating hyperammonemia in a patient with liver disease, comprising:
determining the degree of hepatic impairment or receiving information on the degree of hepatic impairment of a patient with liver disease who is in need of treatment of hyperammonemia;
administering a first amount of ornithine phenylacetate administered to the patient during a first period of time;
monitoring plasma concentration of phenylacetic acid in the patient; and
adjusting the amount of ornithine phenylacetate administered to the patient during a second period of time based on the plasma concentration of phenylacetic acid.
16 . The method of claim 1 , further comprising measuring a serum ammonia level of the patient prior to administering the first amount of ornithine phenylacetate to the patient.
17 . The method of claim 16 , wherein the serum ammonia level of the patient is ≥21 μmol/L.
18 . The method of claim 1 , wherein the patient has cirrhosis.
19 . The method of claim 1 , wherein the patient is at risk of hepatic encephalopathy or has had at least one episode of hepatic encephalopathy, or the patient is hospitalized due to one or more hepatic encephalopathy episodes.
20 . The method of claim 1 , wherein the patient has received at least 4 hours to 6 hours of standard of care prior to the administration of the first amount of ornithine phenylacetate.
21 . The method of claim 1 , wherein ornithine phenylacetate is administered as an aqueous solution comprising about 200 mg/mL to about 400 mg/mL ornithine phenylacetate.
22 . A pharmaceutical formulation comprising an aqueous solution of about 200 mg/mL to 400 mg/mL of ornithine phenylacetate and at least one pH adjusting agent, wherein the aqueous solution has a pH range of about 5.4 to about 6.5.
23 . A method of treating or ameliorating hyperammonemia in a patient with liver disease, comprising administering a first amount of ornithine phenylacetate to the patient during a first period of time and administering a second amount of ornithine phenylacetate to the patient during a second period of time, wherein:
(A) (i) the first amount of ornithine phenylacetate is 20 g and the first period of time is 6 hours; and
(ii) the second amount of ornithine phenylacetate is the same or less than 20 g and the second period of time is 18 hours; or
(B) if the patient in need of treatment of hyperammonemia is suffering from hepatic impairment and/or has a body weight of <50 kg;
(i) the first amount of ornithine phenylacetate is 15 g and the first period of time is 6 hours; and
(ii) the second amount of ornithine phenylacetate is the same or less than 15 g and the second period of time is 18 hours;
wherein the first and second amounts of ornithine phenylacetate are administrable by intravenous infusion.
24 . The method of claim 23 , wherein a further third amount of ornithine phenylacetate is administered during a third period of time, wherein the third period of time is for up to 4 days and wherein:
(i) the third amount of ornithine phenylacetate administered per day (24 hours) is the same or less than 15 g; or
(ii) if the patient in need of treatment of hyperammonemia is suffering from hepatic impairment and/or has a body weight of <50 kg, the third amount of ornithine phenylacetate administered per day (24 hours) is 10 g.
25 . The method of claim 24 , wherein the third period of time is about 4 days.