Dosage and use of ornithine phenylacetate for treating hyperamminemia

A technology of phenylacetate and hyperammonemia, which is applied in the dosage and application field of ornithine phenylacetate for treating hyperammonemia, and can solve the problems of long-term treatment of glutamine concerns and the like

Pending Publication Date: 2022-07-22
OCERA THERAPEUTICS INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the risk of long-term treatment and continued glutamine depletion remains a concern in cirrhotic patients with poor muscle mass

Method used

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  • Dosage and use of ornithine phenylacetate for treating hyperamminemia
  • Dosage and use of ornithine phenylacetate for treating hyperamminemia
  • Dosage and use of ornithine phenylacetate for treating hyperamminemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] A multicenter, randomized, double-blind, placebo-controlled phase 3 study to evaluate the role of LOPA (an intravenous formulation of L-ornithine phenylacetate) in cirrhosis and hyperammonemia associated with the onset of hepatic encephalopathy Efficacy, Safety, and Tolerability in Hospitalized Patients with Symptoms.

[0099] goal and destination

[0100] The primary objectives and endpoints listed below will be used to evaluate LOPA+Standard of Care (SoC) versus placebo+SoC in hospitalized patients with cirrhosis who experience an overt HE episode associated with hyperammonemia.

[0101] Table 1: Primary Goals / Endpoints

[0102]

[0103] h: hours; HEST: Hepatic Encephalopathy Grading Tool; IV: Intravenous; SoC: Standard of Care

[0104] Time to confirm clinical response and time to complete response will be reviewed at the last time point measured in the absence of adequate patient improvement. However, in the case of death or liver transplantation, this time ...

Embodiment 2

[0203] Example 2. Exposure of phenylacetic acid (PAA) and phenylacetylglutamine (PAGN) in different subpopulations and their correlation with Correlation of good events

[0204] This example summarizes various clinical studies of intravenous administration of L-ornithine phenylacetate (LOPA) in healthy subjects and subjects with varying degrees of cirrhosis.

[0205] Clinical Research and Analytical Methods

[0206] PK and AE data from five clinical studies are described below:

[0207] Study 1: Healthy subjects were given two intravenous doses of LOPA: (a) single ascending dose (SAD); (b) multiple ascending dose (MAD). The doses tested in SAD were 1 g, 10 g, 20 g and 30 g injected for 4 hours, and 30 g, 40 g and 60 g injected for 24 hours. The doses tested in the MAD were 1 g, 3 g, 10 g and 20 g administered as a 24 hour injection for 5 days.

[0208] Study 2: A SAD study was conducted in patients with stable cirrhosis [Liver Function Class A (C-P A), n=31; Liver Functio...

Embodiment 3

[0248] In this example, aqueous solutions containing different concentrations of L-ornithine phenylacetate and various pH were prepared, and their long-term storage stability was tested and evaluated.

[0249] Solubility and pH

[0250] In a pilot study, the solubility of LOPA at a concentration of 400 mg / mL was evaluated at pH values ​​of 5.0, 5.1, 5.2, 5.3, and 5.4. The pH of the LOPA solution was adjusted by adding concentrated HCl, solubilization was performed at room temperature and stored at 2-8°C. It was found that pH values ​​above 5.4 at 5°C avoided precipitation of LOPA, with varying amounts of crystallisation found in all samples below pH 5.4, and the observed crystallisation increased as the pH of the samples decreased.

[0251] In a follow-up study, the solubility of LOPA at different pH values ​​at room temperature and 5 °C was investigated, and the results are shown in Table 5 below. The pH of the LOPA solution was adjusted by adding citric acid and the soluti...

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Abstract

Embodiments of the present disclosure relate to doses of ornithine phenylacetate for use in treating or ameliorating hyperammonemia and methods of administering such doses of ornithine phenylacetate in patients suffering from chronic liver disease, such as cirrhosis. In some embodiments, the patient also has hepatic encephalopathy as a complication of the liver disease.

Description

Background technique [0001] Acute-on-chronic liver failure initially presents with abnormal behavior and cognitive impairment. Although the onset of hepatic encephalopathy (HE) is rarely clinically determined, it is a feature of patients with advanced liver disease. 60% to 70% of patients with cirrhosis are expected to have at least mild signs of neurocognitive impairment, and HE is the main diagnosis in hospitalized patients with cirrhosis. The prevalence of overt HE in the cirrhotic population is approximately 30% of the approximately 150,000 annual hospitalizations in the United States. In the first year alone, severe HE in cirrhotic patients was associated with more than 50% mortality. [0002] Hepatic encephalopathy is a neuropsychiatric disorder that occurs when gut-derived toxins—mostly ammonia—bypass a failing liver, which normally detoxifies the drug; these toxins enter the bloodstream and Cross the blood-brain barrier, resulting in impaired neurotransmission and c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/198A61K31/192A61P1/16A61P7/00
CPCA61K31/192A61K2300/00A61K31/198A61P1/16A61K47/12A61K9/0019A61K9/08
Inventor X·王瑞尔斯J·曾C·麦N·波拉R·比尔切斯A·蓬蒂斯S·范米特J·斯坦格
Owner OCERA THERAPEUTICS INC
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