Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C6H10N2O5 |
Molecular Weight | 190.154 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
NC(=O)N[C@@H](CCC(O)=O)C(O)=O
InChI
InChIKey=LCQLHJZYVOQKHU-VKHMYHEASA-N
InChI=1S/C6H10N2O5/c7-6(13)8-3(5(11)12)1-2-4(9)10/h3H,1-2H2,(H,9,10)(H,11,12)(H3,7,8,13)/t3-/m0/s1
Carglumic acid is a Carbamoyl Phosphate Synthetase 1 (CPS 1) allosteric modulator. CPS1 is found in the mitochondria and is the first enzyme of the urea cycle, which converts ammonia into urea. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS1 but it does not help to regulate the urea cycle. Carglumic acid under the trade name Carbaglu indicated as adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). In addition, as maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). This rare genetic disorder results in elevated blood levels of ammonia, which can eventually cross the blood–brain barrier and cause neurologic problems, cerebral edema, coma, and death.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL2362990 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21403788 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | CARBAGLU Approved UseCarbaglu (carglumic acid) is a Carbamoyl Phosphate Synthetase 1 (CPS 1) activator indicated as:
• Adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.1)
• Maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.2) Launch Date2010 |
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Palliative | CARBAGLU Approved UseCarbaglu (carglumic acid) is a Carbamoyl Phosphate Synthetase 1 (CPS 1) activator indicated as:
• Adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.1)
• Maintenance therapy for the treatment of chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). (1.2) Launch Date2010 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
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2892 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25677217/ |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
2.6 μg/mL |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
23.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25677217/ |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
5.2 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25677217/ |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED |
|
5.6 h |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
CARGLUMIC ACID plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
96.3 mg/kg 2 times / day multiple, oral Recommended Dose: 96.3 mg/kg, 2 times / day Route: oral Route: multiple Dose: 96.3 mg/kg, 2 times / day Sources: |
unhealthy, 5 day n = 21 Health Status: unhealthy Condition: methylmalonic aciduria Age Group: 5 day Sex: M+F Population Size: 21 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
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OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
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Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 11-12, 38 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 11-12, 38 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 11-12, 38 |
no | |||
Page: (PMDA_A100_2 in Japanese) 23, (PMDA_I100_1 in Japanese) 12, 39-42 |
no |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 30, 35 |
no | |||
Page: 30.0 |
no | |||
Page: 30.0 |
no | |||
Page: 30.0 |
no |
PubMed
Title | Date | PubMed |
---|---|---|
Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients. | 2001 Sep |
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Urea synthesis by ruminal epithelial and duodenal mucosal cells from growing sheep. | 2004 Jun |
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Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. | 2004 Oct |
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Misleading diagnosis of partial N-acetylglutamate synthase deficiency based on enzyme measurement corrected by mutation analysis. | 2005 Jan |
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[A newborn infant with hyperventilation]. | 2008 Jun 26 |
|
N-acetylglutamate synthase: structure, function and defects. | 2010 |
Sample Use Guides
Adult Dosage: The recommended initial dose for acute hyperammonemia is 100 mg/kg/day to 250 mg/kg/day. Concomitant administration of other ammonia lowering therapies is recommended. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms.
The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses and rounded to the nearest 100 mg. (i.e. half a Carbaglu Tablet)
Pediatric Dosage: The recommended initial dose for acute hyperammonemia is 100 mg/kg/day to 250 mg/kg/day. Concomitant administration of other ammonia lowering therapies is recommended. Dosing should be titrated based on individual patient plasma ammonia levels and clinical symptoms. The recommended maintenance dose should be titrated to target normal plasma ammonia level for age. Based on limited data in 22 patients receiving maintenance treatment with Carbaglu in a retrospective case series, maintenance doses were usually less than 100 mg/kg/day. The total daily dose should be divided into 2 to 4 doses.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26885446
Carglumic acid-treated (1, 5, 10 mM) and untreated cancer cells were stained with propidium iodide to determine DNA contents in the human pancreatic adenocarcinoma cell lines, AsPC1 and human triple-negative breast cancer cell lines MDA-MB-231. The results showed that carglumic acid did not induce complete cell cycle arrest. Instead, we observed more sub-G1 cells among carglumic acid-treated AsPC1 and MDA-MB-231 cells than among untreated cells, indicating that cell death occurred in response to carglumic acid. Sub-G1 cells accounted for 1.6% and 26.3% of untreated and treated AsPC1 cells, respectively , and for 1.8% and 12.8% of untreated and treated MDA-MB-231 cells, respectively. In order to further determine whether cancer cells under go cell death through apoptosis after carglumic acid treatment, we measured caspase activity in AsPC1 cells treated with carglumic acid. The results showed that caspase-3 activity increased in a dose-dependent manner. Together, these data suggest that carglumic acid inhibits cancer cell proliferation by inducing apoptosis.
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Classification Tree | Code System | Code | ||
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EMA ASSESSMENT REPORTS |
CARBAGLU (AUTHORIZED: AMINO ACID METABOLISM, INBORN ERRORS)
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FDA ORPHAN DRUG |
109997
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WHO-VATC |
QA16AA05
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EU-Orphan Drug |
EU/3/00/007
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NDF-RT |
N0000184144
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WHO-ATC |
A16AA05
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NCI_THESAURUS |
C78275
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FDA ORPHAN DRUG |
352111
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m3108
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SUB20051
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CARGLUMIC ACID
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121396
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CHEMBL1201780
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N0000184143
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71028
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DB06775
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SUB13236MIG
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ALTERNATIVE |
ACTIVE MOIETY