Carglumic Acid

A16A - Other alimentary tract and metabolism products ATC A16AA05 Small molecule approved 2003 Oral First-in-class Natural product

JFDA label: Carbaglu

Mechanism of Action

Positive Allosteric Modulator of Carbamoyl-phosphate synthase [ammonia], mitochondrial — Carbamoyl-phosphate synthase [ammonia], mitochondrial positive allosteric modulator

Target	Action	Gene / class
Carbamoyl-phosphate synthase [ammonia], mitochondrial efficacy	POSITIVE ALLOSTERIC MODULATOR	CPS1

Indications

Approved

Hyperammonemia

Contraindications

Source: Lexicomp

Additional contraindications (not in US labeling): Hypersensitivity to carglumic acid or any component of the formulation Absolute
There are no contraindications listed in the manufacturer’s labeling Absolute
breastfeeding Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (2)

Very Common Headache

Common Drowsiness

Blood and lymphatic system disorders (2)

Very Common Anemia · decreased hemoglobin

Metabolism and nutrition disorders (1)

Common Weight loss

Gastrointestinal disorders (5)

Very Common abdominal pain · diarrhea · Vomiting

Common Anorexia · dysgeusia

Skin and subcutaneous tissue disorders (2)

Common Hyperhidrosis · skin rash

Musculoskeletal and connective tissue disorders (1)

Common Weakness

Ear and labyrinth disorders (1)

Very Common Otic infection

Infections and infestations (2)

Very Common Infection

Common Influenza

General disorders and administration site conditions (1)

Very Common Fever

Respiratory, thoracic and mediastinal disorders (3)

Very Common nasopharyngitis · Tonsillitis

Common Pneumonia

Dosing

Source: Lexicomp

Acute hyperammonemia: Oral: 100 to 250 mg/kg/day given in 2 or 4 divided doses (rounded to the nearest 100 mg); titrate to age-appropriate plasma ammonia levels. Concomitant adjunctive ammonia-lowering therapy recommended. Chronic hyperammonemia: Oral: Usual dose (based on limited data):

(For additional information see "Carglumic acid: Pediatric drug information") Acute hyperammonemia: Infants, Children, and Adolescents: Oral: 100 to 250 mg/kg/day given in 2 or 4 divided doses; titrate to age-appropriate plasma ammonia levels. Concomitant adjunctive ammonia-lowering therapy recommended. Chronic hyperammonemia: Infants, Children, and Adolescents: Oral: Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Experienced physician

Acute symptomatic hyperammonemia is a life-threatening emergency; management of hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency should be done in coordination with those experienced in the management of metabolic disorders.

Nutritional management

Since hyperammonemia is the result of protein catabolism, complete protein restriction is recommended to be maintained for 24-48 hours and caloric supplementation should be maximized to reverse catabolism and nitrogen turnover.

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in animal reproduction studies. There are no adequate and well-controlled studies in pregnant women. However, due to the potential for irreversible fetal neurologic damage for untreated NAGS deficiency, women with this condition must remain on treatment throughout pregnancy.

Lactation

Avoid

It is not known if carglumic acid is excreted in breast milk. Breastfeeding is not recommended.

Monitoring

Clinical pearl	Plasma ammonia; monitor for physical signs/symptoms of hyperammonemia (eg, lethargy, ataxia, confusion, vomiting, seizures, and memory impairment).

Chemistry & Properties

Formula	C6H10N2O5
Molecular weight	190.16 g/mol
IUPAC name	(2S)-2-(carbamoylamino)pentanedioic acid
CAS	1188-38-1
PubChem CID	121396
InChIKey	`LCQLHJZYVOQKHU-VKHMYHEASA-N`
logP	-1.03 (XLogP -2.4)
Polar surface area	129.72 Å²
H-bond acceptors / donors	3 / 4
Drug-likeness (QED)	0.44
Lipinski violations	0

SMILES

NC(=O)N[C@@H](CCC(=O)O)C(=O)O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.226 h
Volume of distribution	0.263 L/kg
Protein binding	18.4%
BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Carbaglu	Tablet 200 mg	60 tab pack varies	Garden drug store	—
Carbaglu	Tablet 200 mg	5 tab pack varies	Garden drug store	—