February 27, 2017
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Mechanism Of Action

Carglumic acid is a synthetic structural analogue of N-acetylglutamate (NAG), which is an essential allosteric activator of carbamoyl phosphate synthetase 1 (CPS 1) in liver mitochondria. CPS 1 is the first enzyme of the urea cycle, which converts ammonia into urea. NAG is the product of Nacetylglutamate synthase (NAGS), a mitochondrial enzyme. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS 1.


In a retrospective review of the clinical course in23 patients with NAGS deficiency, carglumic acid reduced plasma ammonia levels within 24 hours when administered with and without concomitant ammonia lowering therapies. No dose response relationship has been identified.


The pharmacokinetics of carglumic acid has been studied in healthy male volunteers using both radiolabeled and non-radiolabeled carglumic acid.


The median Tmax of Carbaglu® was 3 hours (range:2-4). Absolute bioavailability has not been determined.


The apparent volume of distribution was 2657 L (range: 1616-5797). Protein binding has not been determined.


A proportion of carglumic acid may be metabolized by the intestinal bacterial flora. The likely end product of carglumic acid metabolism is carbon dioxide, eliminated through the lungs.


Median values for the terminal half-life was 5.6 hours (range 4.3-9.5), the apparent total clearance was 5.7 L/min (range 3.0-9.7), the renal clearance was 290 mL/min (range 204-445), and the 24-hour urinary excretion was 4.5 % of the dose (range 3.5-7.5). Following administration of a single radiolabeled oral dose of 100 mg/kg of body weight, 9% of the dose was excreted unchanged in the urine and up to 60% of the dose was excreted unchanged in the feces.

Drug Interaction Studies

No drug interaction studies have been performed. Based on in-vitro studies, Carbaglu® is not an inducer of CYP1A1/2, CYP2B6, CYP2C, and CYP3A4/ 5 enzymes, and not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19,CYP2D6, CYP2E1, and CYP3A4/5 enzymes.

Clinical Studies

Responses Of Patients With NAGS Deficiency To Acute And Chronic Treatment

The efficacy of Carbaglu® in the treatment of hyperammonemia due to NAGS deficiency was evaluated in a retrospective review of the clinical course of 23 NAGS deficiency patients who received Carbaglu® treatment for a median of 7.9 years (range 0.6 to 20.8 years).

The demographics characteristics of the patient population are shown in Table 2.

Table 2: Baseline Characteristics of the 23 NAGS deficiency patients

Gender Male 14 (61%)
Female 9 (39%)
Age at initiation of Carbaglu® therapy (years) Mean (SD) 2 (4)
Min-Max 0-13
Age groups at initiation of Carbaglu® therapy < 30 days 9 (39%)
> 30 days - 11 months 9 (39%)
≥ 1 -13 years 5 (22%)
NAGS gene mutations by DNA testing homozygous 14 (61%)
heterozygous 4 (17%)
Not available 5 (22%)
Patients current treatment status On-going 18 (78%)
Discontinued 5 (22%)

The clinical observations in the 23 patient case series were retrospective, unblinded and uncontrolled and preclude any meaningful formal statistical analyses of the data. However, short-term efficacy was evaluated using mean and median change in plasma ammonia levels from baseline to days 1 to 3. Persistence of efficacy was evaluated using long-term mean and median change in plasma ammonia level. Table 3 summarizes the plasma ammonia levels at baseline, days 1 to 3 post-Carbaglu® treatment, and long-term Carbaglu® treatment for13 evaluable patients. Of the 23 NAGS deficiency patients who received treatment with Carbaglu®, a subset of 13 patients who had both well documented plasma ammonia levels prior to Carbaglu® treatment and after long-term treatment with Carbaglu® were selected for analysis.

All 13 patients had abnormal ammonia levels at baseline. The overall mean baseline plasma ammonia level was 271 Ámol/L. By day 3, normal plasma ammonia levels were attained in patients for whom data were available. Long-term efficacy was measured using the last reported plasma ammonia level for each of the 13 patients analyzed (median length of treatment was 6 years; range 1 to 16 years). The mean and median ammonia levels were 23 Ámol/L and 24 Ámol/L, respectively, after a mean treatment duration of 8 years.

Table 3: Plasma ammonia levels at baseline and after treatment with Carbaglu ®

Timepoint Statistics
(N = 13*)
Ammonia** (μmol/L)
Baseline (prior to first treatment with Carbaglu ®) N 13
Mean (SD) 271 (359)
Median 157
Range 72-1428
Missing Data 0
Day 1 N 10
Mean (SD) 181 (358)
Median 65
Range 25-1190
Missing Data 3
Day 2 N 8
Mean (SD) 69 (78)
Median 44
Range 11-255
Missing Data 5
Day 3 N 5
Mean (SD) 27 (11)
Median 25
Range 12-42
Missing Data 8
Mean: 8 years
Median: 6 years 1 to 16 years (last available value on Carbaglu® treatment)
N 13
Mean (SD) 23 (7)
Median 24
Range 9-34
Missing Data 0
* 13/23 patients with complete short-term and long-term plasma ammonia documentation
** Mean ammonia normal range: 5 to 50 μmol/L

The mean plasma ammonia level at baseline and the decline that is observed after treatment with Carbaglu® in 13 evaluable patients with NAGS deficiency is illustrated in Figure 1.

Figure 1: Ammonia response for 13 evaluable NAGS deficiency patients at baseline and after treatment with Carbaglu®

Carbaglu® (carglumic acid) Figure 1 Illustration

Last reviewed on RxList: 1/26/2016
This monograph has been modified to include the generic and brand name in many instances.

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