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 N-acetylglutamate synthase (NAGS), a mitochondrial enzyme. Carglumic acid acts as a replacement for NAG in NAGS deficiency patients by activating CPS 1.

Pharmacodynamics

In a retrospective review of the clinical course in 23 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.

Pharmacokinetics

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

Absorption

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

Distribution

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

Metabolism

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.

Elimination

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.

Clinical Studies

Responses of Patients with NAGS Deficiency to Acute and Chronic Treatment

The efficacy of Carbaglu (carglumic acid tablets) 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 (carglumic acid tablets) 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

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 (carglumic acid tablets) treatment, and long-term Carbaglu (carglumic acid tablets) treatment for 13 evaluable patients. Of the 23 NAGS deficiency patients who received treatment with Carbaglu (carglumic acid tablets) , a subset of 13 patients who had both well documented plasma ammonia levels prior to Carbaglu (carglumic acid tablets) treatment and after long-term treatment with Carbaglu (carglumic acid tablets) were selected for analysis.

All 13 patients had abnormal ammonia levels at baseline. The overall mean baseline plasma ammonia level was 271 μmol/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 μmol/L and 24 μmol/L, respectively, after a mean treatment duration of 8 years.

Table 3: Plasma ammonia levels at baseline and after treatment with Carbaglu (carglumic acid tablets)

The mean plasma ammonia level at baseline and the decline that is observed after treatment with Carbaglu (carglumic acid tablets) 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 (carglumic acid tablets)

Last reviewed on RxList: 4/15/2010
This monograph has been modified to include the generic and brand name in many instances.