"Researchers from the National Institutes of Health have entered into an agreement with biotechnology company Vtesse, Inc., of Gaithersburg, Maryland, to develop treatments for Niemann-Pick disease type C (NPC) and other lysosomal storage disor"...
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.
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.
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.
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.
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
|Age at initiation of Carbaglu therapy (years)||Mean (SD)||2 (4)|
|Age groups at initiation of Carbaglu therapy||< 30 days||9 (39%)|
|> 30 days - 11 month||9 (39%)|
|≥ 1- 13 years||5 (22%)|
|NAGS gene mutations by DNA testing||homozygous||14 (61%)|
|Not available||5 (22%)|
|Patients current treatment status||On-going||18 (78%)|
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 for 13 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 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
(N = 13*)
|Baseline (prior to first treatment with Carbaglu)||N||13|
|Mean (SD)||271 (359)|
|Mean (SD)||181 (358)|
|Mean (SD)||27 (11)|
|Long-term Mean: 8 years Median: 6 years 1 to 16 years (last available value on Carbaglu treatment)||N||13|
|*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
Last reviewed on RxList: 8/16/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Carbaglu Information
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