Mechanism Of Action
The mechanism of action of the
amino acid L-glutamine in treating sickle cell disease (SCD) is not fully
understood. Oxidative stress phenomena are involved in the pathophysiology of
SCD. Sickle red blood cells (RBCs) are more susceptible to oxidative damage
than normal RBCs, which may contribute to the chronic hemolysis and
vaso-occlusive events associated with SCD. The pyridine nucleotides, NAD+ and
its reduced form NADH, play roles in regulating and preventing oxidative damage
in RBCs. L-glutamine may improve the NAD redox potential in sickle RBCs through
increasing the availability of reduced glutathione.
In vivo analyses demonstrated
that L-glutamine supplementation improved NAD redox potential.
The pharmacokinetics of
L-glutamine has been studied in healthy subjects and a variety of disease states.
Relevant results from published literature are summarized below.
Following single-dose oral
administration of L-glutamine at 0.1 g/kg, mean peak L-glutamine concentration was 1028 μM (or 150 mcg/mL) occurring approximately 30 minutes after
The pharmacokinetics following
multiple oral doses has not been characterized.
After an intravenous (IV) bolus
dose, the volume of distribution was estimated to be approximately 200 mL/kg.
After an intravenous bolus
dose, the terminal half-life of L-glutamine was approximately one hour.
participates in various metabolic activities, including the formation of glutamate,
and synthesis of proteins, nucleotides, and amino sugars. Exogenous L-glutamine
is anticipated to undergo similar metabolism.
Metabolism is the major route
of elimination for L-glutamine. Although L-glutamine is eliminated by glomerular
filtration, it is almost completely reabsorbed by the renal tubules.
The safety of Endari has not
been established in patients with renal or hepatic impairment.
No drug interaction studies
have been conducted.
The efficacy of Endari in sickle cell disease was
evaluated in a randomized, double-blind, placebocontrolled, multi-center
clinical trial entitled “A Phase III Safety and Efficacy Study of L-Glutamine
to Treat Sickle Cell Disease or Sickle β0-thalassemia”
[NCT01179217] (see Table 3).
The clinical trial evaluated
the efficacy and safety of Endari in 230 patients (5 to 58 years of age) with sickle
cell anemia or sickle β0-thalassemia who
had 2 or more painful crises within 12 months prior to enrollment. Eligible
patients stabilized on hydroxyurea for at least 3 months continued their
therapy throughout the study. The trial excluded patients who had received
blood products within 3 weeks, had renal insufficiency or uncontrolled liver
disease, or were pregnant (or planning pregnancy) or lactating. Study patients
received Endari or placebo for a treatment duration of 48 weeks followed by 3
weeks of tapering.
Efficacy was demonstrated by a
reduction in the number of sickle cell crises through Week 48 and prior to the
start of tapering among patients that received Endari compared to patients who
received placebo. A sickle cell crisis was defined as a visit to an emergency
room/medical facility for sickle cell disease-related pain which was treated
with a parenterally administered narcotic or parenterally administered
ketorolac. In addition, the occurrence of chest syndrome, priapism, and splenic
sequestration were considered sickle cell crises. Treatment with Endari also
resulted in fewer hospitalizations due to sickle cell pain at Week 48, fewer
cumulative days in hospital and a lower incidence of acute chest syndrome.
Table 3: Results from the
Endari Clinical Trial in Sickle Cell Disease
(n = 152)
(n = 78)
|Median number of sickle cell crises (min,max)1
||3 (0, 15)
||4 (0, 15)
|Median number of hospitalizations for sickle cell pain (min, max)1
||2 (0, 14)
||3 (0, 13)
|Median cumulative days in hospital (min, max)1
||6.5 (0, 94)
||11 (0, 187)
|Median time (days) to first sickle cell crisis (95% CI) 1,2
||84 (62, 109)
||54 (31, 73)
|Patients with occurrences of acute chest syndrome (%)1
|1 Measured through 48 weeks of treatment
2 Hazard Ratio=0.69 (95% CI=0.52, 0.93), estimated based on
unstratified CoxÃ¢â¬™s proportional model.Median time and 95% CI were estimated
based on the Kaplan Meier method.
The recurrent crisis event time
analysis (Figure 1) yielded an intensity rate ratio (IRR) value of 0.75 with
95% CI= (0.62, 0.90) and (0.55, 1.01) based on unstratified models using the Andersen-Gill and Lin, Wei, Yang and Ying methods,
respectively in favor of Endari, suggesting
that over the entire 48- week period, the average cumulative crisis count was
reduced by 25% from the Endari group over the placebo group.
Figure 1: Recurrent Event
Time for Sickle Cell Crises by Treatment Group