Esomeprazole: Drug Profile
Introduction :
Esomeprazole, the S-isomer of omeprazole (a racemic mixture of S-& R-
optical isomers), is the first PPI to be developed as a single optical isomer.
It
has a better pharmacokinetic profile and provides greater acid suppression
than omeprazole.
Chemical structure:
Esomeprazole
Mechanism of action:
Esomeprazole is a weak base, which is converted to its active sulfenamide
form in the acidic environment of the gastric parietal cell. Like other PPIs,
Esomeprazole acts by inhibiting the H+/K+ ATPase enzyme (Proton pump),
the final step in acid production, thus reducing gastric acidity. This effect is
dose-related upto a daily dose of 20 to 40 mg.
Esomeprazole inhibits basal as well as stimulated gastric acid secretion.
Anti-secretory activity:
The effect of esomeprazole on intragastric pH was determined in patient
with GERD. In this study 36 patients received 20mg and 40mg dose of
esomeprazole over 5 days. The results of the study are shown in the
following table.
Effect on intragastric pH on day 5 :
! Parameter Esomeprazole 20mg Esomeprazole 40mi
Median 24 hour Ph 4.1 4.9
% time gastric pH >4 53%
70%
(hours) 12.7 hrs
16.8 hrs
Comparative anti-secretory activity:
A) Omeprazole:
A comparative study4 has shown that esomeprazole produces greater and
more sustained acid suppression as compared to omeprazole. The results
of
the study are as follows :
Parameter Esomeprazole Esomeprazole Omeprazole
Mean 24 hours median 20 mg 40 mg 20 mg
.....................................................................................................................................................................................................
intragastric pH 4% 4.9% 3.6%
.....................................................................................................................................................................................................
.....................................................................................................................................................................................................
Ph>4 for >12 hrs 54% 92% 44%
.....................................................................................................................................................................................................
* P<0.01 & <0.001 .respectively
** P < 0.001
B) Lansoprazole:
In a comparative study5 acid control with esomeprazole 40mg was
superior
to that with lansoprazole 30mg once daily.
Effect on intragastric pH on day 5 :
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Parameter Esomeprazole Lansoprazole
Intragastric 40 mg 30 mg
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
pH>4 for >12 hours 90% 57%
(p<0.05)
24-hr median 4.8% 4.2%
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
C) Pantoprazole:
Esomeprazole 40mg once daily was also more effective for control of
acid
secretion than pantoprazole 40mg once daily in another 5-day crossover
trial in 31 patients with symptomatic GERD. In this study more
number of
patients who received esomeprazole had intragastric pH>4for>12hours
& for >16 hours as compared to those who received 40mg pantoprazole.
Results of intragastric pH on day 5 :
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Parameter Esomeprazole Pantoprazole
Intragastric 40 mg 40 mg
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
pH>4 for >12 hours 90% 30%
(p<0.001)
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Pharmacokinetics
Absorption:
β’ After oral administration peak plasma levels (Cmax) occur at
approximately 1 .5
hours Omax)- The C,,, increases proportionally when the dose is
increased :
(Cmax 'β’ 20mg dose ->2.1 micromol/L, 40mg dose ->4.7 micromol/L)
β’ The absolute bioavailability (F) and Area Under the Curve (AUC) of
esomeprazole increase from day 1 to day 5 of administration.
F values increased from 50% to 68% with 20mg/day dose and from 64%
to 89% with 40mg/day dose.
While the AUC values increased as follows :
20 mg dose : from 1 .34 on day 1 to 2.55 micromol/L.h on day 5.
40 mg dose : from 4.32 on day 1 to 1 1.21 micromol/L.h on day 5.
The AUC of esomeprazole decreases if it is administered after a meal.
Hence, esomeprazole should be taken at least one hour before meals.
Distribution:
Esomeprazole is 97% bound to plasma proteins. Its apparent volume of
distribution at steady state is approximately 16 L
Metabolism:
Like other PPIs, esomeprazole is extensively metabolized in the liver
by the
cytochrome P450 enzyme system. The metabolites of esomeprazole do not
have anti-secretory activity.
As compared to omeprazole, esomeprazole undergoes less first pass
metabolism.
The major part of esomeprazole's metabolism is dependent upon the
CYP2C19 isoenzymes which forms the hydroxy and desmethyl metabolites.
CYP2C19 isoenzyme exhibits polymorphism in the metabolism of
esomeprazole. Approximately 15 - 20% of Asians lack CYP2C19 and are
termed poor metabolisers.
The rest of the population is considered extensive metabolisers. The
remaining amount is metabolized by CYP3A4, which forms the sulphone
metabolite.
Excretton;
The plasma elimination half-life of esomeprazole is approximately 1.5
hours. Approximately 80% of the oral dose is excreted as inactive
metabolites in the urine and the remainder is found as inactive
metabolites
in the faeces.
Pharmacokinetics in special populations :
a) Geriatric:
There is a slight increase in Cmax and AUC in the elderly (>65 years)
as
compared to younger subjects at steady state. Usually there is no need
to
adjust the dose in elderly patients.
b) Paediatric:
The pharmacokinetics of esomeprazole have not been studied in patients
<18 years of age.
c) Renal dysfunction:
The pharmacokinetics of esomeprazole in patients with renal impairment
are not expected to be altered as less than 1% of esomeprazole is
excreted
unchanged in urine.
d) Hepatic dysfunction:
In patients with mild and moderate hepatic insufficiency (Child Pugh
class
A & B), there is no significant change in the AUCs of esomeprazole,
while in
patients with severe hepatic insufficiency (Child Pugh Class C) the
AUCs are
2 to 3 times higher than in patients with normal liver function.
There is no need to adjust the dose of esomeprazole in patients with
mild
to moderate liver dysfunction. However, in patients with severe liver
dysfunction a dose of 20 mg once daily should not be exceeded.
Clinicai efficacy
The efficacy and safety of esomeprazole has been evaluated in a large
numbel
of patients suffering from GERD and Peptic Ulcer disease. Following is
tht
summary of major published clinical trials conducted with esomeprazole.
I. Treatment of erosive reflux esophagitis in patients
with gord.
Two large, randomized, double-blind studies found that endoscopic
appearance was normal in a statistically significantly greater
proportion of
patients receiving esomeprazole 40mg daily than those receiving
omeprazole 20mg daily at week 4 and by week 8.
The percentage of patients experiencing heartburn resolution, as
assessed
by investigators at week 4 was also statistically significantly higher
for
patients receiving esomeprazote 40mg daily than for those receiving
omperazole (68.3% vs 58.1 % p<0.001 7. Esomeprazole 20mg daily did not
differ significantly from omeprazole 20mg in terms of healing
or
investigator-assessed heartburn resolution at week four.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Study Study Treatment Regimen Outcome(ITT
Polulation Length analysis)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Erosive Reflux oesophagitis and GORD
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Percentage of patients
healed
(Cumulative life table
estimates)
4 weeks 8 weeks
GORD,1960 Pts 20 mg E od(n=656) 70.5 89.9*
Endoscopically 8 weeks 40 mg E od(n=654) 75.9* 94.1*
Confirmed erosive 20 mg O od(n=650) 64.7 86.9O
esophagitis (p<0.05 vs 20
mg O od)
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
GORD, 2425 Pts 40 mg E od(n=1216) 81.7* 93.7*
Endoscopically 8 weeks 20 mg O od(n=1209) 68.7 84.2
Confirmed erosive (p<0.01
vsoesophagitis 20 mg O od )
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
E = Esomeprazole, 0 = Omeprazole
* In both the trials,~ 8, the percentage of days and nights without
heartburn
favoured esomeprazole over omeprazole (p<0.002 & p<0.001). Resolution
of heartburn was also better and occurred faster with esomeprazole.
2. Maintenance therapy in patients with GORD .-'md heak-d
oesophagitis:
Two randomized, double-blind, six-month studies found esomeprazole
10, 20 and 40mg daily to be statistically significantly more effective
than
placebo at maintaining healing in patients with endoscopically proven
healed erosive oesophagitis (p<0.001).9Β·' O
The percentage of patients maintaining healing at six months was
markedly higher in the esomeprazole 20 and 40mg groups. A statistically
significant difference between each of the esomeprazole groups and the
placebo group was found at one month for the proportion of patients who
had experienced seven consecutive days without heartburn (investigator
assessment, p<0.001).
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Study Study Treatment Regimen Outcome(ITT
Analysis)
Polulation Length
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Maintenance Therapy
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Complete
healing
At 6 months(%)
GORD, 375 Pts
(healed erosive 6 months 10 mg E od (n=91) 54.2
oesophagitis) 20 mg E od (n-98) 78.7
40 mg e od (n=92) 87.9
Placebo od (n=94) 29.1
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
GORD, 318 Pts 10 mg E od (n=77) 57.1
Healed 6 months 20 mg E od (n=82) 93.2
Oesophagitis) 40 mg E od (n=77) 93.6
Placebo od (n=77) 29.0
(p<0.01 vs
placebo)
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
-
4. Healing of H.pylori-associated duodenal ulcer and prevention
of relapse of peptic ulcer.
A randomized, double-blind study found that neither healing nor
H.pylori eradication rates differed significantly between patients
receiving
triple therapy with esomeprazole or omeprazole. H.pylori eradication
was
determined by [1 3C] - urea breath test and histology at (four weeks
after the
end of therapy.
A further randomized, double-blind study'4 comparing the effects o1
seven-day triple therapy with esomeprazole or omeprazote was conducted
in 448 H.pylori-positive patients with inactive duodenal ulcer
disease.
Eradication of H.pylori infection was confirmed by negative [13 C]-
urea
breath test at weeks four and eight. No statistically significant
difference in
eradication rate was noted between the groups.
Ulcer Healing/Prevention of relapse
Study Study Treatment Regimen Outcome (ITT
Analysis)
Population Length
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
duodenal ulcer 4 weeks 20mg E bd+A and CI, ulcer healing and
(0.5 cm 1 weeks triple followed by 3 weeks H.pylori eradication
diameter and therapy plus 3 placebo (n=222) occurred in
H.pylori- wee ks 20 mg O bd+A CI, 91% (95% CI 87%-95%)&
positive monotherapy / followed by 3 weeks 86% (95 CI 81%-90%)
446 pts 13 placebo O 20 mg (n=224) of pts in the E group & 92% (95% CI 88-95%) & 88% (95% CI 83-92%)
for those receiving O.
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
H.pylori positive 7 days triple 20 mg E bd+A and H.pylori eradication
History of therapy CI (n=224) rates (% pts) were
Duodenal ulcer, 20 mg O bd+A and 89.7%.
448 pts 14 CI (n=224) (95% CI 84.7-93.5%)
& 87.8 * 95% CI
82.3-92.0%
in the E and O group,
respectively.
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
E = Esomeprazole
O = Omeprazole
A =Amoxycillin1000mgbd
Cl = Clarithromycin 500 mg bd
Approved indications:
1. Gastro-esophageal Reflux Disease (GERD) :
a) Treatment of symptomatic GERD.
b) Healing of erosive oesophagitis
c) Long term maintenance therapy to prevent relapse of GERD.
2. Eradication of H.pylori to reduce recurrence of duodenal ulcer.
(In combination with appropriate antibacterials).
3. Healing of duodenal ulcers associated with H.pylori infection
Dosage and administration:
The recommended adult dosage and duration of therapy of esomeprazole
Is as follows :
Indication Dose (mg) Duration
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Healing of erosive oesophagitis 20-40 4-8 Weeks
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Symptomatic relief of GERD 20 4 Weeks
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
To Prevent relapse of GERD 20 Once daily for upto
6 months
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
For eradication of H.pylori 40 Once daily for
Infection 10 days
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* = For patients who do not respond after 4-8 weeks, an additional 4-8
week of treatment
may be considered.
** = In combination with : Amoxycillin lgm BD + Clarithromycin 500mg
BD.
Esomeprazole should be taken at least one hour before meal
Dose adjustment in special populations :
1. There is no need to adjust its dose in elderly patients (>65
years), ii
patients with renal dysfunction and in patients with mild to moderate
live
impairment (Child Pugh classes A & B).
2. For patients with severe liver impairment (Child Pugh Class C), a
dose c
20 mg of esomeprazole should not be exceeded.
Safety Profile :
The safety of esomeprazole was evaluated in over 10,000 patients (aged
1 8
- 84 years) during worldwide clinical trials. Over 2,900 patients were
treated
in long term studies for up to 6-12 months.
The adverse effect profile for esomeprazole is similar to that
reported for
other PPIs. In general, it was well tolerated by majority of patients
in both
short and long term studies.
In comparative clinical trials, the most frequently observed adverse
effects
of esomeprazole therapy were headache, abdominal pain, diarrhoea,
flatulence, nausea and dry mouth.
Long term safety:
In more than 1,000 patients who received esomeprazole for up to 6-12
months, there was an increase in the prevalence of ECL cell
hyperplasia. This
finding is consistent with the pharmacological action of a PPI. No
patient
developed ECL cell carcinoids, dysplasia or neoplasia in the gastric
mucosa.
Atrophic gastritis has been noted occasionally in gastric biopsies
from
patients treated long-term with omeprazole, of which esomeprazole is an
enantiomer.
Drug interactions:
Like other PPIs, esomeprazole may interfere with the absorption of
drug
where gastric pH is an important determinant of bioavailability.
1. Esomeprazole may increase absorption of digoxin by about 10%.
This
slight increase in digoxin absorption is likely to be of little or
no clinical
consequence.
2. Increase in gastric pH with esomeprazole therapy may lead to
decreased absorption of weak bases such as ketoconazole,
itraconazole
and cefpodoxime proxetil.
3. Antacids do not appear to influence the absorption of
esomeprazole.
4. In vitro & in vivo studies have shown that esomeprazole is not
likely
to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 & 3A4. No clinically
relevant
interactions with drugs metabolized by these CYP enzymes would be
expected. Drug interaction studies have shown that esomeprazole does
not have any clinically significant interactions with amoxycillin,
clarithromycin, phenytoin, warfarin, diazepam or quinidine.
Precautions:
1. Exclude malignancy before starting therapy in patients with
gastric ulcer.
2. Efficacy and safety of esomeprazole in paediatric patients and
in pregnant women have not been established.
3. Use in nursing mothers :
The excretion of esomeprazole in breast milk has not been studied.
However, omeprazole concentrations have been measured in breast milk
following administration of 20mg dose.
Because esomeprazole is likely to be excreted in breast milk and
because of the potential for serious adverse reactions in nursing
infants,
a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug
to the mother.
Contraindications:
Esomeprazole is contraindicated in patients with known
hypersensitivity to substituted benzimidazoles or to any component of
the formulation.