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Oral esomeprazole vs. intravenous pantoprazole: a comparisonof the effect on intragastric pH in healthy subjects
D. ARMSTRONG*, D. BAIR*, C. JAMES*, L. TANSER� , S. ESCOBEDO� & K. NEVIN�*Division of Gastroenterology, McMaster University & Hamilton Health Sciences, Hamilton, ON, Canada; and �AstraZeneca
Canada Inc., Mississauga, ON, Canada
Accepted for publication 10 July 2003
SUMMARY
Background: Intravenous (IV) proton-pump inhibitor
therapy is used in patients who cannot take oral
medications or require greater acid suppression. Oral
esomeprazole produces greater acid suppression than
oral pantoprazole; however, no comparative data exist
for oral esomeprazole and IV pantoprazole.
Aim: To compare acid suppression (time with pH > 3.0,
4.0, 5.0 and 6.0) produced by standard doses of oral
esomeprazole and IV pantoprazole in healthy subjects.
Methods: A randomized, two-way crossover study in
30 subjects receiving oral esomeprazole (40 mg o.d.)
or IV pantoprazole (40 mg o.d.) for 5 days followed by
a 2-week washout period before the second 5-day drug
administration period using the crossover drug
regimen.
Results: Oral esomeprazole produced greater acid sup-
pression than IV pantoprazole on day 1 [pH > 3.0
(56.9%, 35.8%; P < 0.001), pH > 4.0 (43.4%, 25.0%;
P < 0.001) and pH > 5.0 (28.7%, 15.6%; P < 0.001)]
and on day 5 [pH > 3.0 (70.4%, 45.9%; P < 0.001),
pH > 4.0 (59.2%, 33.9%; P < 0.001), pH > 5.0
(45.5%, 23.9%; P < 0.001) and pH > 6.0 (19.6%,
12.6%; P ¼ 0.045)]. The adverse event profiles indica-
ted both treatments to be safe and well tolerated.
Conclusions: In healthy subjects, esomeprazole, 40 mg
o.d. dispersed in water, produces greater acid suppres-
sion than pantoprazole 40 mg IV o.d. after 1 and 5 days
of medication.
INTRODUCTION
Oral proton-pump inhibitor therapy produces a high
degree of acid suppression and is very effective for the
management of acid-related disorders. High-dose, intra-
venous proton-pump inhibitor therapy given as a bolus
followed by a continuous infusion is recommended for
patients with upper gastrointestinal haemorrhage;
intravenous proton-pump inhibitor therapy may also
be required for patients who are unable to take oral
medication.1, 2 Currently, pantoprazole is the only IV
proton-pump inhibitor commercially available in North
America, and its use in the hospital environment has led
to increasing concerns about appropriate use of IV acid
suppressants and the potential for increased costs.3, 4
With this in mind, oral proton-pump inhibitors might be
prescribed more readily for hospital inpatients if it could
be shown clearly that they are comparable to IV proton-
pump inhibitors.
Esomeprazole, the S-isomer of omeprazole, has an
improved pharmacokinetic profile leading to greater
acid suppression than that produced by omeprazole,
pantoprazole, lansoprazole and rabeprazole.5 In clinical
studies, the greater acid suppression produced by
esomeprazole has translated into higher healing rates
and more effective symptom relief when compared to
lansoprazole and omeprazole in gastro-oesophageal
Correspondence to: Dr D. Armstrong, Division of Gastroenterology, HSC-
4W8, McMaster University Medical Centre, 1200 Main Street West,
Hamilton, Ontario L8N 3Z5, Canada.
E-mail: armstro@mcmaster.ca
Aliment Pharmacol Ther 2003; 18: 705–711. doi: 10.1046/j.1365-2036.2003.01743.x
� 2003 Blackwell Publishing Ltd 705
reflux disease (GERD) patients.6–8 A recent study
showed no difference between the oral and IV formu-
lations of pantoprazole (20 and 40 mg) with respect to
reduction of gastric acid output in patients with GERD.9
Furthermore, subjects who received 30 mg of lansop-
razole (administered nasogastrically with apple sauce)
demonstrated a higher 24-h intragastric pH and
sustained more intragastric pH than when they received
40 mg of pantoprazole IV.10 Thus, it can be postulated
that oral esomeprazole will produce acid suppression
greater than that produced by IV pantoprazole.
Oral esomeprazole, which is available in many coun-
tries as a dispersible, multiple-unit, enteric-coated pellet
formulation, can be used in patients with a nasogastric
tube in situ. Stability data for the multiple unit pellet
system (MUPS) tablet has shown the enteric-coated
pellets to remain intact for up to 30 min when dispersed
in water or in apple sauce and to be bioequivalent to the
intact tablet.11, 12 The purpose of this study was to
compare the pharmacodynamics, and thereby the
degree of acid suppression, produced by standard doses
of oral esomeprazole and IV pantoprazole by comparing
the median 24-h pH values and the percentages of the
24-h recording period during which intragastric pH was
greater than 3, 4, 5 and 6 on days 1 and 5 of drug
administration in healthy Helicobacter pylori negative
subjects. The primary hypothesis of this study was that
oral esomeprazole administered as an oral suspension
produces greater acid suppression than IV pantoprazole,
as indicated by the time during which intragastric pH is
greater than 4.0 on day 1 of drug administration.
MATERIALS AND METHODS
Subjects
Thirty healthy male and female subjects participated in
a single-centre study at the McMaster University
Medical Centre site of Hamilton Health Sciences.
Subjects were enrolled if a prescreen assessment
indicated a normal medical history, physical examina-
tion, electrocardiogram (ECG) and laboratory findings.
Inclusion in the trial required written informed
consent from the subject, a body mass index (BMI)
between 19 and 27 kg/m2 and weight between 50 and
100 kg. Absence of H. pylori infection was established
by 13C-urea breath test (UBT) (Isodiagnostika Inc.,
Edmonton, AB, Canada); breath samples were analysed
at McMaster University Medical Centre by isotope ratio
mass spectrometry according to standard protocols
(Breath Mat, Finnigan Mat, Bremen, Germany). The
major exclusion criteria were the presence of any
upper gastrointestinal tract symptoms, any significant
concurrent disease or clinical illness during 14 days
prior to enrolment, a blood donation or the use of an
investigational drug or device within 12 weeks prior to
enrolment, the use of prescription drugs within
14 days prior to baseline pH recording, or the use of
over-the-counter drugs within 7 days prior to the
baseline visit; acetaminophen and oral contraceptives
were permitted. Proton-pump inhibitors, prokinetic
agents, antibiotics and bismuth-containing compounds
were not allowed for 30 days prior to baseline
recordings. Subjects with a history of past or current
drug or alcohol abuse were ineligible, as were female
subjects who were pregnant or lactating.
Design
This was a randomized, open-label, two-way crossover
study. After an initial prescreen visit to determine
eligibility and a 24-h baseline pH recording within
2 weeks of drug administration, subjects were random-
ized to initial therapy with either oral esomeprazole
(40 mg o.d.), administered as an oral suspension or
IV pantoprazole (40 mg o.d.) for five consecutive days.
This was followed by a 2-week washout period before
the second 5-day drug administration period using the
crossover drug regimen. Subjects were instructed not to
smoke or use alcohol at any time during the trial
(Figure 1).
Oesophageal manometry was performed during the
prescreen visit to determine the location of the lower
oesophageal sphincter (LOS). The pH electrode was
passed transnasally into the stomach and positioned
10 cm below the manometrically defined LOS. Sequen-
tial gastric pH values were recorded every 4 s by the
data recorder, and then downloaded to a native format
Esomeprazole(oral 40 mg od)
Pantoprazole(IV 40 mg od)
Day 1 5 Day 1 5
pH pH
Washout Period> 14 days
Esomeprazole(oral 40 mg od)
Pantoprazole(IV 40 mg od)
pHpHpHBaseline
Pre-screen
Observation> 7 days
Figure 1. Study flow chart.
706 D. ARMSTRONG et al.
� 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 705–711
Medtronic pH data file before conversion to an ASCII file
for analysis. Analysis of pH data was performed
according to established techniques using dedicated
software for summary and graphical presentation.13 In
all, five ambulatory pH recordings were performed using
a single-channel, internally referenced glass pH elec-
trode (Ingold M440, Medtronic) attached to a Digitrap-
per III pH data recorder (Medtronic, Mississauga, ON,
Canada); one 24-h recording was performed on days 1
and 5 of drug administration after an initial, baseline
pre-treatment recording.
Subjects fasted from midnight until the start of the
recording the following morning, and were then
provided with one of two standard nutrition regimens
based on body weight. Each regimen consisted of three
meals and one snack for each day of pH recording.
Breakfast was taken 1 h following pH probe place-
ment, lunch was taken between 12:00 and 13:00,
dinner between 18:00 and 19:00 and a light snack at
20:00. Routine clinical chemistry and haematology
were performed at the prescreen visit and on day 5 of
drug administration for evaluation of safety data (Core
Laboratory, Hamilton Health Sciences, Hamilton, ON,
Canada). A serum human chorionic gonadotropin
(hCG) test was performed for all female subjects at
the prescreen visit, day 1 of the second drug admin-
istration period and on the final visit. A follow-up
telephone contact was arranged 2 weeks following the
last visit (the fifth day of drug administration during
the second crossover treatment period) to monitor
subjects for ongoing adverse events.
Study drug
Esomeprazole MUPS tablets (rapid dispersible formula-
tion; AstraZeneca R & D, Molndal, Sweden) 40 mg,
were taken orally once each morning on the days of
drug administration. Tablets were dispersed in 100 mL
of noncarbonated, room-temperature water and stirred
for approximately 2 min, until the tablet had dispersed
completely; stability data indicate that the enteric-
coated pellets of esomeprazole remain intact for up to
30 min after dispersal in water.11 The solution was
drunk within 15 min of dispersal and the glass was
rinsed with 100 mL of water, which was drunk
immediately to ensure ingestion of any tablet residue.
Pantoprazole IV solutions were also administered once
daily in the morning. The solution was prepared by
injecting 10 mL of 0.9% NaCl into the vial containing
the dry lyophilized powder (pantoprazole 40 mg; pan-
toprazole sodium 42.3 mg; Altana Pharma, Constanz,
Germany). The reconstituted solution, diluted with
90 mL of 0.9% NaCl injection, was infused over
15 min and used within 6 h of preparation.
Statistics
The number of subjects was calculated to demonstrate
that oral esomeprazole (40 mg o.d.) is more effective in
controlling intragastric pH, to IV pantoprazole (40 mg
o.d.) by at least 6% with respect to the percentage of
time during which pH was greater than 4.0 on day 1.
Assuming a within-subject standard deviation of 11%,
detection of a difference of this magnitude, with a power
of 0.8 and a type I error of 0.05, required 26 subjects.
Assuming a dropout rate of 20% (including protocol
violators, technical failures and withdrawals), 30 vol-
unteers were included.
For each 24-h recording period the median 24-h pH
was calculated. Statistical analysis used parametric
tests and presented the data as the mean of the median
24-h pH values. A mixed analysis of variance (anova)
was carried out for the percentage of time that gastric
pH was greater than 3.0, 4.0, 5.0 and 6.0, with the
mean of the 24-h median pH as the dependent
variable, the sequence, period and treatment as fixed
effect factors, and the subject as a random effect factor.
Confidence intervals and P-values were used to assess
the treatment effects within and between treatments.
Ninety-five percent confidence interval estimates of the
individual true mean effects, least-square means (LSM)
of percentage time pH > 3.0, 4.0, 5.0 and 6.0 were
calculated. The percentages of subjects having a pH
greater than 3.0, 4.0, 5.0 and 6.0 for the first 4 h of
each recording were also calculated and compared
between treatments for day 1 using the v2-test.
Likewise, the number of subjects that maintained their
pH greater than 4.0 during 12 and 16 h after drug
administration during both days 1 and 5 were
compared between esomeprazole and pantoprazole
using McNemar’s test. A spline interpolation was used
to smooth the individual pH data for the 24-h pH data
plot.
RESULTS
Thirty subjects were randomized and received at least
one dose of study medication. Two subjects were
GASTRIC pH WITH ORAL ESOMEPRAZOLE OR IV PANTOPRAZOLE 707
� 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 705–711
excluded from selected analyses due to technical failures
leading to the loss of pH and other data; one subject had
incomplete pH data and the other had incomplete
demographic data, pK data and pH data due to technical
failure. Demographics for the 29 subjects with complete
pH data (20 males; 9 females) showed a mean (s.d.) age
of 25.3 (5.9) years, weight 77.5 (10.5) kg, height
175.4 (9.3) cm and BMI 25.1 (1.9) kg/m2.
Oral esomeprazole produced a significantly greater
percentage of time during which pH was greater than
4.0 compared to pantoprazole IV on day 1 of drug
administration (43.4, 25.0; P < 0.001). Similarly, on
day 1 of drug administration, oral esomeprazole
produced a significantly greater percentage of time with
pH greater than 3.0 (56.9, 35.8) and 5.0 (28.7, 15.6)
(P < 0.001) compared with IV pantoprazole. There
were no significant differences between the two
treatments with respect to the percentage of time with
pH > 6.0 on day 1 (10.5, 7.5; P ¼ 0.27). Similar
results were observed on day 5; oral esomeprazole
produced a significantly greater percentage of time with
pH greater than 3.0 (70.4, 45.9), 4.0 (59.2, 33.9), 5.0
(45.5, 23.9) (P < 0.001 for all) and 6.0 (19.6, 12.6;
P ¼ 0.045) compared with IV pantoprazole (Figure 2).
Oral esomeprazole produced a greater increase in
intragastric pH on day 1 that was evident throughout
the 24-h recording periods, compared with IV pantop-
razole (Figure 3). At baseline the group mean value
% 2
4-hr
rec
ordi
ng
0
10
20
30
40
50
60
70
80
90
100
pH > 4.0 pH > 5.0 pH > 6.0pH > 3.0
pH threshold
* P < 0.05
** P < 0.001
****
**
**
**
**
*
Esomeprazole day 1Pantoprazole day 1Esomeprazole day 5Pantoprazole day 5
Figure 2. Mean percentages of the 24-h
recording period (95% CI) on day 1 (first 2
bars) and day 5 (last 2 bars) during which
intragastric pH exceeded thresholds of 3.0,
4.0, 5.0 and 6.0 for esomeprazole (dark
bars) and pantoprazole (light bars).
Med
ian
pH
B L D Sn
Day 1
Figure 3. Median 24-h intragastric pH
curves (n ¼ 28) for day 1 showing the
baseline pH curve (before therapy) as a
reference for each graph (solid line,
esomeprazole; dashed line, pantoprazole).
Arrows indicate the timing of the standard
meals (B, breakfast; L, lunch; D, dinner;
Sn, snack).
708 D. ARMSTRONG et al.
� 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 705–711
[95% confidence interval (CI)] for the median 24-h pH
was 1.75 (1.63–1.87), and on day 1 oral esomeprazole
[mean 3.6 (3.2–4.0)] produced a higher median 24-h
pH than IV pantoprazole [2.5 (2.1–2.9); P < 0.001].
This difference was maintained (Figure 4) at day 5 [oral
esomeprazole: 4.6 (4.2–5.0) compared with IV panto-
prazole: 2.9 (2.5–3.3); P < 0.001].
Intragastric pH was greater than 4.0 for 12 or more
hours in 35.7% and 3.6% of esomeprazole and pantop-
razole subjects, respectively, on day 1 (P ¼ 0.002) and
85.7% and 7.1%, respectively, on day 5 (P < 0.0001).
Esomeprazole maintained gastric pH > 4.0 for greater
than 16 h in 7.1% of patients compared with 3.6% for
pantoprazole on day 1 (P > 0.05), and in 32.1% of
patients compared with 3.6% pantoprazole on day 5
(P ¼ 0.005) (Figure 5).
Intragastric pH during the first 4 h of the recording on
day 1 was greater than 5.0 (esomeprazole, 96.4%;
pantoprazole, 64.3%; P < 0.01) and 6.0 (esomeprazole,
60.7%; pantoprazole, 25%; P < 0.05) in a greater
proportion of subjects after oral esomeprazole than after
IV pantoprazole; a similar trend was seen for pH greater
than 3.0 (esomeprazole, 100%; pantoprazole, 96.4%;
P > 0.05) and 4.0 (esomeprazole, 96.4%; pantoprazole,
85.7%; P > 0.05) (Figure 6). Analysis of pharmaco-
kinetic data indicates that both study drugs achieved
adequate drug levels indicative of subject compliance
with the administration schedules.
There were no significant differences in the incidence
of adverse events between the two treatments. The most
commonly reported adverse events for both treatments
were headache, sore throat, bloating and diarrhoea.
Both drugs were safe and well tolerated in all subjects.
DISCUSSION
The results of the present study are consistent with the
results of previous comparative studies. As oral
esomeprazole (40 mg o.d.) produces a greater reduc-
tion in gastric acidity than oral pantoprazole (40 mg
o.d.),14 it had been hypothesized that oral esomepraz-
ole (40 mg o.d.) would produce a greater increase in
Med
ian
pH
B L D Sn
Day 5
Figure 4. Median 24-h intragastric pH
curves (n ¼ 28) for day 5 showing the
baseline pH curve (before therapy) as a
reference for each graph (solid line, eso-
meprazole; dashed line, pantoprazole). Ar-
rows indicate the timing of the standard
meals (B, breakfast; L, lunch; D, dinner; Sn,
snack).
Esomeprazole
Pantoprazole
Day 1 Day 5
12 hours 16 hours12 hours 16 hours
35.7% 7.1% 85.7% 32.1%
3.6% 3.6% 7.1% 3.6%
Figure 5. Percentage of subjects who had
an intragastric pH greater than 4.0 for 12
and 16 h (or more) per day during
treatment on days 1 and 5 with esomep-
razole and pantoprazole.
GASTRIC pH WITH ORAL ESOMEPRAZOLE OR IV PANTOPRAZOLE 709
� 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 705–711
gastric pH than intravenous pantoprazole (40 mg
o.d.). This hypothesis was confirmed unequivocally,
and although the degree of acid suppression produced
by both proton-pump inhibitors increased from day 1 to
day 5 of administration, the difference between the
two proton-pump inhibitors was, if anything, greater
at day 5. Furthermore, oral esomeprazole produced a
greater increase in pH during the first 4 h after drug
administration on day 1, indicating that IV adminis-
tration does not necessarily produce a faster onset of
action.
For patients with acid-related disorders such as erosive
oesophagitis and peptic ulcer disease, lesion healing and
symptom relief are related directly to the degree of acid
suppression achieved by medical therapy.15–18 Proton-
pump inhibitors are the most effective acid-suppressing
agents currently available and, in the vast majority of
patients, oral proton-pump inhibitors are highly effect-
ive therapeutic agents for most acid-related disorders.
Indeed, the indications for intravenous or enteral
proton-pump inhibitor administration are quite limited;
patients requiring proton-pump inhibitors who cannot
take anything by mouth should receive their medication
intravenously. However, it is not uncommon for IV
proton-pump inhibitors to be used for patients who are
unable to swallow, even if there is a nasogastric tube
in situ. This may be due, in part, to a perception that an
oral proton-pump inhibitor is less effective than an
intravenous formulation and, in part, to concerns that
oral proton-pump inhibitors cannot be administered
easily via a nasogastric tube.
Oral esomeprazole, the S-isomer of omeprazole, has
higher bioavailability than either the R-isomer or
racemic omeprazole, and it produces a greater degree
of acid suppression at a standard, once-daily dose, with
a higher median 24-h pH, and a greater proportion of
the 24-h recording period during which gastric pH
exceeds 4.0.19 More recently, it has been reported that
oral and intravenous pantoprazole are also equivalent,
even when administered at a high dose (280–290 mg
daily) in healthy volunteers, comparable to doses used
for the management of upper gastrointestinal tract
haemorrhage (80 mg bolus, followed by an infusion of
8 mg/ h).19, 20
This study was conducted in healthy subjects, and the
results should therefore be extrapolated with caution to
patients in an intensive care unit (ICU) and those who
are being treated for upper gastrointestinal bleeding.
The baseline pH data indicate that all subjects had
normal gastric secretory function, unlike some ICU
patients in whom gastric acid secretion may be
compromised by severe concomitant illness. The route
of administration is also important, particularly for ICU
patients. Patients being treated for upper gastrointesti-
nal haemorrhage may be able to take oral medication,
but many ICU patients can take medications only
intravenously or via a nasogastric tube. In the present
study, esomeprazole was not administered nasogastri-
cally; however, given that the total volume of the
suspension is only slightly larger than that which can
be given nasogastrically, and given that the dispersed
MUPS tablet is bioequivalent to the intact tablet, it is
unlikely that the administration of an oral suspension
altered the observed intragastric pH significantly.8
Subjects in this study were not fasted, and the effect of
food ingestion on gastric pH is evident in the mean pH
curves, with pH rises occurring at 3, 6 and 12 h after
the start of the recordings (Figures 3 and 4). However,
subjects took the same standardized meals throughout
all recording periods, so the observed difference between
the two medications is very unlikely to have been meal-
related. Although the present study was conducted in
healthy subjects, there is no indication from previous
studies that differences between proton-pump inhibitors
are limited to a specific subset of individuals. The effect
of oral esomeprazole, compared with intravenous
proton-pump inhibitors, should now be tested in ICU
patients able to take proton-pump inhibitors by mouth
or nasogastric tube. In addition, these data may also
provide a basis for an appropriate transition from
intravenous to oral proton-pump inhibitor therapy for
hospital inpatients; this has important cost implications
because there are now increasing data to indicate that
pH>3.0 pH>4.0 pH>5.0 pH>6.0
Per
cent
age
of S
ubje
cts
0102030405060708090
100
Esomeprazole
Pantoprazole
pH threshold
N.S. N.S.P < 0.01
P < 0.05
Figure 6. Mean percentages of the initial 4-h segment of the
recording period (95% CI) on day 1 during which intragastric pH
exceeded thresholds of 3.0, 4.0, 5.0 and 6.0 for esomeprazole
(white columns) and pantoprazole (grey columns).
710 D. ARMSTRONG et al.
� 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 705–711
much of the current inappropriate use of intravenous
proton-pump inhibitors is due to a delayed transition to
oral medication rather because of an inappropriate
institution of intravenous therapy.3, 4, 21 The results of
this study demonstrated that oral esomeprazole dis-
persed in water produced greater intragastric acid
suppression than IV pantoprazole in equal doses
(40 mg o.d.). It is also possible, at higher doses than
those used in the current study, that oral therapy with
esomeprazole may produce greater acid suppression, at
equivalent doses, than IV pantoprazole.
ACKNOWLEDGEMENTS
Supported by an unrestricted grant from AstraZeneca
Canada Inc, Mississauga, ON, Canada.
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GASTRIC pH WITH ORAL ESOMEPRAZOLE OR IV PANTOPRAZOLE 711
� 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 705–711