Alimentary Pharmacology and Therapeutics

An open-label, parallel, multiple-dose study comparing the

pharmacokinetics and gastric acid suppression of rabeprazole
extended-release with esomeprazole 40 mg and rabeprazole
delayed-release 20 mg in healthy volunteers
G. Morelli*, H. Chen , G. Rossiter , B. Rege  & Y. Lu 

https://doi.org/10.1111/j.1365-2036.2011.04580.x

*St. Mary’s Hospital, McGill SUMMARY

University, Westmount, Montreal, QC,
Canada.
Eisai Inc., Woodcliff Lake, NJ, USA.
Correspondence to:
Dr H. Chen, Eisai Inc., 155 Tice Blvd,
Woodcliff Lake, NJ 07869, USA.
E-mail: huachun_chen@eisai.com
Publication data
Submitted 24 November 2010
First decision 30 November 2010
Resubmitted 5 January 2011
Accepted 6 January 2011
EV Pub Online 28 January 2011
Background
Novel rabeprazole extended-release (ER) formulations were developed to
provide prolonged gastric acid suppression and potentially improved clini-
cal outcomes in GERD patients.
Aim
To evaluate the pharmacodynamics and pharmacokinetics of six rabeprazole-ER
formulations vs. esomeprazole 40 mg and rabeprazole delayed-release (DR) 20 mg.
Methods
Helicobacter pylori-negative healthy subjects were randomised to receive one of
eight treatments once daily for 5 days. Twenty-four-hour intragastric pH was
monitored on days )1, 1 and 5. Rabeprazole plasma concentrations were mea-
sured on day 5.

Results
A total of 248 subjects (N = 31 ⁄ group) were enrolled in the study. On day 5, rabep-
razole-ER groups provided mean durations of 18.5–20.2 h (77.0–84.1% of 24-h)
with intragastric pH >4.0 vs. esomeprazole 40 mg (15.9 h ⁄ 66.1% of 24-h) and rab-
eprazole-DR 20 mg (15.2 h ⁄ 63.2% of 24-h). A similar increase was observed on
day 1. While percentage of daytime (8 AM–10 PM) with intragastric pH >4.0 on day
5 was overall similar across the groups, percentage of night-time (10 PM-8 AM) with
intragastric pH >4.0 was higher with the rabeprazole-ER groups (57.0–72.4%) vs.
esomeprazole 40 mg (32.8%) and rabeprazole-DR 20 mg (34.0%).

Conclusion
Rabeprazole-ER once daily for 5 days demonstrated a significantly longer dura-
tion of gastric acid suppression in 24 h vs. esomeprazole 40 mg and rabeprazole-
DR 20 mg. The increase in acid suppression was predominantly due to prolonged
acid suppression during the night-time; this was supported by the extended-
release phamacokinetic characteristics.

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doi:10.1111/j.1365-2036.2011.04580.x
G. Morelli et al.
INTRODUCTION
Proton pump inhibitors (PPIs) are substituted benzimi-
dazoles that effectively reduce gastric acid by covalently
binding to the H+,K+-ATPase in the gastric parietal cells,
thereby blocking the final step of acid secretion. As a
result, PPIs have been the cornerstone in the manage-
ment of gastro-oesophageal reflux disease (GERD).1–3
Despite the high degree of efficacy of PPIs, some
patients may not achieve the desired outcome with a
once-daily treatment regimen, partly due to the limited
duration of acid control throughout the 24-h period. For
example, patients with moderate-to-severe erosive GERD
[Los Angeles (LA) grade C or D] showed lower healing
rates than those with mild disease (LA grade A or B)
after 4–8 weeks of once-daily treatment,4–9 as the sever-
ity of oesophagitis is associated with the duration of
oesophageal acid exposure.3, 10 Evidence suggests that
intragastric acid suppression, as assessed by percentage
of the 24-h period gastric pH >4.0, is positively corre-
lated with healing of erosive oesophagitis.11, 12 These
data suggest that unmet needs in some GERD patients
such as patients with moderate-to-severe oesophagitis
may be addressed by a PPI agent with a longer duration
of acid suppression.
Conventional delayed-release PPI formulations includ-
ing the approved rabeprazole sodium delayed-release
(rabprazole-DR) tablets have relatively short plasma
elimination half-lives9, 13–16 and proton pumps synthes-
ised and activated after PPI plasma levels fall will not be
inhibited. For this reason, gastric acid suppression
diminishes for part of the night-time period if once-daily
dosing occurs in the morning.17 Maintaining the plasma
exposure of a PPI over a longer period within the 24-h
duration has the potential to provide improved gastric
acid control, thereby leading to potentially better clinical
outcomes such as healing of moderate-to-severe erosive
oesophagitis.
Based on these findings, novel extended-release (ER)
formulations of rabeprazole were developed. Each rabep-
razole-ER prototype formulation contained a single rab-
eprazole enteric-coated tablet and multiple rabeprazole
pulsatile release tablets. The enteric-coated tablet was
designed to release rabeprazole in the proximal small
intestine and the pulsatile release tablets to release the
drug in the distal small intestine and colon in a non-pH-
dependent manner. This combination was designed to
not only provide initial acid suppression similar to the
delayed-release tablet, but also to maintain sufficient
plasma exposures over the 24-h period to have a pro-
longed pharmacodynamic effect.
846
This study was designed to evaluate the pharmacody-
namic (intragastric pH profile) and pharmacokinetic pro-
files of six once-daily rabeprazole-ER prototype
formulations by comparing with the currently marketed
esomeprazole 40 mg and rabeprazole-DR 20 mg. In
addition, the safety and tolerability of the six rabepraz-
ole-ER formulations were evaluated.
MATERIALS AND METHODS
This was a randomised, open-label, multiple-dose, paral-
lel group study conducted in a single centre in Canada.
Subjects and study design
Study subjects included healthy males and nonpregnant,
nonlactating females aged 18–45 years, with a body mass
index from 18 to 30 kg ⁄ m2 at the time of screening. Key
exclusion criteria included a positive Helicobacter pylori
test performed at screening; a positive test for hepatitis B,
hepatitis C or human immunodeficiency virus; evidence
of drug abuse on urine test; a history of gastrointestinal
disorders or surgery likely to influence drug absorption; a
history of hypersensitivity reactions to any PPI, and a
need to use any prescription or over-the-counter medica-
tions (except multivitamins and oral contraceptives in
females) 2 weeks before screening and during the study.
Occasional use of acetaminophen was permitted (up to
2 g ⁄ day) at the discretion of the investigator.
Qualified subjects were randomly assigned in equal
proportions to receive 1 of the 8 treatments once daily
for 5 days. Each subject was randomised to treatment
only once. Prespecified randomization codes with con-
cealed allocation were generated by the Sponsor. Subjects
received daily oral doses of study drugs with 240 mL
water, under fasting conditions at 8 AM with standardised
meals provided at 1, 5 and 10 h post dose and fluids
were restricted. The eight treatment groups included
groups 1 and 2 (G1, G2) which were esomeprazole
40 mg and rabeprazole-DR 20 mg, respectively; and
groups 3 through 8 (G3-G8) which were 6 different
rabeprazole-ER formulations. Each rabeprazole-ER
formulation contained 10 or 20 mg delayed-release
enteric-coated (EC) tablets and a varying number and
composition of pulsatile release (PR) tablets (30–60 mg
rabeprazole), with a combined total rabeprazole dose of
40–80 mg (Table 1). Of note, the different types of PR
tablets (Types C, D or F) differed in the compositions of
the coating of the PR tablets.
This study followed the guidelines of the 1996 declara-
tion of Helsinki and the International Conference on
Harmonisation (ICH) Good Clinical Practice (GCP), as
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Table 1 | Summary of treatment
groups Group
G1 (ESO 40 mg)
G2 (RAB-DR)
G3 (RAB-ER)
G4 (RAB-ER)
G5 (RAB-ER)
G6 (RAB-ER)
G7 (RAB-ER)
G8 (RAB-ER)
ESO, esomeprazole; RAB-DR, rabeprazole delayed-release; RAB-ER, rabeprazole
extended-release; EC, enteric-coated tablet; PR-C, pulsatile release Type C tablet; PR-D,
pulsatile release Type D tablet; PR-F, pulsatile release Type F tablet.
well as the requirements of national drug and data pro-
tection laws and other applicable regulatory require-
ments. The study protocol was reviewed and approved
by the appropriate regulatory authorities of the partici-
pating country and by the study centre’s institutional
review board before subjects were screened for entry.
Subjects provided written informed consent prior to
enrolment in the study.
Pharmacodynamic assessments
Two days before the first dose of study medication, the
lower oesophageal sphincter (LES) was located manomet-
rically. After an overnight fast, continuous intragastric
pH monitoring was commenced at approximately 7 AM,
2 h before breakfast, at baseline (day )1), days 1 and 5.
Intragastric pH was continuously recorded every 4 s over
the 24-h period using an ambulatory pH recording sys-
tem (Digitrapper 400; Medtronics, Minneapolis, MN,
USA), with a disposable antimony electrode and an
internal standard single-use pH catheter (Medtronic
Zinetics 24 or Medtronics Slimline; Medtronics). The pH
catheter was inserted intranasally and was positioned
in the stomach 10 cm below the manometrically deter-
mined LES. Prior to insertion, the electrode was cali-
brated using standard commercial buffer solutions of pH
1 and pH 7. For each 24-h pH-monitoring interval, the
pH recording for each subject was downloaded from the
Digitrappers and processed using Medtronic Polygram
98 for Windows v.2.20.
All subjects were to be studied using the Medtronic
Zinetics 24 pH catheter. However, this catheter was dis-
continued by the manufacturer after 98 subjects com-
pleted the study (12 subjects ⁄ group randomised to
groups 1–3 or groups 5–7; 13 subjects ⁄ group randomised
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Rabeprazole extended-release acid suppression
Total
Formulation rabeprazole
Esomeprazole 40 mg –
Rabeprazole DR 20 mg 20 mg
10 mg EC + 10 mg PR-C + 10 mg PR-D + 10 mg PR-F 40 mg
20 mg EC + 20 mg PR-C + 20 mg PR-D + 20 mg PR-F 80 mg
10 mg EC + 40 mg PR-D 50 mg
10 mg EC + 40 mg PR-F 50 mg
10 mg EC + 30 mg PR-D 40 mg
20 mg EC + 40 mg PR-D 60 mg
to group 4 or group 8). Consequently, the remaining 150
subjects (19 subjects ⁄ group randomised to groups 1–7;
18 subjects randomised to group 8) were studied using
the Medtronic Slimline pH catheter. The 98 subjects
evaluated with the Zinetics 24 catheter and the 150 eval-
uated with the Slimline catheter were evenly distributed
among the eight treatment groups. A review of the base-
line pH data from all subjects showed that baseline pH
values recorded with the Slimline catheter were lower
than those recorded with the Zinetics 24 catheter. There-
fore, a conversion factor based on the Medtronic temper-
ature correction factors as described previously18 was
used to adjust the distribution of baseline gastric pH val-
ues recorded with the Slimline catheter so that it would
be the same as the distribution of baseline gastric pH
values recorded with the Zinetics 24 catheter. This
adjustment was then applied to all pH values recorded
with the Slimline catheter.
Pharmacokinetic assessments
For the measurement of plasma concentrations of
rabeprazole and its thioether metabolite, (2-[4-(3-meth-
oxypropoxy)-3-methyl-2-pyridinyl]-methyl]thio]-lH-benz-
imidazole, PTBI) for each treatment group (except group
1 for esomeprazole 40 mg), blood samples were collected
prior to the administration of the study drug on days 1
and 5, and at 1, 2, 3, 4, 6, 7, 8, 10, 12, 16, 20 and 24 h
following dosing on day 5. Plasma concentrations of
rabeprazole and PTBI were measured by Quest Pharma-
ceutical Services, LLC, Newark, Delaware using a vali-
dated LC ⁄ MS ⁄ MS assay. Each analytical run included
appropriate standards and quality control samples. The
lower limit of quantification (LLOQ) for this study was
5 ng ⁄ mL for both rabeprazole and PTBI.
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G. Morelli et al.
Endpoints
The primary pharmacodynamic endpoint was the per-
centage of time with gastric pH >4.0 in the 24 h post
dose on day 5. The secondary pharmacodynamic end-
point was the percentage of time with gastric pH >4.0 in
the 24 h post dose on day 1. Key exploratory pharmaco-
dynamic endpoints included the percentage of daytime
(8 AM–10 PM) and night-time (10 PM to 8 AM) with
gastric pH >4.0 on days 1 and 5; mean changes from
baseline in percentage of time pH >4.0 in 24-h period on
days 1 and 5; mean changes from baseline in percentage
of daytime and percentage night-time on days 1 and 5;
and mean changes from baseline in gastrin concentra-
tions on days 2, 5 and 6.
Pharmacokinetic parameters assessed for rabeprazole
and PTBI included the maximum observed plasma con-
centration (Cmax); time of maximum observed plasma
concentration (Tmax); area under the plasma concentra-
tion–time curve from time zero to time of the last quan-
tifiable plasma concentration (AUC(0–t)); time of the last
quantifiable plasma concentration (Tlast); and the last
quantifiable concentration (Clast).
Safety assessments
The safety and tolerability were monitored based on
adverse events reported by subjects, physical examina-
tion, clinical laboratory testing (haematology, chemistry,
urinalysis and serum gastrin), and 12-lead electrocardio-
grams (ECGs). Treatment-emergent adverse events were
defined as those started at or after the time of first dose,
or if they were present prior to the first dose and
increased in severity during the study. For measuring the
serum gastrin concentration, blood samples were col-
lected predose on day 1, and then on days 2, 5 and 6
approximately 24 h after the last daily dose was adminis-
tered.
Statistical analyses
Analyses of the 24-h gastric pH data were based on the
pharmacodynamic population, defined as all randomised
subjects completing the full course of treatment with at
least 21 h of valid pH data for each 24-h period. For
each subject, the mean percentage of time pH >4.0 over
each 24-h period was calculated based on recorded pH
data by 15-min interval with a total of 96 intervals over
the 24-h monitoring period. A mean and a 95% confi-
dence internal were constructed for each treatment
group and pair-wise comparisons of the mean percent-
age of time pH >4.0 between the treatment groups were
performed using the t-test. In addition, post hoc analysis
848
was performed to evaluate the number of subjects
achieving specified thresholds of durations of response
(number of hours over a 24-h period gastric pH >4.0)
for a rabeprazole-ER 50 mg group (G5) compared with
esomeprazole 40 mg and rabeprazole-DR 20 mg.
Pharmacokinetic analyses of rabeprazole and PTBI
were conducted based on the pharmacokinetic popula-
tion, defined as all subjects who received rabeprazole-DR
or rabeprazole-ER and had sufficient rabeprazole plasma
concentration data (i.e. the blood samples should be col-
lected for at least 2 ⁄ 3 of the sampling schedule). The
pharmacokinetic parameters for rabeprazole and PTBI
were derived by noncompartmental analysis of the day 5
plasma concentration–time data for the rabeprazole-DR
and the six rabeprazole-ER groups. Mean plasma con-
centrations at any individual time point were calculated
if at least two-thirds of the individual values were quanti-
fiable. Actual sample times were used in the calculations
of pharmacokinetic parameters which were summarised
by descriptive statistics.
Demographic and safety data were summarised by
treatment group using descriptive statistics based on the
safety population, defined as all randomised subjects who
received ‡1 dose of study medication.
Approximately 24 subjects per treatment group were
planned. This sample size was estimated to have 80%
power to detect a 13% difference between a rabeprazole-
ER formulation and the rabeprazole-DR 20 mg with
respect to the primary pharmacodynamic endpoint (per-
centage of time intragastric pH >4.0 during the 24-h per-
iod on day 5)19 assuming a 15% standard deviation and
a two-sided test with alpha = 0.05 without adjusting for
multiplicity.
RESULTS
Subject characteristics
This study was conducted between March and June
2006. A total of 248 subjects (31 subjects per treatment
group) were randomised and dosed; 247 subjects com-
pleted the study. One subject discontinued from the
study due to an adverse event. The eight treatment
groups were overall balanced with respect to demo-
graphic characteristics (Table 2).
Pharmacodynamics
A total of 231 subjects were included in the pharmaco-
dynamic analyses. Rabeprazole-ER once daily for 5 days
provided mean durations of 18.5–20.2 h (77.0–84.1%) of
the 24-h period with intragastric pH >4.0 compared with
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Table 2 | Baseline subject demographics and clinical characteristics (safety population)

Aliment Pharmacol Ther 2011; 33: 845–854

Treatment group

G1 (ESO 40 mg) G2 (RAB-DR) G3 (RAB-ER) G4 (RAB-ER) G5 (RAB-ER) G6 (RAB-ER) G7 (RAB-ER) G8 (RAB-ER)

Characteristics N = 31 N = 31 N = 31 N = 31 N = 31 N = 31 N = 31 N = 31
Gender, n (%)
Male 23 (74.2) 25 (80.6) 19 (61.3) 23 (74.2) 22 (71.0) 18 (58.1) 18 (58.1) 18 (58.1)
Female 8 (25.8) 6 (19.4) 12 (38.7) 8 (25.8) 9 (29.0) 13 (41.9) 13 (41.9) 13 (41.9)
Race, n (%)
White 31 (100) 26 (83.9) 25 (80.6) 29 (93.5) 21 (67.7) 26 (83.9) 25 (80.6) 24 (77.4)
Black 0 (0.0) 2 (6.5) 4 (12.9) 0 (0.0) 1 (3.2) 4 (12.9) 2 (6.5) 3 (9.7)
Hispanic 0 (0.0) 3 (9.7) 2 (6.5) 1 (3.2) 9 (29.0) 1 (3.2) 2 (6.5) 3 (9.7)
Asian ⁄ Pacific 0 (0.0) 0 (0.0) 0 (0.0) 1 (3.2) 0 (0.0) 0 (0.0) 2 (6.5) 1 (3.2)
Age (years)
Mean (s.d.) 33.0 (8.4) 31.7 (6.8) 32.6 (7.2) 31.3 (7.4) 33.3 (6.4) 33.6 (7.2) 32.3 (8.3) 33.2 (7.4)
Body weight (kg)
Mean (s.d.) 72.6 (9.4) 73.0 (8.2) 71.0 (10.8) 73.3 (10.6) 71.3 (9.9) 69.6 (10.4) 66.9 (9.0) 71.8 (9.5)
Min, Max 54.7, 93.7 55.7, 88.2 52.9, 95.4 54.2, 96.4 50.0, 96.4 49.7, 88.5 52.6, 88.9 50.1, 91.0
ESO, esomeprazole; RAB-DR, rabeprazole delayed-release; RAB-ER, rabeprazole extended-release; s.d., standard deviation.
Rabeprazole extended-release acid suppression

849
G. Morelli et al.

Table 3 | Percentage of time gastric pH >4.0 during 24-h period on days 1 and 5 (pharmacodynamic population)
Mean % Time pH>4 in Mean % difference P value vs. ESO
24-h (s.d.) from ESO 40 mg 40 mg
Total
Group rabeprazole N Day 1 Day 5 Day 1 Day 5 Day 1 Day 5
G1 (ESO 40 mg) – 28 54.4 (17.8) 66.1 (10.0) NA NA NA NA
G2 (RAB-DR) 20 mg 29 45.2 (15.3) 63.2 (14.5) )9.25 )2.9 0.0399 0.3822
G3 (RAB-ER) 40 mg 28 59.0 (17.1) 77.0 (11.2) 4.6 10.9 0.3304 0.0003
G4 (RAB-ER) 80 mg 27 70.2 (11.6) 81.2 (11.4) 15.8 15.1 0.0003 <0.0001
G5 (RAB-ER) 50 mg 29 67.8 (12.1) 78.9 (12.2) 13.4 12.8 0.0015 <0.0001
G6 (RAB-ER) 50 mg 30 68.7 (16.6) 84.1 (12.8) 14.3 18.0 0.0026 <0.0001
G7 (RAB-ER) 40 mg 29 62.2 (16.8) 77.9 (10.6) 7.8 11.8 0.0965 <0.0001
G8 (RAB-ER) 60 mg 31 65.5 (13.5) 82.5 (15.4) 11.1 16.4 0.0091 <0.0001
ESO, esomeprazole; RAB-DR, rabeprazole delayed-release; RAB-ER, rabeprazole extended-release; s.d., standard deviation.

once-daily esomeprazole 40 mg (mean 15.9 h, 66.1% of
the 24-h period) and once-daily rabeprazole-DR 20 mg
(mean 15.2 h, 63.2% of the 24-h period, Table 3). All six
rabeprazole-ER formulations (G3-G8) demonstrated sta-
tistically significant increase vs. esomeprazole 40 mg
(10.9–18.0%; P < 0.001) and vs. rabeprazole-DR 20 mg
(13.8–20.9%, P < 0.001) in the mean percentage of time
with gastric pH >4.0 in the 24-h period on day 5
(Table 3). The mean percentage of time in 24-h period
with gastric pH >4.0 on day 1 was also increased with
the six rabeprazole ER formulations (59.0–70.2%) com-
pared with esomeprazole 40 mg (54.4%) and rabepraz-
ole-DR 20 mg (45.2%). The mean percentage of daytime
(8 PM–10 AM) with gastric pH >4.0 on days 1 and 5 for
the six rabeprazole-ER groups (89.4–93.0%) was overall
similar to that of the esomeprazole 40 mg group
(90.2%); but higher than that of rabeprazole-DR 20 mg
(83.9%, Table 4). The mean percentages of night-time
(10 AM–8 PM) with gastric pH >4.0 on days 1 and 5 were
higher with the six rabeprazole-ER formulations (57.0–
72.4%) compared with esomeprazole 40 mg (32.8%) and
rabeprazole-DR 20 mg (34.0%, Table 4). Results from
the exploratory pharmacodynamic endpoints were simi-
lar to those of the primary and secondary pharmacody-
namic endpoints.
The mean gastric pH profiles by 15-min interval dur-
ing the 24-h period on day 5 after treatment with the
rabeprazole-ER 50 mg (G5), esomeprazole 40 mg and

Table 4 | Percentage of time gastric pH >4.0 during the daytime (8 AM–10 PM) and night-time (10 PM–8 AM) period on
day 5 (pharmacodynamic population)
% Time pH>4.0 night-time on day
% Time pH>4.0 daytime on day 5 5

Total Mean difference Mean difference

Group rabeprazole N Mean (s.d.) from ESO 40 mg Mean (s.d.) from ESO 40 mg
G1 (ESO 40 mg) – 28 90.2 (6.9) – 32.8 (18.1) –
G2 (RAB-DR) 20 mg 29 83.9 (12.8) )6.3 34.0 (23.1) +1.2
G3 (RAB-ER) 40 mg 28 91.4 (6.1) +1.2 57.0 (22.8) +24.2
G4 (RAB-ER) 80 mg 27 93.0 (6.3) +2.8 64.7 (21.4) +31.9
G5 (RAB-ER) 50 mg 29 90.5 (6.0) +0.3 62.5 (23.5) +29.7
G6 (RAB-ER) 50 mg 30 92.4 (7.4) +2.2 72.4 (21.9) +39.6
G7 (RAB-ER) 40 mg 29 89.4 (7.0) )0.8 61.6 (19.3) +28.8
G8 (RAB-ER) 60 mg 31 92.4 (8.4) +2.2 68.6 (27.0) +35.8
ESO, esomeprazole; RAB-DR, rabeprazole delayed-release; RAB-ER, rabeprazole extended-release; s.d., standard deviation.

850 Aliment Pharmacol Ther 2011; 33: 845–854

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 Rabeprazole extended-release acid suppression

pH
3

Breakfast Lunch Dinner

Figure 1 | Mean gastric pH 1 (9:00 AM) (1:00 PM) (6:00 PM) Esomeprazole 40 mg
profiles (15 min average) for Rabeprazole-DR 20 mg
8:00 AM
rabeprazole-ER 50 mg (G5), Rabeprazole-ER 50 mg
esomeprazole 40 mg and rab- 0
–1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
eprazole-DR 20 mg.
Time (h)

Table 5 | Percentage of sub- % Subjects

jects who maintained gastric who maintained % Subjects who
pH >4.0 for at least 14 and gastric pH >4.0 maintained gastric
20 h of the 24-h period on for ‡14 of the 24-h pH >4.0 for ‡20
day 5 (pharmacodynamic Group N on day 5 of the 24-h on day 5
population) G1 (ESO 40 mg) 28 83.9 3.2
G2 (RAB-DR 20 mg) 29 61.3 9.7
G5 (RAB-ER 50 mg) 29 93.5 32.3
ESO, esomeprazole; RAB-DR, rabeprazole delayed-release; RAB-ER, rabeprazole
extended-release; s.d., standard deviation.

the rabeprazole-DR 20 mg are illustrated in Figure 1.
Post hoc analyses of duration of response for the G5
rabeprazole-ER 50 mg group revealed that a greater per-
centage of subjects had an overall longer duration with
gastric pH >4.0 when compared with esomeprazole
40 mg and rabeprazole 20 mg DR (Table 5). For exam-
ple, a greater percentage (mean 32.3%) of subjects in the
rabeprazole-ER 50 mg G5 maintained a gastric pH >4.0
for 20 h (i.e. 83% of the 24-h period) on day 5 compared
with 3.2% of subjects in the esomeprazole 40 mg group
and 9.7% of subjects in the rabeprazole-DR 20 mg
group.
Pharmacokinetics
The pharmacokinetic analysis of rabeprazole and the key
metabolite PTBI included a total of 216 subjects. All rab-
eprazole-ER formulations demonstrated an approxi-
mately 2-fold or higher increase in plasma rabeprazole
exposure based on mean AUC(0–t) (935.8–1951 ng h ⁄ mL)
compared with rabeprazole-DR 20 mg (532 ng h ⁄ mL)
(Table 6). Time of the last quantifiable concentration
(Tlast) was greater in all rabeprazole-ER groups (median
16–24 h) than the rabeprazole-DR 20 mg group (median
8 h) (Table 6). Overall, rabeprazole-ER groups 4, 5, 6
and 8 showed higher values for mean AUC(0–t) and med-
ian Tlast. The maximal concentrations (Cmax) for the rab-
eprazole-ER groups ranged from 235.8 to 469.6 ng ⁄ mL,
compared with that of rabeprazole-DR 20 mg
(308.8 ng ⁄ mL, Table 6). Median Tmax for the rabepraz-
ole-ER groups (3–5 h) was similar to that of rabepraz-
ole-DR 20 mg (4 h). Notably, all groups exhibited high
variability in the rabeprazole pharmacokinetic parameters
with most groups having coefficient of variation (CV)
values >50%.
Consistent with the higher rabeprazole exposure, PTBI
exposure was higher in the rabeprazole-ER groups (mean

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G. Morelli et al.

Table 6 | Summary of rabeprazole pharmacokinetic parameters on day 5 (pharmacokinetic population)

Total AUC0–t (ng h ⁄ mL) Clast Tlast (h) Cmax (ng ⁄ mL) Tmax (h)
Group* rabeprazole N Mean (s.d.) (ng ⁄ mL) Median (min, max) Mean (s.d.) Median (min, max)
G2 (RAB-DR) 20 mg 31 532.0 (263.5) 9.8 8.0 (4.0, 24.0) 308.8 (180.4) 4.0 (2.0, 20.0)
G3 (RAB-ER) 40 mg 30 935.8 (576.0) 9.9 16.0 (10.0, 24.1) 235.8 (136.8) 3.0 (2.0, 8.0)
G4 (RAB-ER) 80 mg 31 1951.0 (1255.0) 13.5 24.0 (10.0, 24.1) 460.2 (274.9) 4.0 (2.0, 6.0)
G5 (RAB-ER) 50 mg 31 1079.0 (390.8) 10.2 24.0 (10.0, 24.2) 250.8 (94.0) 5.0 (2.0, 12.0)
G6 (RAB-ER) 50 mg 31 1342.0 (904.3) 18.7 24.0 (16.0, 24.2) 257.5 (112.8) 3.0 (2.0, 16.0)
G7 (RAB-ER) 40 mg 31 1040.0 (673.7) 9.2 20.0 (12.0, 24.1) 273.7 (172.7) 3.0 (2.0, 10.0)
G8 (RAB-ER) 60 mg 31 1844.0 (936.7) 12.9 24.0 (12.0, 24.2) 469.6 (229.6) 3.0 (2.0, 10.0)
* RAB-DR, rabeprazole delayed-release; RAB-ER, rabeprazole extended-release; s.d., standard deviation.

AUC(0–t) 3425–5715 ng h ⁄ mL) than in the rabeprazole-
DR group (mean AUC(0–t) 822 ng h ⁄ mL). The Clast and
Cmax for the rabeprazole-ER groups (mean Clast ranged
80.3–145.1 ng ⁄ mL; Cmax ranged 305.8–521.9 ng ⁄ mL)
were also higher than those for the rebeprazole-DR
20 mg group (12.9 ng ⁄ mL and 116.0 ng ⁄ mL, respec-
tively). Median Tlast of PTBI was 24 h for all groups.
The highest PTBI AUC(0–t) and Clast values occurred in
groups 4, 6 and 8.
Safety and tolerability
A total of 138 treatment-emergent adverse events were
reported by 74 (29.8%) of the 248 subjects who were
included in the safety analysis. Headache was the most
commonly reported adverse event, and was observed in a
total of 18 subjects (7.3%) in the six rabeprazole-ER
groups (3.2–19.4%) vs. no subjects in the esomperazole
40 mg or rabeprazole-DR 20 mg group. All reports of
headache were mild (n = 16) or moderate (n = 2) in
severity. One subject (G3) was discontinued from the
study due to an AE of skin rash, considered possibly
related to study drug. No serious AEs were reported dur-
ing this study. There were no clinically important
changes in vital signs, physical examination, laboratory
tests and ECGs.
At the end of treatment (approximately 24 h after the
day 5 dosing), mean gastrin values were elevated com-
pared with baseline for all six rabeprazole-ER groups
(59.6–80.7 pg ⁄ mL) as well as for the esomeprazole
40 mg (46.9 pg ⁄ mL) and the rabeprazole-DR 20 mg
(46.5 pg ⁄ mL) groups. The six rabeprazole-ER formula-
tions resulted in a greater degree of increase from base-
line in serum gastrin levels after 5 days of treatment
(24.3–37.3 pg ⁄ mL) compared with esomeprazole 40 mg
(10.0 pg ⁄ mL) and rabeprazole-DR 20 mg (7.6 pg ⁄ mL).
Gastrin levels remained within the normal range at all
visits for all treatment groups.
DISCUSSION
The rabeprazole extended-release capsule is a new for-
mulation of the currently marketed rabeprazole-DR
20 mg. The goal of the rabeprazole extended-release for-
mulation was to achieve a release profile which would
maintain a prolonged plasma exposure and thereby
extend the duration of acid suppression. Initial formula-
tion work identified pulsatile release formulations that
would enable release of rabeprazole in the distal intestine
in a non-pH-dependent manner. The delayed-release
tablet contained in the rabeprazole-ER capsule was
intended to release immediately after passing through
the stomach. The pulsatile release tablets were intended
to release in the small intestine and the colon based on
its in vitro dissolution lag time of approximately 7–10 h
(data on file). A separate study using the Enterion site-
specific delivery capsule indicated that rabeprazole can
be absorbed in various parts of the gastrointestinal tract
including jejunum, ileum, ascending colon and descend-
ing colon, although absorption was reduced in the
ascending colon and descending colon (data on file). The
objective of combining an enteric-coated tablet and mul-
tiple pulsatile release tablets was to provide an initial
rapid attainment of a therapeutic concentration driven
by the delayed-release tablet and maintenance of the
therapeutic level of rabeprazole by the subsequent
absorption of the pulsatile release tablets. The current
study was designed to evaluate the pharmacokinetic,
pharmacodynamic and preliminary safety profiles of the
6 extended-release prototype formulations of rabeprazole
with various combinations of the two types of tablets to
guide further development decisions.

852 Aliment Pharmacol Ther 2011; 33: 845–854

ª 2011 Blackwell Publishing Ltd

All six rabeprazole-ER formulations demonstrated a
significant increase in the percentage of time with gastric
pH >4.0 in 24-h period on day 5 (77.0–84.1%) compared
with esomeprazole 40 mg (66.1%, P < 0.001) and rabep-
razole-DR 20 mg (63.2%, P < 0.001). The increase in
acid suppression in 24-h period on day 5 observed with
the rabeprazole-ER formulations compared with esomep-
razole 40 mg and rabeprazole-DR 20 mg was predomi-
nantly due to the increased suppressive activity during
the night-time period (24.2–39.6% increases). Similarly,
the rabeprazole-ER groups showed a greater percentage
of time over a 24-h period with gastric pH >4.0 on day
1. All six rabeprazole-ER formulations also exhibited
extended-release pharmacokinetic characteristics after
5 days including increase in total exposure (AUC(0–t))
and Clast, and prolonged Tlast compared with rabepra-
zole-DR 20 mg, confirming an extended-release pharma-
cokinetic profile.
Among the different rabeprazole-ER groups, groups 4,
5, 6 and 8 exhibited overall better pharmacodynamic
responses, which were consistent with their key pharma-
cokinetic parameters. Group 6 (50 mg rabeprazole, con-
sisting of 1 · 10 mg rabeprazole enteric-coated tablet
and 4 · 10 mg pulsatile release tablets) had the highest
percentage of time pH >4.0 over a 24-h period. Although
group 6 had a lower AUC0–t than group 4 and group 8,
it had the greatest number of individuals with Tlast rang-
ing from 16 to 24 h and the highest mean Clast. These
data show that increased AUC(0–t) driven by the pro-
longed duration of rabeprazole exposure translated into
improved pharmacodynamic properties of the extended-
release formulations. The greater Clast and Tlast for group
6 were associated with a greater night-time effect. The
Tmax for the six rabeprazole-ER groups (3–5 h) was simi-
lar to that of rabeprazole-DR 20 mg (4 h) and therefore
appeared to have no impact on the pharmacodynamic
effect. The Cmax for the six rabeprazole-ER groups
(235.8–469.6 ng ⁄ mL) and the rabeprazole-DR 20 mg
(308.8 ng ⁄ mL) observed in this study were within the
range of variations previously observed for the rabepra-
zole-DR 20 mg.20, 21
As shown in Tables 3, 4 and 5, there does not appear
to be a clear correlation between the total rabeprazole
dose and the pharmacodynamic ⁄ pharmacokinetic param-
eters among the six rabeprazole-ER formulations. For
example, if taking into consideration the primary phar-
macodynamic endpoint and key pharmacokinetic param-
eters (AUC(0–t), Clast, Tlast), formulations with a total
rabeprazole of 60 mg (group 8) or 80 mg (group 4) did
not seem to exhibit significantly better pharmaco-
Aliment Pharmacol Ther 2011; 33: 845–854
ª 2011 Blackwell Publishing Ltd
Rabeprazole extended-release acid suppression
dynamic and pharmacokinetic profiles than the 50 mg
formulations (groups 5 and 6). Both groups 5 and 6
rabeprazole-ER 50 mg showed expected pharmaco-
dynamic and pharmacokinetic profiles. Although phar-
macodynamic results were numerically better for group
6, group 5 rabeprazole-ER 50 mg formulation was
selected for further clinical evaluations considering its
manufacturing suitability. The group 5 rabeprazole-ER
50 mg formulation provided a longer duration (by
approximately 3 h or 13% of 24-h period) of gastric acid
suppression on both days 1 and 5 compared with
esomeprazole 40 mg, which is correlated with its pro-
longed plasma exposure (AUC) compared with rabepra-
zole-DR 20 mg, without an increase in Cmax. As the
percentage of time over a 24-h period with gastric pH
>4.0 on day 5 has been shown to be positively correlated
with a greater healing of erosive oesophagitis,11, 12
increase in acid suppression by the rabeprazole-ER
50 mg formulation may translate into improved clinical
outcomes such as earlier healing.
Gastrin levels at post-baseline visits were elevated for
all treatment groups; however, they remained within the
normal range. Changes from baseline in serum gastrin
levels after 5 days of treatment were greater for the six
rabeprazole-ER groups (24.3–37.3 pg ⁄ mL) compared
with esomeprazole 40 mg (10.0 pg ⁄ mL) and rabeprazole-
DR 20 mg (7.6 pg ⁄ mL). These results are consistent with
those described previously for PPIs.9, 13–16
The rabeprazole-ER formulations with total rabeprazole
up to 80 mg appeared to be well tolerated by this group of
healthy subjects. Of note, in this study, headache was
observed in each of the rabeprazole-ER groups (3.2–
19.4%), but not in the esomeprazole 40 mg, nor in the
rabeprazole-DR 20 mg group. A dose-related increase in
reports of headache has not been observed in other studies
using similar formulations or studies previously conducted
with the high-dose rabeprazole-DR formulations. Recogn-
ising limitations of a Phase 1 study in identifying safety
signals, adverse events such as headache have subsequently
been evaluated in large-scale randomised controlled stud-
ies in GERD patients (data to be submitted).
This study was designed to evaluate 6 prototype for-
mulations to guide further development by comparing
with two reference treatments. As there were a total of
eight treatment groups, a cross-over design would not
have been possible; therefore, a parallel group design was
adopted. The key limitation with a parallel design was
inherent inter-individual variations in the pharmaco-
dynamic or pharmacokinetic responses. Previous studies
in healthy volunteers with a cross-over design comparing
853
G. Morelli et al.

intragastric acid control of esomeprazole with rabepra-
zole have also shown variations in the mean percentage
of pH >4.0 in 24-h period on day 5 (58.5–61.0% for
esomeprazole 40 mg and 45.0–62.9% for rabeprazole-DR
20 mg).17, 22, 23 Similarly, the pharmacokinetic parame-
ters shown for rabeprazole-DR 20 mg in this study were
within the range of variations reported previously in sim-
ilar studies.20, 21
In conclusion, all six rabeprazole-ER formulations
demonstrated a significantly longer gastric acid suppres-
sion over a 24-h period compared with esomeprazole
40 mg and rabeprazole-DR 20 mg after once-daily treat-
ment for 5 days. The increase in the acid suppression
over a 24-h period was predominantly due to prolonged
acid suppression during the night-time period. The rab-
eprazole-ER formulations also exhibited extended-release
pharmacokinetic characteristics such as prolonged
plasma rabeprazole concentrations without significant
increases in the peak concentration as compared with
the rabeprazole-DR 20 mg.
ACKNOWLEDGEMENTS
Declaration of personal interests: Dr G. Morelli has
no personal and funding interests to disclose. Drs H.
Chen, G. Rossiter, B. Rege and Y. Lu are employees of
Eisai Inc. The authors thank Jerry Gardner for his
assistance in the analysis of gastric pH data. Declaration
of funding interests: This study was funded by Eisai Inc.

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ª 2011 Blackwell Publishing Ltd