Drug Profile

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Rabeprazole for the treatment

of acid-related disorders
Expert Rev. Gastroenterol. Hepatol. 6(4), 423435 (2012)

Silvia Marelli*1 and

Fabio Pace2,3
Janssen-Cilag SpA, Via Buonarroti, 23,
20093 Cologno Monzese, Milan, Italy
2
Department of Clinical Sciences,
University of Milan, Milan, Italy
3
Gastrointestinal Unit at Ospedale
Bolognini, Seriate, Via Paderno,
21,24068 Seriate, Bergamo, Italy
*Author for correspondence:
Tel.: +39 02 2510 1
Fax: +39 02 2510 418
smarelli@its.jnj.com
1

Proton pump inhibitors are widely used for the treatment of acid-related disorders. Rabeprazole
is a potent and irreversible inhibitor of H + /K+ -ATPase gastric pump, and it is indicated for
the treatment of gastroesophageal reflux disease, Zollinger Ellison syndrome, duodenal and
gastric ulcers and for the eradication of Helicobacter pylori in combination with antibiotics.
Pharmacokinetic and pharmacodynamic data show that rabeprazole achieves a pronounced
acid suppression from the first administration that is maintained with repeated use; this may
translate into faster onset of symptom relief for patients, particularly suitable when the indication
is for the on-demand long-term maintenance of gastroesophageal reflux disease. Due to its
predominantly nonenzymatic metabolism, rabeprazole has a lower potential for drugdrug
interactions. The objective of this article is to update efficacy and safety data of rabeprazole in
the treatment of acid-related disorders, following a previous review dated 2008.
Keywords: acid-related disorders acid secretion gastroesophageal reflux disease Helicobacter pylori eradication
peptic ulcer disease proton pump inhibitors rabeprazole Zollinger Ellison syndrome

Gastric acid secretion is a complex phenomenon

under neural and hormonal influence. The stimulation of the proton pump (H+/K+ -ATPase) in
the gastric parietal cell represents the final step of
acid secretion. A class of drugs, the proton pump
inhibitors (PPIs), are targeted at blocking this
enzyme, and they have become the agents of first
choice for the treatment of acid-related disorders. While Helicobacter pylori prevalence in the
western population is decreasing, acid-related
diseases, especially reflux disease, continue to
rise; moreover, they are chronic and relapsing
conditions with the majority of patients requiring long-term maintenance therapy. Rabeprazole
is a second-generation PPI that, on covalently
binding with the pump, inactivates it causing
a rapid and consistent inhibition of the gastric
acid production and the raising of the gastric
pH [1,2] . Rabeprazole is used for the treatment
of erosive or ulcerative gastroesophageal reflux
disease (GERD), nonerosive ref lux disease
(NERD), duodenal and gastric ulcers, Zollinger
Ellison syndrome (ZES) and in the eradication
of H.pylori. As a result of differences in its pharmacokinetic (PK) and pharmacodynamic (PD)
profiles, rabeprazole may offer clinical advantages over older PPIs. This review will provide an
update on the pharmacology and clinical profile
of rabeprazole.
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10.1586/EGH.12.18

Overview of the market

Over the previous two decades, the prevalence

of GERD has increased by 5% annually [3] . This
disease has an important negative effect on quality of life, it concerns patients in the working
phase of their life and it is associated with substantial costs in terms of loss of productivity and
healthcare utilization [4] . Symptom severity and
nocturnal heartburn are significantly associated
with a reduction in work productivity, especially
if they interfere with sleep [5,6] .
PPIs are the mainstay of medical treatment of
GERD, they are the most effective pharmaco
logical agents to reduce acid secretion and are
among the most widely prescribed drugs on
the market today. Americans spend in excess
of US $10 billion/year on PPIs; PPIs comprise
the majority of gastrointestinal medications in
the market, and the number of PPI prescriptions/year has doubled since 1999 in the USA
[7] . Since the introduction of omeprazole in 1989,
other PPIs became available in the EU market,
for example, lansoprazole (1995), pantoprazole
(1997), rabeprazole (1998) and esomeprazole,
the S enantiomer of omeprazole (2001).
PK and PD differences between PPIs are
reflected in their influence on both speed
and degree of gastric acid suppression, which
subsequently may affect their clinical efficacy [8].

2012 Expert Reviews Ltd

ISSN 1747-4124

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Drug Profile

Marelli & Pace

CH3
N

OCH2CH2CH2OCH3

O
S

CH2

N
Na

Figure 1. Structure of rabeprazole sodium.

Introduction to the drug

Rabeprazole is marketed worldwide under the trade names of

Pariet, Aciphex and Alfence (Eisai Ltd, Hertfordshire, UK;
Janssen Pharmaceuticals Inc., NJ, USA). It has been available in
Europe since 1998 (in Italy since 1999) as an enteric-coated oral
tablet in two dosages: 10mg rabeprazole sodium tablets (containing 9.42mg rabeprazole free acid) and 20mg rabeprazole sodium
tablets (containing 18.85mg rabeprazole free acid).
It is a potent and irreversible inhibitor of H+/K+ -ATPase gastric pump, and, in the EU, it is used for the treatment of adults
with conditions requiring a reduction of gastric acid secretion.
It is indicated for the treatment of active duodenal ulcer, active
benign gastric ulcer, erosive or ulcerative GERD, symptomatic
NERD, long-term management of GERD and pathological
hypersecretory conditions including ZES. It is also indicated for
the eradication of H. pylori in combination with antibiotics.
PK and PD data show that rabeprazole achieves a pronounced
acid suppression from the first administration, which is maintained with repeat use; this may translate into faster onset of
symptom relief for patients and could be a suitable profile for
on-demand use (rapid onset of action, prolonged action and good
safety profile with minimal drugdrug interactions).
Chemistry & pharmacological properties

Rabeprazole sodium is 2-[[[4-(3-methoxypropoxy)-3-methyl2-pyridinyl]-methyl]sulfinyl]-1H-benzimidazole sodium salt

(molecular formula C18H20N3NaO3S). Its structural formula is
shown in Figure 1. It is a white to slightly yellowish-white powder
and has a molecular weight of 381.43Da. It is a racemate owing
to its chiral sulfoxide moiety, weak base and its instability at acidic
pH and under humid conditions.
PPIs are prodrugs and are converted to active drugs in a series
of steps. The first is the concentration of these compounds in the
acidic secretory canaliculi of the gastric parietal cells, where they
are converted to the active sulfenamide form, through protonations
Table 1. pKa values of marketed proton pump
inhibitors.
Proton pump inhibitor

pKa1

pKa2

Omeprazole/esomeprazole

4.06

0.79

Lansoprazole

3.83

0.62

Pantoprazole

3.83

0.11

Rabeprazole

4.53

0.62

424

and a subsequent spontaneous rearrangement. Then, the sulfenamide moiety is capable of covalently binding the surface-exposed
cysteines (disulfides) of the gastric proton pump, causing an irreversible inhibition of the pump. Nongastric proton pumps, for example
in lysosomes, have no cysteine residues on their acid accumulation
side; in such cases, PPIs do not inhibit proton secretion.
How quickly a PPI inhibits the H+/K+ -ATPase depends on its
capability to accumulate in the secretory canaliculi and to be
protonated at the pyridine nitrogen (this is partly a function of
its pKa1, the pH at which the number of inactive not protonated
forms and that of active protonated forms are equal, in other
words, the relative acid stability) [9] . Depending on various substitutes on the two ring structures, the five PPIs on the market
differ in terms of acid stability (Table 1) . For example, pantoprazole,
because of the difluoromethoxy substituent on the benzimidazole, has the lowest pKa1, which probably accounts for its slower
activation and ATPase activity inhibition [1] . Rabeprazole has the
highest pKa1 (~5.0), and this, allowing for a quicker conversion to
sulfenamide, can explain the higher accumulation of rabeprazole
in the canaliculus (10-times higher than that of omeprazole), even
in the weakly acidic environment of old parietal cells, its faster
and more consistent inhibition of acid secretion (within 5min
rabeprazole inhibits 100% of the proton pumps) and its higher
clinical potency as determined by a comprehensive assessment of
dose-dependent effects on intragastric pH [1,2,1012] .
Moreover, the higher pKa1 of rabeprazole has a special significance after multiple PPI administrations: in this situation, the
intragastric environment changes from strong to weak acid, but
rabeprazole continues to be more efficiently converted to its active
form than other PPIs.
PK, PD & metabolism

Rabeprazole is marketed as an oral enteric-coated formulation

because PPIs are instable in acid environment. The absorption
is rapid, the time to reach maximum plasma concentration is
approximately 3.5h after a single dose and is dose independent.
Considering a dose range of 1080mg, maximum plasma concentration and area under the curve are linear, suggesting nonsaturable first-pass metabolism. After an oral dose of rabeprazole
20mg in tablet formulation, the bioavailability is approximately
52% (compared with intravenous administration) and it does
not increase with repeat dosing, unlike other PPIs (i.e., omeprazole/esomeprazole where the sulphone metabolite inhibits
CYP2C19). It is not influenced by the co-administration of an
antacid and food. In the plasma, rabeprazole is 97% bound to
proteins and its plasma half-life (t1/2) is approximately 1h. Almost
90% of the dose is eliminated in urine, mainly as mercapturic acid conjugate and carboxylic acid, and 10% in the feces.
Dosing adjustment is not required in special populations such as
the elderly, in subjects aged 1216 years and in conditions such
as end-stage renal failure and mild-to-moderate chronic compensated cirrhosis because no clinically relevant drug accumulation
was observed in these cases [1316] .
Rabeprazole differs from most PPIs in terms of metabolism
because CYP3A4 and CYP2C19 pathways play minor roles, while
Expert Rev. Gastroenterol. Hepatol. 6(4), (2012)

Rabeprazole for the treatment of acid-related disorders

5-O-desmethyl-omeprazole

Drug Profile

3-hydroxy-omeprazole
Lansoprazole sulfide

Omeprazole sulfide
CYP2C19

CYP3A4
Omeprazole
Esomeprazole

Lansoprazole

CYP2C19
(CYP3A4)

CYP3A4

5-hydroxy-omeprazole

Omeprazole sulphone

CYP3A4

CYP2C19
(CYP3A4)

CYP3A4

5-hydroxylansoprazole

Lansoprazole sulphone

CYP2C19

Omeprazole hydroxysulphone

Pantoprazole sulfide

Rabeprazole

Pantoprazole

CYP2C19

CYP3A4

Demethylated
rabeprazole

Nonenzymatic

Rabeprazole
thioether
Rabeprazole
sulphone

CYP2C19
Dealkylated metabolite

CYP3A4
Pantoprazole sulphone

Sulfotransferase
Pantoprazole sulfate

Figure 2. Metabolism of the five proton pump inhibitors. The darker arrows indicate the pathways that contribute more.
Data taken from [21] .
Adapted with permission from [71] .

it is mainly converted by nonenzymatic reduction in a thioether

metabolite (Figure 2) . Therefore, rabeprazole is less susceptible to
the influence of CYP2C19 genetic polymorphisms (extensive,
intermediate, poor metabolizers) in terms of bioavailability
(Figure3) [1719] and of predictivity in the antisecretory/clinical
effect [2026] . For example, in a study performed on 103 Japanese
patients with reflux esophagitis, who were treated with rabeprazole
for 8 weeks, the healing rates were 86.1,92and 82.4% in extensive,
intermediate and poor metabolizers, respectively, and according
to Mantel Haenszel test, there was no significant difference in the
healing rates among the three genotype groups [24] . Comparing this
trial with a similar one [27] conducted on 65 patients with erosive
esophagitis treated for 8weeks with lansoprazole, where the lowest
cure rate was achieved in the extensive metabolizers (45.8 vs 67.9%
in intermediate and 84.6% in poor metabolizers), it is possible to
conclude that CYP2C19 genotype status is significantly associated
with the success or failure of curing GERD with lansoprazole
but not with rabeprazole. In the study reported earlier, the low
cure rate with lansoprazole in patients with extensive metabolizer
genotype appeared to be a result of these patients having the
lowest plasma lansoprazole levels among the three genotype
groups. A recent paper has shown that rabeprazole can overcome
the impact of CYP2C19 polymorphism on quadruple therapy for
H. pylori eradication and that rabeprazole-based regimens had
better efficacy than esomeprazole-based regimens [28] .
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Moreover, a recently published study in which the influences

of different PPIs on CYP activity were evaluated using the
[13C]-aminopyrine breath test has demonstrated that omeprazole and lansoprazole at the standard doses inhibit CYP activity
but rabeprazole does not. This aspect, in addition to the peculiar
metabolism, is very useful in the case of polymedicated/elderly
patients because it reduces the potential of drugdrug interaction
with rabeprazole [29] .
From a PK point of view, rabeprazole rapidly and dramatically
reduces gastric acid secretion [3032] .
Recently, Kirchheiner etal. conducted a systematic analysis of
all the available clinical studies measuring the effects of PPIs on
mean 24-h intragastric pH. To minimize the effect of genetic
polymorphism, they restricted the selection to those targeting
Caucasian populations, both healthy volunteers and GERD
patients. Based on pH data from 57 studies, the relative potencies
of the five PPIs were estimated and quantified. Rabeprazole has
stood out as the most potent PPI: compared with omeprazole, the
relative antisecretory potencies were 0.23, 0.90, 1.00, 1.60 and
1.82 for pantoprazole, lansoprazole, omeprazole, esomeprazole
and rabeprazole, respectively (Figure 4) [12]. Unfortunately, head-tohead studies, with clinical outcomes, that could demonstrate the
superiority of rabeprazole versus all the other PPIs are lacking. A
recent trial with a noninferiority design, comparing rabeprazole
and esomeprazole for the resolution of heartburn and regurgitation
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Drug Profile

Marelli & Pace

Extensive metabolizers
7

6.3

6
5
AUC (ratio)

complications, eradication of H. pylori

infection and ZES. New literature evidences are emerging about extraesophageal
manifestations of GERD, particularly sleep
disturbances.

Poor metabolizers

4.7

Gastroesophageal reflux disease

GERD is a widely diffuse disease affecting

a large part of the Western population and
3
increasing also in the Eastern areas. It has
1.8
increasingly been recognized that being over2
weight and obesity are important risk factors
1
1
1
1
1
for GERD, since the pathophysiological
factors leading to GERD are more
0
frequent/severe in the former [34]. GERD
Rabeprazole
Lansoprazole
Pantoprazole
Omeprazole
is a spectrum disease, with multiple manifestations ranging from the so-called typical
Figure 3. Comparison of the mean values for area under the plasma
concentrationtime curve after one oral dose of omeprazole, rabeprazole,
esophageal syndrome without esophageal
lansoprazole and pantoprazole in extensive metabolizers versus poor
damage to esophagitis or its complications,
metabolizers.
such as stricture or Barretts esophagus.
AUC: Area under the curve.
Finally, many atypical or extraesophageal
Data taken from [1719] .
manifestations have been described, some
in uninvestigated GERD patients within a primary care setting, with an established association with pathological GERD, some
demonstrated that rabeprazole 20mg and esomeprazole 40mg are others where the association is still proposed but not fully estabsimilarly effective for the control of symptoms [33].
lished, such as pharyngitis, sinusitis, idiopathic pulmonary fibrosis
and otitis media [35]. PPIs are the mainstay of both acute and
Clinical efficacy profile
maintenance therapy of typical esophageal syndrome (also referred
The main indications of rabeprazole are acid-related diseases: to as NERD) and esophagitis, whereas their role in the treatment
GERD, treatment of duodenal and gastric ulcers and their of Barretts esophagus or extraesophageal symptoms is much less
evident. In a previous review, these topics
have been covered up to 2007 [36].
4

Pantoprazole

NERD

0.23

Lansoprazole

0.90

Omeprazole

1.00

Esomeprazole

1.60

Rabeprazole

1.82

0.5

1.5

Relative antisecretory potency

Figure 4. Relative potencies of the five proton pump inhibitors based on a

metaanalysis of 57 studies measuring the mean 24-h gastric pH.
Data taken from [12] .

426

This is likely the most frequent phenotype

of GERD [37] . In the previous review, the
evidences regarding the superiority of
rabeprazole over placebo in the treatment
of nonerosive GERD patients are presented
[36] . A very recent paper has addressed the
issue as to whether the doses of 5or 10mg
are differently effective in the treatment
of NERD patients [38] . The study was
conducted in 288 subjects who were
nonresponders to a previous open-label
antisecretory therapy; those subjects were
treated for 4 weeks, in the frame of a doubleblind trial with either placebo or rabeprazole
5 or 10mg/day. After this period, a complete
heartburn relief was observed in 21% of
placebo-treated patients as compared with
34% in those given rabeprazole 5mg and
44% in those given rabeprazole 10mg. Only
the highest dose of rabeprazole proved to
be statistically superior to placebo. The
prognostic factors that might influence the
Expert Rev. Gastroenterol. Hepatol. 6(4), (2012)

Rabeprazole for the treatment of acid-related disorders

efficacy of the 10-mg dose were assessed; however, age, BMI, hiatal
hernia, H. pylori infection, frequency and severity of heartburn or
CYP2C19 genotypes did not affect the outcome. The conclusions
of the study were that rabeprazole at the dose of 10mg, but not
5mg, provided significantly more potent heartburn relief than
placebo and was less dependent upon baseline features of patients.
Despite this indirect evidence of a greater efficacy of the 10-mg
dose, another study coming from the same group of Japanese
authors and conducted on NERD patients has found no marked
difference in reducing esophageal acid exposure (EAE) between
the two doses [39] . In this multicenter, randomized, parallel-group,
double-blind PD study, 22 patients, in whom heartburn was not
improved by antacid administration, were randomly assigned to
a double-blind treatment with rabeprazole 5 or 10mg/day for 4
weeks. Patients were investigated by means of a 24-h esophageal
pH monitoring before and while on treatment (during week 4) to
assess the change of EAE achieved by the doses of rabeprazole.
The results showed that median EAE, expressed as the percentage of time at pH <4, decreased from 4.3% before treatment to
1.1% during treatment with rabeprazole 5mg (with a change from
baseline of -2.5%), whereas the median EAE in the rabeprazole
10-mg group was 7.4 and 0.5%, respectively (with a change from
baseline of -6.6%). Similarly, the decrease of median number of
reflux episodes from baseline was -18.0 with rabeprazole 5mg and
-44.0 with rabeprazole 10mg. Authors of the study concluded
that the administration of 5- and 10mg rabeprazole achieved a
similar degree of inhibition of EAE and relieved heartburn episodes in NERD patients previously refractory to antacid therapy.
The lack of differences between the two doses may be due to the
insufficient power of the study. In the everyday clinical practice,
the diagnosis of NERD requires that no macroscopic esophageal
damage be found on upper endoscopy conducted in a symptomatic patient. Currently, NERD is an umbrella diagnosis [40] covering different entities ranging from true NERD to functional
heartburn. A more precise diagnosis needs further investigations,
such as pH metry or pH impedance monitoring, to be clarified. It
has been proposed, instead of invasive examination, to perform a
rabeprazole test to differentiate the various subgroups of NERD
patients [41] . The authors of this study investigated the possibility
of categorizing NERD patients according to symptom types and
response to rabeprazole 10mg/day. NERD patients were classified
as grade N (endoscopically normal), M (minimal change) or erosive
GERD and answered a 51-item, yes-or-no questionnaire pre- and
post-treatment. The authors concluded that, compared with erosive GERD, clear differences existed in pretreatment prevalence
of symptoms and responsiveness to rabeprazole in grades N and
M. However, it seems that, on the contrary, a huge overlap exists
between the two subgroups N and M, and, therefore, the clinical response to the PPI may not be used in clinical practice as a
clearcut criterion to differentiate various NERD subgroups.
Erosive esophagitis

In a review conducted 5 years ago on the comparative efficacy of

the PPIs available on the market at that time, it was concluded
that esomeprazole consistently demonstrated higher healing rates
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Drug Profile

when compared with the remaining PPIs used at standard doses

[42] . Limitations of this paper include the fact that it is not a meta-

analysis and that a head-to-head clinical comparison between

esomeprazole and rabeprazole delayed release does not exist. In
the previous review, the pivotal Phase III trials of rabeprazole in
the treatment of esophagitis were presented [36] ; in this section, new
publications are focused upon. A group of Oklahoma researchers
has recently conducted a postmarketing study [43] updating the
results of a previously published large open-label trial [32] performed
in a setting closely mirroring routine clinical practice. The goals
of the study were to evaluate the timing of symptom relief and
changes in symptom severity with rabeprazole administered to
patients with confirmed erosive GERD. Safety was also addressed,
and there was special emphasis on the assessment of quality-of-life
issues. The results showed that patients in this study (n=2449)
demonstrated significant overall improvement versus baseline (p<
0.001), with a substantial symptom relief seen throughout the 8
weeks of treatment. By week 4, complete relief of daytime and
night-time heartburn, belching, regurgitation and dysphagia was
observed in 87.5, 90.7, 50.7, 77.6 and 75.1% of patients, respectively.
The percentage of patients demonstrating improvement in
symptoms at week 8, although slightly lower, was comparable with
those observed at week 4 (daytime heartburn: 77.4%, nocturnal
heartburn: 73.2%, belching: 55.0% and regurgitation: 52.4%).
Improvements were seen in rabeprazole-treated patients (<65 or
65 years), with a range of baseline symptom severities and across
different racial groups. Rabeprazole was well tolerated by the vast
majority of patients. The authors concluded that the results of
this open-label, large-scale, community-based trial of rabeprazole
conducted in a wide range of erosive GERD patients and mirroring
the actual clinical practice supports the premise that rabeprazole
provides fast and sustained relief of common symptoms of
GERD (including daytime and night-time heartburn, belching,
regurgitation and dysphagia): overall, approximately 90% of
patients remained symptom-free at week 4. Finally, a study explored
whether in a Japanese population of erosive esophagitis patients,
the CYP2C19 polymorphism might influence the recurrence rate
during PPI maintenance therapy [44] . Ninety-nine patients with
initial healing of GERD (judged by endoscopy) after 8 weeks of
treatment with PPIs were enrolled into a maintenance therapy for
6 months with rabeprazole (10mg/day), omeprazole (20mg/day)
or lansoprazole (15mg/day). The recurrence of GERD symptoms
in the maintenance therapy was assessed by a previously validated
questionnaire, the QUEST one [45] . Globally, the recurrence rate
of GERD symptoms in the group of CYP2C19 homozygous
extensive metabolizers (38.5%) was significantly greater than
those in groups of heterozygous extensive metabolizers (10.9%)
and poor metabolizers (5.6%). Interestingly, the recurrence rates in
patients treated with omeprazole (25%) and lansoprazole (30.8%)
were significantly greater than that with rabeprazole (4.4%).
The gender, age and H. pylori did not significantly affect the
rate. The authors of this study concluded that it was confirmed
that the CYP2C19 genotypes were able to affect the recurrence rate
of GERD symptoms during PPI maintenance therapy; moreover,
they showed that patients treated with 10mg/day rabeprazole
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Drug Profile

Marelli & Pace

experienced a lower recurrence rate, possibly due to its sufficient

acid suppression independent of CYP2C19 genotypes in Japanese
patients.
Extraesophageal manifestations (sleep disorders)

In recent years, it has become increasingly evident that GERD is a

relevant cause of sleep disorders. Published literature estimates that
approximately 75% of patients with heartburn experience nighttime GERD symptoms [5] . Night-time GERD symptoms have
also been shown to have considerable impact on sleep, including
difficulty inducing and maintaining sleep, poorer sleep quality and
greater daytime sleepiness and fatigue [46,47] .
At least three studies have examined the therapeutic role of
rabeprazole in GERD patients presenting with (mainly) sleep
disturbances symptoms. The first, an open study, examined the
prevalence and risk factors of sleep dysfunction, and the effect of
rabeprazole on reflux symptoms and sleep dysfunction in Japanese
GERD patients [48] . One hundred and thirty four GERD patients,
including 82 patients with NERD, entered this study; they were
openly treated with rabeprazole 10mg daily for 8weeks. Patients
completed both a Frequency Scale for Symptoms of GERD (FSSG)
questionnaire and a Pittsburgh Sleep Quality Index (PSQI) questionnaire at baseline and 8 weeks after treatment. In this study, a
sleep dysfunction was a priori defined as a PSQI score >5.5; it was
found that 52.2% of the included GERD patients showed this
abnormality. Interestingly, NERD patients had a sleep dysfunction
significantly more frequently compared with erosive reflux disease
(odds ratio [OR]: 2.18, 95% CI: 1.054.53). However, other factors such as night-time heartburn were not associated with sleep
dysfunction. In this open study, rabeprazole treatment was found
to significantly decrease both the FSSG and the PSQI score. The
authors concluded that this cohort of Japanese GERD patients
exhibited a high prevalence of sleep dysfunction, and that NERD
constituted a risk factor for it, whereas the use of rabeprazole led to
a substantial amelioration of sleep dysfunction. Due to the lack of
an association between night-time heartburn and the sleep dysfunction, the authors claim of a possible different pathogenesis of sleep
dysfunction in Japanese GERD patients compared with GERD
patients in western countries, which remains to be proven.
The second study was conducted on a special group of GERD
patients, those with simultaneous presence of obstructive sleep
apnea syndrome (OSAS) and GERD who were documented by
means of a pathological pH monitoring study [49] . The study,
with a single-site within-subjects design, was designed to assess
the effect of the acid suppression that could be achieved with
rabeprazole 20mg twice daily for 2 months on upper airway
structure and function. Twenty five patients were recruited with
documented mild OSAS and an objective diagnosis of GERD
obtained by means of 24-h pH measurement. Patients underwent
laryngoscopy, polysomnography and 24-h pH monitoring before
and after 8weeks of treatment with rabeprazole, 20mg, twice a
day, given in an open fashion. A subjective assessment of sleep was
obtained via the PSQI and the Epworth Sleepiness Scale (ESS). The
results of this comprehensive and accurate study were twofold: the
finding of a posterior commissure edema was significantly reduced
428

(p < 0.05) after therapy and the laryngoscopic appearance, defined

by the Reflux Finding Score, was markedly, albeit not significantly,
improved (p < 0.07) by treatment. Moreover, some objective sleep
parameters were significantly improved after treatment compared
with baseline; as an example, sleep-onset latency showed a
significant reduction (26.2 vs 11.2; p < 0.05). On the other hand,
total sleep time and other stages of sleep and arousals were not
significantly changed by therapy. Participants reported significantly
less daytime sleepiness after treatment, which was reflected in a
significantly lower ESS score, with a significant improvement
also in the PSQI score after treatment. Finally, sleep-related acid
contact time was significantly reduced (8.0 vs 1.7%; p < 0.001).
There was no significant change in the apneahypopnea index.
The authors concluded that in selected patients with mild OSAS
and documented GERD, acid suppression obtained with 20mg
rabeprazole twice a day for 2months improves upper airway
abnormalities, as well as objective and subjective measures of sleep
quality. However, this study presents some limitations since it is
not a placebo-controlled study, and few subjects were included.
The third study assessed a completely different population, namely
patients with demonstrated insomnia but minimally symptomatic
GERD, to define the prevalence of GERD-related sleep disturbance
and to assess the changes in sleep efficiency in these subjects after
vigorous acid suppression obtained with rabeprazole 20mg twice
daily for 14 days [50] . The population recruited in this study was
composed of subjects aged between 18 and 75 years, who reported
at least 6 months of insomnia, and sleep difficulty at least three
nights per week prior to inclusion. Exclusion criteria were a BMI
>30 and a history of snoring or ongoing use of PPI or H2 receptor
antagonist. Subjects were investigated by means of dual-channel
24-h pH study. The calculated parameters of interest were sleep
efficiency, defined as the percentage of time after sleep initiation
that the subject actually slept, and spontaneous arousal index,
defined as the number of arousals per hour. Following a sleep
study demonstrating poor sleep quality (sleep efficiency of <83%;
>10arousals/h for those aged <45years, and >15for those who
were 45years or older) and the absence of obstructive sleep apnea,
patients were openly treated with rabeprazole 20mg twice daily for
14 days. After this period, they were assessed by pH monitoring.
Additionally, patients were investigated using three questionnaires,
namely the GERD Symptom Assessment Scale (GSAS), the ESS
and the Functional Outcomes of Sleep Questionnaire, which were
administered before and after 2 weeks of therapy. Twenty-four
subjects reported insomnia, 20 of whom met criteria for disordered
sleep and no obstructive sleep apnea; of these, 17 completed
both the first and second studies, and 16 could be satisfactorily
analyzed. The baseline assessment of reflux symptoms by GSAS
demonstrated minimal or absent reflux symptoms in the sample
of 16 patients. In particular, no subject scored over 8 out of 45
on GSAS, corresponding to a median rating of reflux symptoms
of not at all. Pathological reflux was found at pH monitoring in
four of 16 subjects (25%) at baseline; all four proved to have their
esophageal pH normalized on PPI. Furthermore, three of these
four subjects completely normalized their sleep efficiency after
2 weeks of therapy, compared with four out of 12 subjects with
Expert Rev. Gastroenterol. Hepatol. 6(4), (2012)

Rabeprazole for the treatment of acid-related disorders

normal JohnsonDeMeester scores. Polysomnographic analysis

showed significant improvement in spontaneous arousal index
compared with baseline for the whole group (p < 0.0035), whereas
the comparison between pre- and post-therapy ESS and Functional
Outcomes of Sleep Questionnaire scores showed no differences.
Conclusions of authors are that, despite the lack of GERD
symptoms, a relevant minority of subjects with sleep disturbance
have indeed a pathological GER and that PPI treatment of GERD
in such patients may result in improvement in sleep efficiency.
The main limitation of the study is the relatively fewer number of
patients investigated.
Special GERD populations

In the previous review, the authors focused on the unique features

of rabeprazole in the therapy of difficult-to-treat populations,
such as the overweight/obese patients and the Asians, due to a
highly prevalent CYP2C19 polymorphism present in that population. A recent paper has confirmed preliminary observations [51]
that rabeprazole may differ from other PPIs in its effectiveness to
treat subjects with increased BMI [52] .
A post hoc analysis has been performed for erosive esophagitis (EE) healing rate and symptom response stratified by patient
BMI in the subjects of a multicenter, double-blind, randomized,
48week trial comparing EE healing with rabeprazole (20mg
daily) and omeprazole (20mg daily). Analysis of variance, twosample t-test, Blackwelders test for equivalence, log-rank and
CochranMantelHaenszel tests were used to analyze comparisons. It was observed that in the two BMI groups (<25 and
25kg/m2), rabeprazole and omeprazole were equally effective
for mucosal healing regardless of the patients BMI (N=542, p
> 0.05). However, in overweight/obese patients, rabeprazole was
significantly faster than omeprazole in inducing heartburn relief
during the first treatment week (p<0.0001). In fact, in patients
with a BMI 25kg/m2, the mean time to first day of satisfactory heartburn relief with rabeprazole 20mg (2.60.3days) was
significantly shorter versus that observed with omeprazole 20mg
(3.80.4days; p=0.0113). Similarly, significantly more patients
taking rabeprazole in the overweight/obese BMI category achieved
satisfactory heartburn relief in each of the first 3 treatment days
compared with patients who received omeprazole (59.2 vs 46.6%;
p=0.0256). A significant difference between rabeprazole and
omeprazole was also showed by the percentage of patients in the
overweight/obese group with complete night-time heartburn control in the first 3 days of treatment (61.2% for rabeprazole vs
47.9% for omeprazole; p=0.0178). The results of this study show
that the clinical efficacy of rabeprazole is not only maintained in
overweight/obese patients with GERD but that this subgroup of
patients may derive, from rabeprazole, even greater benefit than
lean patients. The study already quoted by Kinoshita etal., conducted on Japanese patients, used a very low rabeprazole dose (5vs
10mg daily) and yet found that both doses were unaffected by
the CYP2C19 genotypes.
Finally, rabeprazole has been tested in an escalating dose study
in GERD patients refractory to an initial low dose (10mg daily).
The study, called TORNADO, was conducted on approximately
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Drug Profile

100symptomatic GERD patients, the majority of whom were

NERD [53] . Patients were all treated with rabeprazole 10mg once
daily for 4 weeks, which can be escalated to 10mg twice daily for
an additional 2 weeks and again to 20mg twice daily for another
2 weeks in case of lack of complete heartburn relief. Clinical
characteristics of patients and efficacy of the drug were assessed
on the basis of a heartburn diary and of an FSSG. At the end of
4 weeks of therapy, 42.5% (31/73) and 67.9% (19/28), respectively, of NERD and EE patients showed complete heartburn
relief. The percentages rose to 68.9 and 91.7%, respectively, after
dose escalation. Parameters found to be associated with resistance to rabeprazole 10mg once daily, at a multivariate analysis,
were female gender, nonsmoking, frequent heartburn, low score
for question4 (Q4) of the FSSG (subconsciously rubbing the
chest), and high scores for both Q3 (heavy stomach after meal)
and Q7 (unusual sensation in the throat). Parameters found to be
associated with resistance to rabeprazole 20mg twice daily were
frequent heartburn and a high score for Q7. Interestingly, FSSG
scores of patients resistant to rabeprazole were significantly higher
in comparison with responders before and during treatment. The
study concluded that FSSG could predict response to a PPI for
symptomatic GERD and confirmed that doubling rabeprazole
dose might prove useful for treatment of GERD refractory to
standard dose.
Peptic ulcer

The second main indication for rabeprazole is the treatment of

peptic ulcer disease (PUD) and its complications, in particular
acute bleeding. This section will include therapy and prophylaxis
of nonsteroidal anti-inflammatory drug gastroduodenal damage
as well as of other iatrogenic damage such as that induced by
endoscopic mucosal dissection.
H. pylori eradication

Presently, the so-called triple therapy with a PPI, clarithromycin

and amoxicillin or metronidazole is considered the standard
first-line regimen for eradication of H. pylori [54]. However,
even with the most effective treatment regimens, eradication of
H. pylori infection is not possible in about 1020% of patients
because of factors such as smoking, drug compliance, regimen
selection and antimicrobial resistance. Moreover, the CYP2C19
metabolizer status has to be considered as a primary determinant
of the outcome of PPI-based triple therapy [55]. Recent evidences
suggest that the pro-inflammatory cytokine IL-1 appears to play
a key role in H. pylori-associated disease as well. IL-1 comprises
a family of three proteins: two agonist forms, IL-1a and IL-1b,
together with an antagonist, the IL-1 receptor antagonist (IL-1ra).
It has recently been shown that IL-1b is upregulated in response
to H. pylori infection and acts on gastric epithelium, where it is
able to inhibit gastric acid production [56]. Two PPIs, namely
rabeprazole, 10mg twice daily, and omeprazole, 20mg twice
daily, were compared with each other as part of triple therapy
with amoxicillin and clarithromycin for H. pylori eradication in
a recent prospective, randomized trial conducted in China. The
efficacy of the therapy was assessed in relation to the CYP2C19,
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Marelli & Pace

IL-1b and IL-1ra genetic polymorphism [57]. Two hundred and

forty Chinese patients with PUD participated, all of whom were
randomly assigned to amoxicillin and clarithromycin together
with omeprazole or rabeprazole (RAC). The CYP2C19*2 and *3
metabolizer status, as well as the IL1-b-511, IL-1b-31, IL-1b+3954
and intron 2 of the IL-1ra genotypes were determined by PCR
restriction fragment length polymorphism. The study showed,
according to an intention-to-treat analysis, that in homozygote
patients with CYP2C19 wild-type the eradication rate of the
RAC regimen was significantly higher than that of the omeprazole
regimen (p=0.014). No significant differences in the eradication
rates were observed among the genotype groups. In addition, all
IL-1ra and IL-1b genotype groups showed similar eradication rates.
In conclusion, although in Chinese patients at large with peptic
ulcer, the effectiveness of 1-week PPI/AC regimen with rabeprazole
10mg twice daily was comparable with that with omeprazole
20mg twice daily; the RAC regimen appeared, however, to have
an advantage for the CYP2C19 extensive metabolizer genotype.
Neither the eradication efficacy of rabeprazole nor omeprazole in
triple-therapy regimen varied according to the IL-1b and IL-1ra
genetic polymorphisms.
Peptic ulcer bleeding

In peptic ulcer bleeding, the first step of management is to achieve a

hemostasis by means of endoscopy-delivered mechanical or thermal
therapy. After successful endoscopic hemostasis, addition of PPIs
reduces the rate of recurrent bleeding by maintaining intragastric
pH at neutral level. A recent study evaluated the effect of various
PPIs given through different routes, on intragastric pH over 72h
after endoscopic hemostasis in bleeding peptic ulcer [58]. In this
study, conducted in India, 90 consecutive patients with bleeding
peptic ulcer, who were successfully treated endoscopically, underwent the 72-h continuous ambulatory intragastric pH study after
being randomly assigned to receive three different regimens: oral
omeprazole 80mg bolus followed by 40mg every 12h for 72h
or 80mg intravenous omeprazole followed by infusion 8mg/h for
72h; oral pantoprazole 80mg bolus followed by 80mg every 12h
for 72h or 80mg intravenous pantoprazole followed by infusion
of 8mg/h for 72h; and oral rabeprazole 80mg bolus followed by
40mg every 12h for 72h or 80mg intravenous rabeprazole followed by infusion 8mg/h for 72h. Five patients received no treatment after successful endoscopic therapy and underwent the 72-h
pH study off therapy. Results of the intragastric pH monitoring,
assessed as mean 72-h gastric pH were oral omeprazole 6.56 versus
6.93 for omeprazole infusion (p=0.48); oral pantoprazole 6.34
versus 6.32 for pantoprazole infusion (p=0.62) and oral rabeprazole 6.11 versus 6.18 rabeprazole infusion (p=0.55). In the group
without PPI therapy, the mean 72-h pH was 2.04. The authors
concluded that high doses of different groups of PPI (omeprazole,
rabeprazole and pantoprazole) when given in different forms (orally
or by infusion) after successful endoscopic therapy achieved an
intragastric pH of 6 and above within 1h of administration and
maintained a pH of more than 6 for more than 98% of the time.
There was an insignificant difference among various PPIs on 72-h
intragastric pH; however, there was a significant difference between
430

the PPI group and non-PPI group. Thus, a high dose of PPI was
able to maintain intragastric pH above 6 regardless of the route
of administration.
Prophylaxis & therapy of gastroduodenal damage

Aspirin decreases cardiovascular (CV) and cerebrovascular events

and mortality because it inhibits the COX-1 function and thromboxane synthesis [59]. A major limitation of aspirin use is the development of PUD, including ulcer bleeding, due to the inhibition
of prostaglandin formation in the gastrointestinal mucosa [60].
PPIs inhibit acid secretions and thus are effective in treating and
preventing aspirin-related PUD [61]. Clopidogrel is an alternative
antiplatelet agent that inhibits ADP-induced platelet aggregation
through the irreversible inhibition of P2 nucleotide receptors on the
platelet surface [62]. Clopidogrel does not inhibit COX-1 function
and prostaglandin formation. In addition, clopidogrel does not
induce endoscopically evident mucosal injury in healthy volunteers.
One gastroprotective strategy is to use clopidogrel instead of aspirin;
however, there are increased bleeding risks in patients receiving
clopidogrel with a history of aspirin-associated ulcer or ulcer bleeding. PPI plus aspirin is superior to clopidogrel alone in preventing
recurrent ulcer bleeding in such patients [63]. A prospective, randomized controlled study was conducted in Taiwan to compare the
ulcer healing rate after 12 weeks in patients with aspirin-related
PUD following treatment with rabeprazole for PUD and simultaneously given either aspirin or clopidogrel for CV prevention
[64]. Patients recruited in this study suffered from nonhemorrhagic
aspirin-related symptomatic ulcers and were randomized to
receive two rabeprazole regimens: rabeprazole (20mg/day) plus
aspirin (100mg/day) or rabeprazole (20mg/day) plus clopidogrel
(75mg/day) for 12 weeks. The primary end point was the complete
healing of ulcer at the intention-to-treat analysis at the end of therapy. The secondary aim of the study was the identification of risk
factors for unsuccessful therapy. The population of patients consisted of 218 patients (109 in the aspirin group and 109 in the clopidogrel group). There were no statistical demographic differences
between the two treatment groups. The success rates of the rabeprazoleclopidogrel and rabeprazoleaspirin groups were similar (86.2
vs 90.0%; p=0.531), and ulcer-related bleeding was not reported
in either group. A multivariate logistic regression analysis showed
that factors adversely affecting healing for aspirin-related PUD were
large ulcer size (>10mm; OR:6.29; 95% CI: 2.5815.37) and
history of PUD (OR: 3.69; 95% CI:1.2410.97). Accordingly,
it can be concluded that rabeprazole plus aspirin was not inferior
to rabeprazole plus clopidogrel in the therapy of aspirin-induced
symptomatic PUD; moreover, large ulcer size (>10mm) and history
of PUD were negatively related to healing.
Endoscopic submucosal dissection ulcer

Endoscopic submucosal dissection (ESD) has come to be considered

a reasonable alternative to surgery for the treatment of early gastric
cancer (EGC). Main advantages of ESD are the possibility of en
bloc resection of gastric lesions and a better quality of life after
tumor resection compared with traditional surgical therapy.
However, especially in the case of large-size EGC, very large
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Rabeprazole for the treatment of acid-related disorders

iatrogenic ulcers may result as a complication of this procedure,

although very few reports have been published regarding the
treatment of such ulcers [65] . Anecdotally, most patients with ESDderived iatrogenic ulcers heal with 8 weeks of treatment with a
PPI, but data are lacking for patients with such lesions and with
severe atrophic gastritis. Following a preliminary experience [66] , a
Japanese group of endoscopists have conducted a study examining
whether healing rates of the ESD-derived iatrogenic ulcers might
be improved by the addition of the non-PPI mucosal healing agent
rebamipide that was administered following ESD [67] . After this
procedure, patients were randomly treated for 8 weeks according
to two different modalities: one group received exclusively PPI,
namely rabeprazole, at a dose of 20mg daily, whereas those in the
combination group received both 20mg of rabeprazole and 300mg
of rebamipide daily. The primary end point was the percentage of
patients showing complete ulcer healing, up to a scar-stage after
56days of ESD. The secondary parameter was the healing rate
in the subset of patients with severe atrophic gastritis. Sixty four
consecutive patients with EGC treated with ESD participated
in the study. Overall, complete healing defined as progression to
scar-stage was observed in 54.8% of patients in the PPI group,
and in 86.7% of those in the combination group (OR: 5.3; 95%
CI:1.5019.02; p=0.006). In the subgroup of patients with severe
atrophic gastritis, complete healing was observed in 30.0% in the
PPI group and in 92.9% in the combination group (OR:30.3;
95% CI: 2.63348.91; p=0.0023). This study shows that a
combined treatment of PPI with rebamipide improves healing
rates at 8weeks for patients with ESD-derived iatrogenic ulcer,
particularly in patients with severe atrophic gastritis.
Safety & tolerability

Because PPIs are widely prescribed in all age populations, often to

patients with comorbid conditions (and therefore polymedicated)
and, in some instances, for prolonged periods of time, their safety
profile is an important aspect to be considered.
The tolerability of rabeprazole is good and similar in both shortand long-term (up to 5 consecutive years) clinical trials, including the maintenance phase [68,69] . A randomized, double-blind
trial evaluating efficacy and safety of 10 or 20mg rabeprazole
compared with 20mg omeprazole for the maintenance of GERD
over 5 years has confirmed that they were safe and well tolerated.
Serum gastrin levels were modestly raised in most patients, but it
was not clinically relevant in the majority of the cases. Particularly
high serum gastrin concentrations were observed in some patients
receiving omeprazole and this was related, possibly, due to genetic
polymorphism of the CYP2C19 and poor omeprazole metabolism. Because rabeprazole metabolism is nearly unaffected by
CYP enzymes, much less variability was observed in the rabeprazole group. Enterochromaffin-like cell hyperplasia occurred
only in a minority of patients and neither dysplasia nor neoplasia
of any enterochromaffin-like cell was observed, confirming the
idea that long-term PPI use does not have harmful effects [69] .
Postmarketing spontaneous reports of suspected adverse reactions confirm observations from clinical trials that the most
common adverse events are headache, nausea and diarrhea [70] .
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Drug Profile

Regarding the risk of drug interactions when PPIs are prescribed in association with other medications, the potential of
rabeprazole is extremely low because it is metabolized mainly via
the nonenzymatic pathway. Conversely from other PPIs, no clinically important interactions are demonstrated if rabeprazole is coadministered with CYP2C19-dependent drugs such as warfarin,
clopidogrel, ticlopidine, diazepam and phenytoin [18,19,7176] .
PK and PD studies, using platelet assays as surrogate end points,
showed that some PPIs affected the conversion of clopidogrel to
its active metabolite by inhibition of CYP2C19 with possible
attenuation of the antiplatelet function of clopidogrel. Because
the strongest evidence was for omeprazole and esomeprazole
[77,78], European and American Health Authorities replaced
the class warning for all PPIs with a warning stating that only
concomitant use of clopidogrel and omeprazole or esomeprazole
should be discouraged. On the other hand, a single prospective
randomized clinical trial is available in this setting and it showed
that omeprazole, given with clopidogrel, did not increase major
adverse CV events, but this study was prematurely interrupted
because of the sponsors financial issues. As the study did not enroll
sufficient number of patients, it is significantly underpowered and
does not exclude a potentially clinical interaction between the
two drugs, particularly in patients with acute coronary syndromes
(which, moreover, represented less than half of the sample size)
[79]. Adding to this, other studies demonstrated that PPIs with
less CYP2C19 inhibitory capacity could represent a more suitable
treatment in patients who require both clopidogrel and a PPI
[80]. Specifically, in this open debate on the potential interaction
between clopidogrel and PPI, two new studies with rabeprazole
have been recently presented at international congresses. The
first one was a crossover PK/PD study, in healthy volunteers,
comparing the effect of 20mg rabeprazole versus 20mg omeprazole
and versus placebo on antiplatelet activity of clopidogrel,
measured by the vasodilator-stimulated phosphoprotein
(VASP) phosphorylation test. The study end point was the
relative decrease on day7 in platelet reactivity index. This trial
demonstrated that, in a good antiplatelet responder population,
rabeprazole did not influence clopidogrel antiaggregation effect
versus placebo (difference between rabeprazole and placebo in
relative change in VASP test=3.4%; p=0.26), while omeprazole
reduced platelet inhibitory effects of clopidogrel in a statistically
significant manner (difference between omeprazole and placebo
in relative change in VASP test=7.5%; p=0.017 vs placebo)
[74]. The second one investigated the effect of CYP2C19
genetic polymorphism and concomitant use of rabeprazole or
esomeprazole on the antiplatelet effect of clopidogrel in CV
and neurologic patients. Esomeprazole seemed to exhibit an
inhibitory effect on the activity of clopidogrel independently of
loss of function mutations in CYP2C19 (on multivariate logistic
regression, use of esomeprazole was the only independent variable
associated with an abnormal in vitro response to clopidogrel;
p=0.021; OR=2.75) while rabeprazole did not appear to exert any
measurable effect. Some patients with abnormal in vitro response
to clopidogrel showed improvement in antiplatelet activity after
stopping esomeprazole or switching to rabeprazole[75].
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Marelli & Pace

Conclusion

Five-year view

With its peculiar PK/PD features, rabeprazole is a useful option

for the treatment of acid-related disorders. It provides fast and
sustained symptom relief, which can help ensure patient acceptance of therapy and aid in patient compliance. With its fast onset
of action, rabeprazole might be the ideal candidate for the ondemand maintenance therapy. Moreover, the fact that rabeprazole
shows its efficacy independently of the BMI and that it has a
low potential for drugdrug interactions could be the rationale
of choice in complex patients (e.g., overweight/obese patients,
polymedicated/elderly subjects).

With their profound, prolonged effect on acid inhibition, PPIs

are considered the first-choice therapy for acid-related disorders.
However, some improvements are still needed, especially with
the goal to better control overnight pH, to obtain a consistent
and reliable response in all GERD patients, including those with
NERD, and to improve healing of higher grade erosive esophagitis. To address these unmet therapeutic needs, new PPI formulations, novel long-acting PPIs, for example, tenatoprazole, and
new antisecretory agents, for example, the so-called reversible
inhibitors of proton pump (potassium competitive acid blockers),
are under clinical investigation. The rationale to develop these
drugs is that prolonged acid suppression can allow an improved
healing rate of severe esophagitis (due to a longer-lasting reduction of esophageal exposure to acid) and a reduction in frequency
and duration of nocturnal acid breakthrough episode, translating into better control of nocturnal symptoms without add-on
medication (H2 receptor antagonists). However, none of the above
drugs, for different reasons, has actually entered the market and
probably will not in the future as well. The last PPI introduced
into the US market, dexlansoprazole modified-release (designed
to provide a dual-peaked PK profile that prolongs the plasma
concentrationtime profile of the drug), is not available in Europe
and Italy. Thus, the next 5-year view is the availability of the
current PPIs, with no further progress.

Expert commentary

Rabeprazole is a second-generation PPI with peculiar PK and

PD properties. It has the highest pKa1, the fastest onset of action
and the most potent effect after first administration. It is also less
influenced by CYP2C19 genotype status of the patient.
Comparative head-to-head trials between rabeprazole and
esomeprazole, which have been shown to be superior in the healing of esophagitis to omeprazole, lansoprazole and pantoprazole
by a recent meta-analysis, are lacking [42,81] . However, in specific
subgroups of patients, that is, overweight/obese subjects, not only
is the clinical efficacy of rabeprazole maintained, but this subgroup of patients seems to benefit more from the drug, in that they
respond faster, in terms of symptom relief, to rabeprazole compared with omeprazole [52] . Although it is difficult to compare the
results obtained with other PPIs in different studies due to different patient populations and different experimental design, other
studies showed that the activity of other PPIs (i.e.,esomeprazole)
is influenced negatively by BMI [82,83] . Safety and tolerability
of rabeprazole are excellent, as documented also by continuous
administration for 5 years [62,63] , and the potential of drugdrug
interactions is very low [18,19,7176] .

Financial & competing interests disclosure

S Marelli belongs to Medical Department of Janssen-Cilag Italy. The authors

have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the
subject matter or materials discussed in the manuscript apart from those
disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
Rabeprazole is a more rapid and potent inhibitor of the gastric pump than other proton pump inhibitors.
Clinical studies of rabeprazole show rapid onset of action, with faster symptom relief, even on the first day of therapy.
Rabeprazole is safe and well tolerated, and due to its peculiar metabolism, reduced risks of drugdrug interactions are expected.
In long-term maintenance therapy, rabeprazole is suitable for on-demand modality.
Rabeprazole has shown clinical advantages in some subsets of gastroesophageal reflux disease patients, that is, polymedicated and
overweight/obese subjects.

Papers of special note have been highlighted as:

of interest
of considerable interest
1

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432

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960970 (2008).

Pharmacol. Ther. 17(12), 15071514

(2003).

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