Eur J Clin Pharmacol (2009) 65:19–31

DOI 10.1007/s00228-008-0576-5

REVIEW ARTICLE

Relative potency of proton-pump inhibitors—comparison

of effects on intragastric pH
Julia Kirchheiner & Silke Glatt & Uwe Fuhr &
Ulrich Klotz & Ingolf Meineke & Thomas Seufferlein &
Jürgen Brockmöller

Received: 23 June 2008 / Accepted: 22 September 2008 / Published online: 17 October 2008
# Springer-Verlag 2008

Abstract were restricted to those targeting the Caucasian population,

Aim Comparative potency of proton-pump inhibitors (PPIs) and healthy volunteers or gastroesophageal reflux disease
is an important clinical issue. Most available trials have (GERD) patients. The dose-effect relationships for mean
compared the different PPIs at one or a few selected 24-h intragastric pH and for percentage of time with pH>4
specific dosages, making it difficult to derive quantitative in 24 h were analyzed for each PPI using pharmacodynamic
equivalence dosages. Here we derived PPI dose equivalents modeling with NONMEM and a model integrating all
based on a comprehensive assessment of dose-dependent available data.
effects on intragastric pH. Results Fifty-seven studies fulfilled the inclusion criteria.
Methods All available clinical studies reporting the effects Based on the mean 24-h gastric pH, the relative potencies
of PPIs on mean 24-h intragastric pH were sought from of the five PPIs compared to omeprazole were 0.23, 0.90,
electronic databases including Medline. Studies included 1.00, 1.60, and 1.82 for pantoprazole, lansoprazole,
omeprazole, esomeprazole, and rabeprazole, respectively.
Compared with healthy volunteers, patients with GERD
needed a 1.9-fold higher dose and Helicobacter pylori-
positive individuals needed only about 20% of the dose to
J. Kirchheiner (*) : S. Glatt
achieve a given increase in mean 24-h intragastric pH.
Institute of Pharmacology of Natural Products and Clinical
Pharmacology, University of Ulm, Conclusion The present meta-analysis provides quantitative
Helmholtzstr. 20, estimates on clinical potency of individual PPIs that may be
89081 Ulm, Germany helpful when switching between PPIs and for assessing the
e-mail: julia.kirchheiner@uni-ulm.de cost-effectiveness of specific PPIs. However, our estimates
U. Fuhr must be viewed with caution because only a limited dose
Department of Pharmacology, Clinical Pharmacology, range has been tested and not exactly the same study
University of Cologne, conditions were applied for the different substances.
Cologne, Germany

U. Klotz Keywords Proton-pump inhibitor . PPI . Gastric pH .

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Acid suppression . Omeprazole . Lansoprazole .
Stuttgart, Germany Pantoprazole . Rabeprazole
T. Seufferlein
Department of Internal Medicine I, University of Halle,
Halle, Germany Introduction

I. Meineke : J. Brockmöller
Proton-pump inhibitors (PPIs) are the most effective drugs
Department of Clinical Pharmacology,
Georg August University Göttingen, in current treatment of acid-related gastrointestinal dis-
Göttingen, Germany orders such as gastroesophageal reflux disease (GERD) and
20 Eur J Clin Pharmacol (2009) 65:19–31

gastric or duodenal ulcer with and without Helicobacter uals, with higher mean pH values and better efficacy of
pylori infections. At present, there are five different PPIs in Hp-positive individuals [12–14]. There also might
substances on the market that have been extensively studied be differences in gastric pH values among patients with
in numerous comparative clinical trials [1–3]. Data from GERD since gastric acid production is significantly higher
meta-analyses indicate little difference in cure rates of acid- in GERD patients than in non-GERD patients due to
related diseases (i.e., GERD) at the approved doses of PPIs. differences in nocturnal acid production [15]. Finally, the
Also H. pylori eradication rates did not differ very much CYP2C19 genotype has been shown to have substantial
among different PPIs, indicating similar efficacy with effects on PPI exposure with higher plasma concentrations
different doses reflecting differences in potency [4, 5]. and better acid suppression in poor metabolizers [16]. This,
For the majority of the population, the currently used however, is epidemiologically more relevant in Asian
PPI doses may be in the flat plateau part of the dose countries where the frequency of the CYP2C19 poor
response curve, and therefore from comparative trials with metabolizer genotype is about 20% compared to only about
clinical endpoints, no precise estimates on relative potency 3% in Caucasians [17]. Optimally, the individual CYP2C19
of the PPIs can be deduced. To our knowledge, no genotype should be available for the comparison, but most
generally accepted tables or guidelines about equipotent studies did not provide this data.
PPI dosages have been developed. In clinical practice, For all the reasons given above, a comparative analysis
however, knowledge of the dose needed to obtain a certain has to consider the underlying disease, and potency of PPIs
effect in a patient is very important. Such information can only be compared within a given group (healthy
would also provide the rationale for dose selection when volunteers, ulcer patients, GERD patients) and within one
replacing one PPI by another, which is often desired as ethnic group (Africans, Asians, or Caucasians). In this
hospital formularies may be limited to a single PPI. In systematic analysis, we evaluated all available clinical
addition, in spite of the generally high efficacy, there are studies measuring effects on gastric pH in relation to drug
numerous poor responders to PPI treatment, and in such and dose in order to generate information on clinically
patients, one might wish to switch between different comparative dosages. Specifically, we derived equivalent
substances and would like to know the relative potencies dosages of PPIs from the mean 24-h pH and from the
more precisely. Finally, it may be relevant to know what percent of time with pH>4, taking the diagnosis of study
PPI potency can be obtained at what price. Due to the high participants into account.
prevalence of acid-related disorders this question is of
major pharmacoeconomic impact.
Pharmacodynamic effects of PPIs can be assessed in Methods
different ways. One common parameter is the continous
measurement of the intragastric pH over 24 h. In patients Data search and selection
with GERD, especially patients not responding to usual
therapies, esophageal and gastric pH monitoring is a useful A systematic search in Medline (http://www.ncbi.nlm.nih.
technique to assess compliance, pH control, and to inves- gov/entrez/query.fcgi) was performed using the international
tigate the association of reflux with therapy-refractory nonproprietary names of PPIs (esomeprazole, lansoprazole,
symptoms [6]. Intragastric pH monitoring in healthy omeprazole, pantoprazole, rabeprazole) in combination with
individuals allows direct assessment of acid suppression key terms “intragastric,” “gastric,” “pH,” “acid suppression,”
achieved with an agent and is useful for head-to-head “mean pH,” “intragastric acidity,” “acid secretion,” “24-
comparisons of antisecretory therapies, but it also may be hour.” In addition, we manually searched the bibliographies
helpful to guide clinicians in dose titration and in evaluating of key original or review articles for references not captured
the effect when switching agents. In clinical trials, acid by the systematic keyword search strategy. Since we found
suppression is typically assessed and summarized as the few data beyond that, we decided not to include articles from
mean pH over a defined time interval or as the percentage non-peer-reviewed journals, data published only on the
of time during which the pH is above 4 (used as surrogate manufacturer’s websites or given in the drug labeling,
parameter for the healing of GERD) or above 3 (used as conference abstracts, or studies available only on the
surrogate parameter for the healing of peptic ulcer) [7–9]. webpage of the U.S. Food and Drug Administration (FDA)
When evaluating variability in individual gastric pH (http://www.fda.gov/cder/approval/index.htm).
response, factors such as dose timing and food effect, as Two independent reviewers extracted the information
well as pharmacogenetic factors play a role [10, 11]. from the relevant articles into a database. Data were taken
Differences in intragastric pH have been described between from the text, tables, and figures. All clinical studies
Helicobacter pylori (Hp)-positive and Hp-negative individ- published through January 2007 in patients with GERD or
Eur J Clin Pharmacol (2009) 65:19–31 21

in healthy volunteers with intragastric 24-h pH monitoring For studies with the same PPI and dosage, overall means
were included. We restricted the patient studies to those weighted by sample size were calculated for the effect
with GERD because very few studies with 24-h pH assess- parameters as described in Eq. 1:
ment were available for other diseases such as peptic ulcer
or Zollinger-Elison syndrome. Studies performed exclu- P
M
sively in Hp-positive healthy volunteers or patients were nj x j
j¼1
analyzed separately [12, 13]. Finally, included studies were X ¼ ð1Þ
N
limited to those performed in Caucasians since there are
substantial interethnic differences influencing the relation-
with X being the overall mean, M the number of studies, N
ship between dose and effects on intragastric pH between
the overall number of subjects, nj the number of subjects in
Caucasian and Asian populations such as frequency of the
the individual study and xj the means of the individual
CYP2C19 metabolic genotype, which is relevant for all
studies. The overall variance S2 was calculated from the
PPIs, other genetic differences, mean body mass index, and
individual study means xj ; the individual sample size per
epidemiology of diseases [17, 18]. Thus, data obtained in
study n, and the individual standard deviations of the
Asian populations must be analyzed and published sepa-
studies (Eq. 2):
rately and may even result in a different ranking of the
relative potencies of the PPIs compared to Caucasian !
populations due to a differential impact of the CYP2C19 P
M P
n
2
s2
ðn  1Þ þ n
x2 N
X
genotype for the different PPIs. j¼1 i¼1
Finally, we only included data obtained with standard S2 ¼ ð2Þ
N 1
solid oral formulations (tablets or capsules). All doses
provided in this review refer to the dosing information as with i representing the individual subjects in the studies,
given by the manufacturer. Since rabeprazole doses refer to j representing the individual studies, M the number of
rabeprazole sodium, which contains 94.2% pure rabepra- studies, N the sum of the sample size of all studies and X
zole as the active pharmaceutical ingredient (API), whereas the overall mean calculated as weighted mean as described
all other PPIs doses refer to the pure base equivalent to above. Overall standard deviation was calculated as the
100% API, the true rabeprazole dose is 94% of the dose square root of that variance.
given in the drug description. Studies on intragastric pH after a single dose of a PPI
The aim was to gather data on as many drug dosages as were analyzed separately from studies in which pH
possible. Therefore, relatively broad inclusion criteria were measurement was performed under steady-state conditions
chosen. Since only the dose-effect relationship was analyzed, after several days of administration of the same dose. Data
we did not restrict the search to randomized controlled trials for patients with GERD were analyzed separately from data
only. In particular, phase I trials on intragastric pH in healthy in healthy volunteers. Studies that did not test for Hp status,
volunteers were conducted without a comparison group and studies with the average percentage of Hp-positive individ-
were included. If trials contained different study arms, the uals in the population, and studies excluding Hp-positive
arms relevant for our analysis were included, if possible. individuals were grouped together for analysis. In contrast,
studies including only Hp-positive individuals were ana-
Data analysis lyzed separately.

The following parameters were taken from each study when Estimation of equivalence dosages
available: identity and dosage of PPI, sample size, mean
24-h intragastric pH, and percentage of time with pH>4 in All available data concerning 24-h pH (125 different groups
24 h. When available, mean values for the effect parameters with sample sizes between 4 and 65 with a total of 2,738
and the respective parametric measurements of variability patients) were analyzed in one integrated model using
(standard deviation, standard error of the mean, or NONMEM V version 1.1. The individual studies were
confidence interval) were extracted. Standard errors of the weighted according to their sample size. The 24-h pH
mean and confidence intervals were transformed to stan- obtained during steady-state treatment with the respective
dard deviation for subsequent calculations. In some studies, PPI was analyzed in dependence of dose according to an
only median and nonparametric variability parameters such Emax model with baseline pH (pHbasal) as follows:
as range or interquartile range were given. In this case, we
included the median instead of the mean but we did not Emax dose
pH ¼ pHbasal þ
include the nonparametric variability parameters. ED50 þdose
22 Eur J Clin Pharmacol (2009) 65:19–31

or to calculate the doses required to achieve specific Potentially relevant trials

(n=304)
24-h pH values:
ED50
dose ¼ No original data (n=87), RCTs
pHpHbasal 
Emax
1 performed in non-Caucasian
populations (n=66)
Trials retrieved for more detailed
Emax is the maximum achievable increase in gastric pH evaluation (n=151)
above the baseline value measured prior to treatment.
ED50 is the dose required to obtain half-maximum increase Studies with other than oral
in pH and is modeled with a variance parameter reflecting formulations, in patients with
other diagnoses than GERD,
inter-disease variability (IIV) in an exponential error model. other outcome parameters than
Potentially appropriate articles
By including this parameter (IIV) for interindividual to be included (57)
24-h intragastric pH (n=93)
variation, differences among the three health-condition
groups (healthy volunteers, Hp-infected patients, GERD
Study arms from RCTs with
patients) were described. Differences in potency of the PPIs other formulations such as
were included in the final model as a factor (K) with intravenous or rapid release
lansoprazole as the reference since the most detailed data Trials with usable information
(n=57)
were available for this PPI. Therefore, K was arbitrarily set
to unity for this drug. Thus, with TVED50 as the overall
population estimate of the dose to achieve maximum
Fig. 1 Flow diagram on inclusion and exclusion of trials (randomized
increase in pH, in the final model it was ED50 =(TVED50 ± controlled trials, RCTs). Adapted from the Quorum statement flow
IIV)×K. diagram [93]
The potency factors were calculated by dividing the
ED50 of omeprazole by the ED50 of each PPI. They were
calculated for the parameters “mean 24-h pH” and was performed in 36 of 57 studies, and individuals positive
“percentage of time pH>4.” The absolute equivalence for Hp were excluded in 24 of the studies. In 10 studies,
doses were calculated compared to omeprazole 20 mg dose Hp-positive subjects (between 10 and 20%) were included.
by dividing by the potency factor. In 21 of the studies, Hp status was not tested and not used
as an inclusion or exclusion criterion.
Statistical testing In Table 1, the mean intragastric pH measured over 24 h
is listed for different doses of a PPI. Data are presented for
Differences among GERD patients, healthy volunteers, single-dose studies and multiple-dose studies (Table 1), and
and Hp-positive volunteers as well as between single and for healthy individuals or GERD patients, separately. The
multiple doses were analyzed using univariate analysis of mean pH and the standard deviations are presented
variance (ANOVA) with study, treatment (single dose/ weighted according to study sample sizes.
multiple dose), and disease status (GERD or healthy) as For omeprazole, data on 10, 20, and 40 mg daily doses
factors and either 24-h pH or percent time pH>4 as were found for single- and multiple-dosing conditions.
dependent variables. Statistical significance of two-group GERD patients had lower mean 24-h pH values than
comparisons was assessed by the Student’s t-test. healthy subjects, and multiple dosing increased pH signifi-
cantly compared to single doses (P<0.001 for both factors,
ANOVA). Even after a relatively small dose of 20 mg,
Results mean gastric pH was significantly higher (3.5 in healthy
[21–23] and 3.6 in patients [1, 3, 24, 25]) after multiple
A total of 304 publications of potentially relevant clinical compared to single dosages (1.8 in healthy [2, 26–28]).
trials were obtained from which 151 citations were retrieved For esomeprazole, data on dosages of 20, 40, and 80 mg
for further analysis. Trials using intravenous administration were identified. Most studies were performed in patients
of the drugs, studies in patients with diseases potentially with GERD, and these patients had a trend towards lower
influencing gastric pH, and studies that did not perform 24 h mean pH compared to healthy individuals after 40 mg
of gastric pH measurement were excluded resulting in 57 esomeprazole (4.4 vs. 4.8, P=0.07, based on seven studies
clinical studies included in the analysis (Fig. 1). Forty-three [1, 3, 24, 29–31, 32]).
of the studies were performed in healthy individuals, 12 in For pantoprazole, data on 10, 20, 40, 60, 80, and 120 mg
GERD patients, and 2 studies were performed exclusively dosages were found. For the 40 mg dose, data on both
in Hp-positive healthy individuals [19, 20]. Testing for Hp patients with GERD as well as healthy volunteers were
Eur J Clin Pharmacol (2009) 65:19–31 23

Table 1 Mean intragastric

pH±standard deviation over Substance Dose Participants pH (n of individuals) References
24 h after single doses and
multiple doses of proton-pump Single-dose studies
inhibitors (PPIs) Omeprazole 10 mg V 1.4 (27) [58]
20 mg V 1.8 (73) [2, 26–28]
40 mg V 3.8 (14) [59]
Esomeprazole 20 mg V 3.2±0.6 (48) [60, 61]
40 mg V 3.6±0.8 (101) [29, 60–62]
40 mg G 3.6±1.1 (94) [3]
Pantoprazole 40 mg V 2.9(132) [2, 26, 27, 38, 63, 64]
G 2.9±0.9 (60) [3, 65]
Lansoprazole 15 mg V 3.1±0.5 (65) [36]
30 mg V 3.4±0.5 (203) [2, 36, 38, 40, 66]
G 3.2±0.6 (30) [3]
Rabeprazole 5 mg HP 3.2±0.3 (19) [19]
10 mg V 3.1±0.6 (120) [36, 58, 61]
HP 3.9±0.3 (19) [19]
20 mg V 3.5±0.6 (218) [2, 28, 36, 60, 61, 65, 67]
G 3.3±1.1 (77) [3, 53, 68]
HP 4.6±0.3 (19) [19]
40 mg HP 5.3±0.3 (19) [19]
Multiple-dose studies
Omeprazole 10 mg V 1.9 (27) [58]
20 mg V 3.5±1.0 (122) [21–23]
G 3.6±0.1 (111) [1, 3, 24, 25]
HP 5.5 (18) [20]
40 mg V 4.6±1.4 (76) [22, 59, 69–71]
Esomeprazole 20 mg V 4.2±0.6 (48) [60, 61]
G 4.1 (36) [24]
40 mg V 4.8±0.7 (116) [29–31]
G 4.4±0.8 (199) [1, 3, 24, 32]
80 mg V 6.4 (30) [72]
G 5.1 (35) [32]
Pantoprazole 10 mg V 2.9±1.4 (36) [73]
20 mg V 3.2±1.7 (51) [73–75]
40 mg V 3.5±1.4 (195) [26, 27, 38, 63, 64, 73, 74–78]
G 3.6±0.9 (75) [1, 3, 79]
60 mg V 3.5 (14) [76]
80 mg V 4.3 (61) [72, 74, 75, 78]
G 4.7 (18) [80]
120 mg V 3.6 (15) [78]
Lansoprazole 10 mg V 4.3 (4) [81]
15 mg V 3.9±0.6 (94) [21, 36]
20 mg V 3.5 (4) [81]
30 mg V 4.1±0.7 (298) [21, 31, 34, 36–38,
Means were calculated as the 40, 41, 71, 81]
sample-size-weighted means of G 3.7±2.2 (100) [1, 3, 32]
the individual studies, the HP 5.4 (18) [20]
number following the ± symbol
60 mg V 4.7 (54) [21, 37, 71, 81]
is the standard deviation
80 mg V 4.4±3.6 (35) [32]
referring to between-subject
90 mg V 5.1 (35) [37, 71]
variability and calculated as
120 mg V 5.0 (35) [37, 71]
given in the “Methods”
section. Numbers in 180 mg V 5.1 (16) [37]
parentheses are the total Rabeprazole 5 mg HP 4.9±0.2 (19) [19]
number of subjects analysed in 10 mg V 4.1±0.6 (143) [36, 58, 61, 82]
the respective group. If only HP 5.7±0.3 (19) [19]
one study was available, the 20 mg V 4.5±0.5 (197) [28, 31, 36, 60, 61, 67, 82]
standard deviation within the G 3.3±1.1 (77) [3, 53, 68]
single study is given HP 6.2±0.3 (19) [19]
V Healthy volunteers, G 40 mg V 4.9 (24) [82, 83]
GERD, HP Helicobacter- HP 6.4±0.2 (19) [19]
positive healthy individuals
24 Eur J Clin Pharmacol (2009) 65:19–31

available (n=195 for healthy individuals and n=75 for 0.23, 0.90, 1.00, 1.60, and 1.82 for pantoprazole, lansopra-
GERD patients). No difference in mean pH was detected zole, omeprazole, esomeprazole, and rabeprazole, respec-
between the two groups (mean pH 3.5 vs. 3.6). tively. Compared with healthy volunteers, patients with
Data on lansoprazole were identified with daily doses of GERD needed a 1.9-fold higher dose and Hp-positive
10, 15, 20, 30, 60, 90, 120, and 180 mg. Most data were individuals needed only 15% of the dose to achieve a given
available for the 30 mg dose (multiple dosing), and signi- increase in mean 24-h intragastric pH (Table 3). There were
ficant differences were observed for mean 24-h pH in not sufficient data to find significant differences among the
healthy individuals versus GERD patients (5.1 versus 4.8, three subgroups (healthy, healthy with Hp, and patients
P=0.004 for 30 mg dose, t-test) [1, 3, 21, 23, 31–41]. with GERD) concerning the basal pH values prior to PPI
Data on single and multiple dosages of 5, 10, 20, and treatment and the maximum achievable pH (Emax).
40 mg of rabeprazole were available. One study in 18 Hp-
positive healthy individuals was included but analyzed
separately. Hp-positive individuals had higher mean pH Discussion
values at the given rabeprazole dosages compared to
healthy individuals (P=0.03 for multiple 20 mg doses). The present analysis provides estimates of the relative
GERD patients had lower mean pH compared to healthy potencies of PPIs based on peer-reviewed published data on
volunteers (mean pH at 20 mg multiple dosages was 3.3 for gastric pH effects. This information provides a rationale for
GERD patients and 4.5 for healthy individuals, P=0.004). mutual replacement of PPIs in clinical practice and for
In addition to the mean pH over time, in many clinical scientific comparisons of studies with different PPIs. Intra-
studies the percentage of time with pH>4 was used as a gastric pH measurements, particularly expressed as percent
surrogate parameter for the efficacy of PPIs in treatment of time with pH>4 (Table 3), are established biomarkers of
GERD. The data obtained for percentage of time (for 24 h) the therapeutic efficacy of PPIs [30]. Maintenance of pH>4
with pH>4 are shown in Table 2. Data are given as sample- is an important objective in management of GERD: when
size-weighted mean and standard deviation in patients and the pH of the acid reflux rate falls below 4, patients may
healthy volunteers for single and multiple doses. As can be experience mucosal injury in the esophagus [42, 43].
seen from the single-dose data, one single PPI dose is not
enough to obtain a pH>4 for 50% of the time or longer but Confounding factors and other limitations
with multiple dosing over several days, the aim to increase
pH above 4 was achieved for at least 70–80% with higher There are several confounding variables leading to vari-
dosages. There were no significant differences in mean ability among the individuals within the studies and to
percentage of time with pH>4 between patients with variability among the studies themselves, and probably not
GERD and healthy individuals for any of the PPIs. everything but only the most important factors should be
In Fig. 2, the reported percentages of time with pH>4 considered in our meta-analysis. Generally, for our analyses
for each PPI dose are depicted for GERD patients and we would have wished that for each of the five PPIs, the
healthy individuals. The values did not differ very much dose-response relationship would have been tested in the
between GERD patients and healthy individuals, which was dose range between 5 and 200 mg under the same clinical
in keeping with similar results in several individual studies. study conditions in subjects well characterized for Hp status
Population pharmacokinetic analysis of the entire dataset and disease status. This was apparently not the case and this
identified no interindividual variation for Emax, the maxi- of course limits the reliablity of the results of our meta-
mum possible increase in pH, and no discernable differ- analysis. Nevertheless, our comprehensive analysis may put
ences in Emax among the five PPIs. However, Hp-infected a new light on the relative potencies of the PPIs, which
patients formed a distinct group with a separate estimator cannot be obtained by in vitro measurements (since these
for ED50. The estimated ED50 values and the estimated would, for instance, not reflect differences in pharmacoki-
doses required to achieve a mean pH of 4 or less for each netics) and which cannot be obtained from studies focusing
PPI are summarized in Table 3. Estimations were only done on clinical endpoints, since these studies are less precise
for multiple-dose conditions, since single doses did not and have not been performed over a sufficient range of
allow the therapeutic goals to be met. dosages.
The estimated relationships between dose and mean Because of different basic pH and different responses
24-h pH are depicted in Fig. 3 for each PPI and separately to PPIs, we stratified the data into studies in healthy
for healthy volunteers, GERD patients, and Hp patients to individuals, GERD patients, and studies exclusively per-
the extent that the respective dose has been studied. formed in Hp-positive individuals. We did not mix up
Based on the mean 24-h gastric pH, the relative studies performed in Asian individuals with Caucasian
potencies of the five PPIs compared to omeprazole were individuals because of the differences in body mass index
Eur J Clin Pharmacol (2009) 65:19–31 25

Table 2 Mean percent dura-

tion of time with intragastric Substance Dose Participants Mean percent time References
pH>4 after single doses with pH<4
and multiple doses of proton-
pump inhibitors (PPIs) Single-dose studies
Omeprazole 10 mg V 10.8 (27) [58]
20 mg V 30.4 (57) [2, 26–28]
Esomeprazole 20 mg V 32.5±9.2 (48) [60, 61]
40 mg V 43.1±17.8 (101) [29, 61, 62, 65]
G 43.9±18.8 (94) [3]
Pantoprazole 40 mg V 29.2±18.0 (149) [2, 27, 34, 38, 64]
G 28.9±20.1 (60) [3, 60]
Lansoprazole 15 mg V 28.1±10 (65) [35]
30 mg V 39.1±12.8 (253) [2, 21, 34, 35, 38, 40, 66]
G 33.4±14.0 (30) [3]
Rabeprazole 10 mg V 29.8±13.2 (120) [36, 58, 61]
20 mg V 42.8±15.9 (177) [2, 28, 36, 60, 61, 65, 67]
G 34.9±15.2 (57) [3, 53, 68]
Multiple-dose studies
Omeprazole 10 mg V 18.3 (27) [58]
20 mg V 48.7±20.5 (126) [21–23, 27, 28, 35, 70]
G 45.5±19.7 (106) [1, 3, 24]
40 mg V 63.2±17.3 (83) [22, 23, 70, 84]
G 53.4±(49) [85]
Esomeprazole 20 mg V 56.3±7.4 (48) [60, 61]
G 53.0 (36) [24]
40 mg V 64.6±15.2 (212) [29–31, 86, 87]
G 62.5±18.9 (199) [1, 3, 24, 32]
80 mg V 84.9 (59) [72, 86]
G 81.0±24.1 (35) [32]
Mean duration of time with Pantoprazole 10 mg V 34.9±21.4 (36) [73]
pH>4 is depicted as sample- 20 mg V 42.4±23.6 (35) [73]
size-weighted mean value of 40 mg V 53.6±19.8 (269) [27, 38, 63, 64, 73, 87, 88]
the means of the different
G 43.3±16.5 (64) [1, 3]
studies. The number following
the ± symbol is the standard 80 mg V 70.8 (30) [72]
deviation referring to between- G 56.2 (18) [80]
subject variability and calcu- Lansoprazole 15 mg V 45.9±14.3 (123) [21, 35, 36, 39]
lated as given in the 30 mg V 55.1±14.4 (360) [21, 23, 31, 33–41]
“Methods” section. Numbers in G 48.0±15.5 (100) [1, 3, 32]
parentheses are the total 45 mg V 58 (12) [39]
number of subjects analyzed in 60 mg V 64.7 (76) [33, 37, 39, 89]
the respective group. Standard G 65.6±18.1 (35) [32]
deviation of the means of the
90 mg V 87 (16) [37]
different studies is given if
120 mg V 83 (16) [37]
more than one study was
available. Otherwise, the Rabeprazole 10 mg V 51.2±13.1 (143) [36, 58, 61, 82]
standard deviation within the 20 mg V 57.7±14.2 (197) [28, 31, 36, 60, 61, 67, 82]
single study is given G 50.8±15.3 (77) [1, 3, 53, 90]
V Healthy volunteers, 40 mg V 70.8 (24) [82]
G GERD

and differences in metabolizing activity due to genetics. In lot of data showing evidence that the CYP2C19 genotype
Asian populations, about 20% are poor metabolizers of has a tremendous impact on pharmacokinetics of PPIs, only
drugs metabolized by CYP2C19 including all PPIs [44]. a few studies in Caucasians assessed the influence of the
The activity and the genotype of the cytochrome P450 CYP2C19 genotype on mean 24-h intragastric pH. Thus,
enzyme CYP2C19, which determines to a large extent the the CYP2C19 genotype could not be integrated into our
pharmacokinetics of all five tested PPIs, was not directly model. However, since the CYP2C19 genotype influences
considered in this analysis because in the majority of drug metabolism, differences between the metabolizer
studies in Caucasians either the CYP2C19 genotype was groups on mean pH can be estimated from the differences
not analyzed or at least was not published. While there are a in drug exposure. In Table 4, the influence of the CYP2C19
26 Eur J Clin Pharmacol (2009) 65:19–31

Fig. 2 The upper figure (a)

shows the percentage of a Pantoprazole Lansoprazole Omeprazole Esomeprazole Rabeprazole
24-h time at which gastric pH
was above 4.0 in relation to the
dose of the PPI. Only data from
multiple dosing studies are 75

Percent time with pH > 4

shown. The lower figure (b)
shows the mean 24-h gastric pH
measurements from all multiple
dose studies analyzed in the 50
present review. These data are
the basis of the nonlinear re-
gression analysis presented in
Fig. 3 and Table 3. Data mea- 25
sured in healthy volunteers are
shown as circles, data from
patients with GERD are shown
as triangles and data from
Helicobacter pylori positive
0 40 80 120 160 0 40 80 120 160 0 40 80 120 160 0 40 80 120 160 0 40 80 120 160
healthy volunteers are shown as
squares Daily dose [mg]

b Pantoprazole Lansoprazole Omeprazole Esomeprazole Rabeprazole

7

6
Mean 24-h pH

0 40 80 120 160 0 40 80 120 160 0 40 80 120 160 0 40 80 120 160 0 40 80 120 160
Daily dose [mg]

Table 3 Parameters reflecting proton-pump-inhibitor effects on 24-h gastric pH according to an integrated population pharmacokinetic model

ED50 (mg/day)a Dose to achieve a mean 24-h pH of 4 (mg/day)

Healthy GERD Hp-infected Healthy GERD Hp-infected

Pantoprazole 239 (185–308) 445 (344–574) No data 89.2 166 No data

Omeprazole 54.2 (42.0–69.0) 101 (78–130) 8.0 (6.2–10.3) 20.2 37.7 3.0
Rabeprazole 29.8 (23.1–38.4) 55.6 (43.1–71.7) 4.4 (3.4–5.6) 11.1 20.7 1.6
Lansoprazole 60.5 (46.9–78.0) 112 (86.8–144) 8.88 (6.9–11.4) 22.6 41.8 3.3
Esomeprazole 33.9 (26.3–43.7) 63.3 (49.1–81.7) No data 12.6 23.6 No data
For all drugs
Basal pHb 3.06 3.06 3.06
Emax (pH)c 3.46 3.46 3.46
a
Numbers are means ± standard deviation calculated from the exponential error model
b
It is likely that basal pH differed between healthy volunteers with and without Helicobacter pylori (Hp) infection and patients with GERD,
however, it was not possible with the data collected in this meta-analysis to find significant differences among the three groups
c
According to the model used (see “Methods” section) this must be added to the basal pH for the maximum pH achieved
Eur J Clin Pharmacol (2009) 65:19–31 27

Fig. 3 Predicted mean 24-h pH

24-h pH according to the population pharmacodynamic modeling

7
values in relation to the dose of
the PPIs. Only predictions for
those dose ranges are shown
which have been studied as
given in Tables 1 and 2. The 6
curves depicted are for healthy
volunteers (circles), patients
with GERD (triangles) and H.p.
positive healthy volunteers 5 Healthy: Pantoprazole
(squares). The analysis yielding GERD
these mean estimates is de- Healthy: Omeprazole
scribed in the “Methods” GERD
section H.p.
4
Healthy: Rabeprazole
GERD
H.p.
Healthy: Lansoprazole
3 GERD
H.p.
Healthy: Esomeprazole
GERD

20 40 60 80 100 120 140 160 180

Dose/day of the respective proton pump inhibitor

genotype is expressed as a dose factor that can be derived population is about 10–20% [53], and because in those
from pharmacokinetic data on clearance or AUC (data studies including Hp-positive individuals, this fraction was
taken from [10, 11, 45–50]) and transformed by using the typically 16–20%, we decided to include such studies since
methods described earlier [51, 52]. Thus, the effects of this fraction of potentially Hp-positive individuals would
genotype on mean pH can be extrapolated when calculating not drastically alter the mean pH of the whole group. In
the genotype-specific dose by applying the dose correction addition, it also reflects the clinical situation in which GERD
factor to the dose given to the patients. patients treated with PPIs are usually not tested for Hp.
One confounding factor that could not be optimally We further neglected the time of dosing during the day
considered was Hp status. In about half of the studies and the dose splitting, and only referred to the daily dosages.
included, Hp was not tested, and in some studies, a small Of course, dose splitting has an effect on pharmacokinetics
fraction of Hp-positive individuals was included. Since the and also intragastric pH, but since in clinical practice, single
percentage of Hp-positive individuals in the normal daily doses are much more practicable and often the exact
time of drug intake is not known, we did not account for the
Table 4 Dose correction factors for CYP2C19 poor and intermediate influences of dose splitting during the day.
metabolizers. Data are from [10, 11, 45–50, 91, 92]

Extensive Intermediate Poor metabolizers: Dose equivalents according to the literature

metabolizers: metabolizers: CYP2C19*2/*2
CYP2C19*1/*1 CYP2C9*1/*2 Different national and international guidelines for dosing
of PPIs exist. The WHO Collaborating Centre for Drug
Omeprazole 1 0.33 0.12
Rabeprazole 1 0.58 0.37
Statistics Methodology (http://www.whocc.no/atcddd/) pro-
Lansoprazole 1 0.59 0.24 poses doses of 20 mg omeprazole, 30 mg esomeprazole,
Pantoprazole 1 0.23a 0.16 30 mg lansoprazole, 40 mg pantoprazole, and 20 mg
Esomeprazole 1 0.77 0.32 rabeprazole to be equivalent for the treatment of GERD.
From this recommendation, it is not at all evident why a
Differences are expressed as percent oral clearance or percent 1/AUC
compared to CYP2C19*1/*1 (normal metabolizer) genotype. Dose
higher dose of esomeprazole is recommended compared to
correction factors can be calculated by multiplying the factor by a that of racemic omeprazole. According to Table 3 and other
common dose in order to obtain the dosage necessary to obtain similar analyses [54], it is well documented that 30 mg omeprazole
pharmacokinetic parameters in CYP2C19 poor metabolizers. In would rather correspond to 20 mg esomeprazole.
contrast, drug exposure can be calculated by dividing a given dose
by the dose correction factor
The Canadian Association of Gastroenterology recom-
a
Data on CYP2C19*1/*2 and pantoprazole were only from one mends 20 mg omeprazole to be equivalent to 40 mg
study [92] esomeprazole, 30 mg lansoprazole, 40 mg pantoprazole,
28 Eur J Clin Pharmacol (2009) 65:19–31

and 20 mg rabeprazole for acute treatment of GERD [55]. patient. The equivalence doses assessed provide a rationale
Again, according to the clinical data, esomeprazole does for the appropriate dose selection for a patient when
not seem to be less potent than omeprazole [54], thus, the switching to a different PPI and for calculating the cost-
basis of the recommendation of twice the esomeprazole effectiveness of individual PPIs.
dose relative to omeprazole may be based on studies
showing a particular value of 40 mg esomeprazole dose Acknowledgements Part of the cost for compilation of this analysis
was provided by an educational grant from Eisai-Deutschland GmbH.
[24], but apparently not on comparison of pharmacologi-
cally defined potencies or efficacies.
The FDA provides dosages for the PPIs for approved Conflict of interest None of the authors has any conflict of interest
indications and for treatment of GERD (http://www.pbm. that might potentially bias this work.
va.gov/reviews/ppiabbreviatedreview.pdf). Different dos-
ages are given for symptom relief, to maintain symptom
control of nonerosive GERD, and to heal or maintain References
symptom relief of erosive or ulcerative esophagitis. The
omeprazole equivalents for symptom relief of GERD 1. Miner P Jr, Katz PO, Chen Y, Sostek M (2003) Gastric acid
are given by the FDA as 1 for esomeprazole, 0.75 for control with esomeprazole, lansoprazole, omeprazole, pantoprazole,
lansoprazole, 2 for pantoprazole, and 1 for rabeprazole. The and rabeprazole: a five-way crossover study. Am J Gastroenterol
98:2616–2620
comparative doses of PPIs according to the FDA were 2. Pantoflickova D, Dorta G, Ravic M, Jornod P, Blum AL (2003)
based on relative efficacies based on subjective or objective Acid inhibition on the first day of dosing: comparison of four
measures of response to treatment reported in double-blind, proton pump inhibitors. Aliment Pharmacol Ther 17:1507–1514
randomized controlled trials or systematic reviews in 3. Rohss K, Lind T, Wilder-Smith C (2004) Esomeprazole 40 mg
provides more effective intragastric acid control than lansoprazole
patients with gastrointestinal acid-related disorders. 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole
One meta-analysis of Caro et al. assessed the endoscopic 20 mg in patients with gastro-oesophageal reflux symptoms. Eur J
healing of erosive esophagitis [56]. The dosages for Clin Pharmacol 60:531–539
obtaining similar 8-week overall healing rates were omep- 4. Klok RM, Postma MJ, van Hout BA, Brouwers JR (2003) Meta-
analysis: comparing the efficacy of proton pump inhibitors in
razole 20 mg/day, lansoprazole 30 mg/day, rabeprazole short-term use. Aliment Pharmacol Ther 17:1237–1245
20 mg/day, and pantoprazole 40 mg/day. These estimates 5. Hellstrom PM, Vitols S (2004) The choice of proton pump
are in a similar range to our findings although the dosage of inhibitor: does it matter? Basic Clin Pharmacol Toxicol 94:106–
omeprazole would be slightly higher according to our data. 111
6. Katz PO (2006) Review article: intragastric and oesophageal pH
Another review comparing pharmacokinetics, acid monitoring in patients with gastro-oesophageal reflux disease.
suppression, and efficacy of PPIs concluded from com- Aliment Pharmacol Ther 23(Suppl 1):3–11
parative studies of acid suppression that lansoprazole and 7. Bell NJ, Hunt RH (1992) Role of gastric acid suppression in the
pantoprazole have a potency similar to that of omeprazole, treatment of gastro-oesophageal reflux disease. Gut 33:118–124
8. Burget DW, Chiverton SG, Hunt RH (1990) Is there an optimal
whereas rabeprazole had a greater potency than omepra- degree of acid suppression for healing of duodenal ulcers? A
zole on a per-milligram basis [57]. However, this was not a model of the relationship between ulcer healing and acid
systematic analysis of all available data on acid suppression suppression. Gastroenterology 99:345–351
at different PPI doses, and therefore could only provide a 9. Howden CW, Hunt RH (1990) The relationship between
suppression of acidity and gastric ulcer healing rates. Aliment
rough estimate of dose equivalents.
Pharmacol Ther 4:25–33
In summary, there are several guidelines for the different 10. Klotz U (2006) Clinical impact of CYP2C19 polymorphism on
PPIs with considerable differences in the dosage, leading the action of proton pump inhibitors: a review of a special
to a confusing picture concerning comparative efficacy of problem. Int J Clin Pharmacol Ther 44:297–302
PPIs. In none of the compilations are dose recommenda- 11. Klotz U, Schwab M, Treiber G (2004) CYP2C19 polymorphism
and proton pump inhibitors. Basic Clin Pharmacol Toxicol 95:2–8
tions comprehensive, and often individual selected studies 12. Verdu EF, Armstrong D, Fraser R, Viani F, Idstrom JP, Cederberg
appeared to be the basis of the recommendations. This lack C, Blum AL (1995) Effect of Helicobacter pylori status on
of true comparative efficacy data may be in part due to the intragastric pH during treatment with omeprazole. Gut 36:539–
comparison of the limited number of fixed doses, which 543
13. Gillen D, Wirz AA, Neithercut WD, Ardill JE, McColl KE (1999)
were not equivalent. In this context, using relevant data Helicobacter pylori infection potentiates the inhibition of gastric
published in an accessible way and under peer-reviewed acid secretion by omeprazole. Gut 44:468–475
conditions, the present analysis attempted to derive dose 14. Giral A, Celikel CA, Ozdogan O, Tozun N, Ulusoy NB, Kalayci
equivalents based on the effect on gastric pH, which is C (2005) Impact of Helicobacter pylori eradication on the anti-
secretory efficacy of lansoprazole in gastroesophageal reflux
known to be representative of the clinical efficacy. Of disease patients. J Gastroenterol Hepatol 20:1886–1891
course, our meta-analysis based on surrogate markers is not 15. Blonski WC, Shih GL, Brensinger CM, Katzka DA, Metz DC
intended to change daily clinical practice in a typical (2006) Analysis of the acidity index and integrated intragastric
Eur J Clin Pharmacol (2009) 65:19–31 29

acidity in 645 patients presenting with gastroesophageal reflux and rabeprazole 20 mg in healthy volunteers. Digestion 68:184–
disease symptoms. Scand J Gastroenterol 41:382–389 188
16. Furuta T, Shirai N, Sugimoto M, Nakamura A, Hishida A, Ishizaki 32. Johnson DA, Stacy T, Ryan M, Wootton T, Willis J, Hornbuckle
T (2005) Influence of CYP2C19 pharmacogenetic polymorphism K, Brooks W, Doviak M (2005) A comparison of esomeprazole
on proton pump inhibitor-based therapies. Drug Metab Pharma- and lansoprazole for control of intragastric pH in patients with
cokinet 20:153–167 symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol
17. Desta Z, Zhao X, Shin JG, Flockhart DA (2002) Clinical Ther 22:129–134
significance of the cytochrome P450 2C19 genetic polymorphism. 33. Dammann HG, von zur Muhlen A, Balks HJ, Damaschke A,
Clin Pharmacokinet 41:913–958 Steinhoff J, Hennig U, Schwarz JA, Fuchs W (1993) The effects
18. Spechler SJ, Jain SK, Tendler DA, Parker RA (2002) Racial of lansoprazole, 30 or 60 mg daily, on intragastric pH and on
differences in the frequency of symptoms and complications of endocrine function in healthy volunteers. Aliment Pharmacol Ther
gastro-oesophageal reflux disease. Aliment Pharmacol Ther 7:191–196
16:1795–1800 34. Freston J, Chiu YL, Pan WJ, Lukasik N, Taubel J (2001) Effects
19. Ohning GV, Barbuti RC, Kovacs TO, Sytnik B, Humphries TJ, on 24-hour intragastric pH: a comparison of lansoprazole
Walsh JH (2000) Rabeprazole produces rapid, potent, and long- administered nasogastrically in apple juice and pantoprazole
acting inhibition of gastric acid secretion in subjects with administered intravenously. Am J Gastroenterol 96:2058–2065
Helicobacter pylori infection. Aliment Pharmacol Ther 14:701– 35. Tolman KG, Sanders SW, Buchi KN, Karol MD, Jennings DE,
708 Ringham GL (1997) The effects of oral doses of lansoprazole and
20. Verdu EF, Fraser R, Armstrong D, Blum AL (1994) Effects of omeprazole on gastric pH. J Clin Gastroenterol 24:65–70
omeprazole and lansoprazole on 24-hour intragastric pH in 36. Tolman KG, Taubel J, Warrington S, Chiu YL, Pilmer BL, Pan
Helicobacter pylori-positive volunteers. Scand J Gastroenterol WJ (2006) Comparison of the effects of single and repeated oral
29:1065–1069 doses of lansoprazole and rabeprazole on ambulatory 24-hour
21. Blum RA, Shi H, Karol MD, Greski-Rose PA, Hunt RH (1997) intragastric pH in healthy volunteers. Clin Drug Investig 26:21–28
The comparative effects of lansoprazole, omeprazole, and ranitidine 37. Blum RA, Hunt RH, Kidd SL, Shi H, Jennings DE, Greski-Rose
in suppressing gastric acid secretion. Clin Ther 19:1013–1023 PA (1998) Dose-response relationship of lansoprazole to gastric
22. Delchier JC, Benamouzig R, Stanescu L, Ropert A, Vallot T, acid antisecretory effects. Aliment Pharmacol Ther 12:321–327
Wirquin V, Roudot F, Lamarque D, Hamelin B (1997) Twenty- 38. Florent C, Forestier S (1997) Twenty-four-hour monitoring of
four-hour intragastric acidity and plasma gastrin during 3-month intragastric acidity: comparison between lansoprazole 30 mg
treatment with omeprazole in healthy subjects. Aliment Pharmacol and pantoprazole 40 mg. Eur J Gastroenterol Hepatol 9:195–
Ther 11:747–753 200
23. Katz PO, Xue S, Castell DO (2001) Control of intragastric pH 39. Harder H, Teyssen S, Stephan F, Pfutzer R, Kiel G, Fuchs W,
with omeprazole 20 mg, omeprazole 40 mg and lansoprazole Singer MV (1999) Effect of 7-day therapy with different doses of
30 mg. Aliment Pharmacol Ther 15:647–652 the proton pump inhibitor lansoprazole on the intragastric pH in
24. Lind T, Rydberg L, Kyleback A, Jonsson A, Andersson T, healthy human subjects. Scand J Gastroenterol 34:551–561
Hasselgren G, Holmberg J, Rohss K (2000) Esomeprazole 40. Huang JQ, Goldwater DR, Thomson AB, Appelman SA, Sridhar
provides improved acid control vs. omeprazole in patients with S, James CF, Chiu YL, Pilmer BL, Keith RG, Hunt RH (2002)
symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol Acid suppression in healthy subjects following lansoprazole or
Ther 14:861–867 pantoprazole. Aliment Pharmacol Ther 16:425–433
25. Sagar M, Tybring G, Dahl ML, Bertilsson L, Seensalu R (2000) 41. Bell N, Karol MD, Sachs G, Greski-Rose P, Jennings DE, Hunt
Effects of omeprazole on intragastric pH and plasma gastrin are RH (2001) Duration of effect of lansoprazole on gastric pH and
dependent on the CYP2C19 polymorphism. Gastroenterology acid secretion in normal male volunteers. Aliment Pharmacol Ther
119:670–676 15:105–113
26. Hartmann M, Theiss U, Huber R, Luhmann R, Bliesath H, Wurst 42. Bell NJ, Burget D, Howden CW, Wilkinson J, Hunt RH (1992)
W, Lucker PW (1996) Twenty-four-hour intragastric pH profiles Appropriate acid suppression for the management of gastro-
and pharmacokinetics following single and repeated oral admin- oesophageal reflux disease. Digestion 51(Suppl 1):59–67
istration of the proton pump inhibitor pantoprazole in comparison 43. Armstrong D (2004) Review article: gastric pH - the most relevant
to omeprazole. Aliment Pharmacol Ther 10:359–366 predictor of benefit in reflux disease? Aliment Pharmacol Ther 20
27. Geus WP, Mathot RA, Mulder PG, Lamers CB (2000) Pharma- (Suppl 5):19–26, discussion 38–39
codynamics and kinetics of omeprazole MUPS 20 mg and 44. Wedlund PJ (2000) The CYP2C19 enzyme polymorphism.
pantoprazole 40 mg during repeated oral administration in Pharmacology 61:174–183
Helicobacter pylori-negative subjects. Aliment Pharmacol Ther 45. Lin CJ, Yang JC, Uang YS, Chern HD, Wang TH (2003) Time-
14:1057–1064 dependent amplified pharmacokinetic and pharmacodynamic
28. Williams MP, Sercombe J, Hamilton MI, Pounder RE (1998) A responses of rabeprazole in cytochrome P450 2C19 poor
placebo-controlled trial to assess the effects of 8 days of dosing metabolizers. Pharmacotherapy 23:711–719
with rabeprazole versus omeprazole on 24-h intragastric acidity 46. Shirai N, Furuta T, Moriyama Y, Okochi H, Kobayashi K,
and plasma gastrin concentrations in young healthy male subjects. Takashima M, Xiao F, Kosuge K, Nakagawa K, Hanai H, Chiba
Aliment Pharmacol Ther 12:1079–1089 K, Ohashi K, Ishizaki T (2001) Effects of CYP2C19 genotypic
29. Hammer J, Schmidt B (2004) Effect of splitting the dose of differences in the metabolism of omeprazole and rabeprazole on
esomeprazole on gastric acidity and nocturnal acid breakthrough. intragastric pH. Aliment Pharmacol Ther 15:1929–1937
Aliment Pharmacol Ther 19:1105–1110 47. Horai Y, Kimura M, Furuie H, Matsuguma K, Irie S, Koga Y,
30. Hunt RH (1995) The relationship between the control of pH and Nagahama T, Murakami M, Matsui T, Yao T, Urae A, Ishizaki T
healing and symptom relief in gastro-oesophageal reflux disease. (2001) Pharmacodynamic effects and kinetic disposition of
Aliment Pharmacol Ther 9(Suppl 1):3–7 rabeprazole in relation to CYP2C19 genotypes. Aliment Pharmacol
31. Wilder-Smith CH, Rohss K, Nilsson-Pieschl C, Junghard O, Ther 15:793–803
Nyman L (2003) Esomeprazole 40 mg provides improved 48. Sakai T, Aoyama N, Kita T, Sakaeda T, Nishiguchi K, Nishitora Y,
intragastric acid control as compared with lansoprazole 30 mg Hohda T, Sirasaka D, Tamura T, Tanigawara Y, Kasuga M,
30 Eur J Clin Pharmacol (2009) 65:19–31

Okumura K (2001) CYP2C19 genotype and pharmacokinetics of 63. Hartmann M, Ehrlich A, Fuder H, Luhmann R, Emeklibas S,
three proton pump inhibitors in healthy subjects. Pharm Res Timmer W, Wurst W, Lucker PW (1998) Equipotent inhibition of
18:721–727 gastric acid secretion by equal doses of oral or intravenous
49. Ieiri I, Kishimoto Y, Okochi H, Momiyama K, Morita T, Kitano pantoprazole. Aliment Pharmacol Ther 12:1027–1032
M, Morisawa T, Fukushima Y, Nakagawa K, Hasegawa J, Otsubo 64. Huang JQ, Hunt RH (2001) Pharmacological and pharmacodynamic
K, Ishizaki T (2001) Comparison of the kinetic disposition of and essentials of H(2)-receptor antagonists and proton pump inhibitors
serum gastrin change by lansoprazole versus rabeprazole during for the practising physician. Best Pract Res Clin Gastroenterol
an 8-day dosing scheme in relation to CYP2C19 polymorphism. 15:355–370
Eur J Clin Pharmacol 57:485–492 65. Warrington S, Baisley K, Dunn K, Boyce M, Morocutti A (2006)
50. Sugimoto M, Furuta T, Shirai N, Kajimura M, Hishida A, Sakurai Effects of single doses of rabeprazole 20 mg and esomeprazole
M, Ohashi K, Ishizaki T (2004) Different dosage regimens of 40 mg on 24-h intragastric pH in healthy subjects. Eur J Clin
rabeprazole for nocturnal gastric acid inhibition in relation to Pharmacol 62:685–691
cytochrome P450 2C19 genotype status. Clin Pharmacol Ther 66. Doan TT, Wang Q, Griffin JS, Lukasik NL, O’Dea RF, Pan WJ
76:290–301 (2001) Comparative pharmacokinetics and pharmacodynamics of
51. Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots lansoprazole oral capsules and suspension in healthy subjects. Am
I, Brockmoller J (2004) Pharmacogenetics of antidepressants and J Health Syst Pharm 58:1512–1519
antipsychotics: the contribution of allelic variations to the 67. Armstrong D, James C, Camacho F, Chen Y, Horbay GL, Teixeira
phenotype of drug response. Mol Psychiatry 9:442–473 B, Husein-Bhabha FA (2007) Oral rabeprazole vs. intravenous
52. Kirchheiner J, Brosen K, Dahl ML, Gram LF, Kasper S, Roots I, pantoprazole: a comparison of the effect on intragastric pH in
Sjoqvist F, Spina E, Brockmoller J (2001) CYP2D6 and CYP2C19 healthy subjects. Aliment Pharmacol Ther 25:185–196
genotype-based dose recommendations for antidepressants: a first 68. Warrington S, Baisley K, Lee D, Lomax K, Delemos B, Boyce M,
step towards subpopulation-specific dosages. Acta Psychiatr Scand Morocutti A (2007) Pharmacodynamic effects of single doses of
104:173–192 rabeprazole 20 mg and pantoprazole 40 mg in patients with GERD
53. Robinson M, Maton PN, Rodriguez S, Greenwood B, Humphries and nocturnal heartburn. Aliment Pharmacol Ther 25:511–517
TJ (1997) Effects of oral rabeprazole on oesophageal and gastric 69. Prichard PJ, Yeomans ND, Mihaly GW, Jones DB, Buckle PJ,
pH in patients with gastro-oesophageal reflux disease. Aliment Smallwood RA, Louis WJ (1985) Omeprazole: a study of its
Pharmacol Ther 11:973–980 inhibition of gastric pH and oral pharmacokinetics after morning
54. Gralnek IM, Dulai GS, Fennerty MB, Spiegel BM (2006) or evening dosage. Gastroenterology 88:64–69
Esomeprazole versus other proton pump inhibitors in erosive 70. Houben GM, Hooi J, Hameeteman W, Stockbrugger RW (1995)
esophagitis: a meta-analysis of randomized clinical trials. Clin Twenty-four-hour intragastric acidity: 300 mg ranitidine b.d.,
Gastroenterol Hepatol 4:1452–1458 20 mg omeprazole o.m., 40 mg omeprazole o.m. vs. placebo.
55. Armstrong D, Marshall JK, Chiba N, Enns R, Fallone CA, Fass R, Aliment Pharmacol Ther 9:649–654
Hollingworth R, Hunt RH, Kahrilas PJ, Mayrand S, Moayyedi P, 71. Timmer W, Ripke H, Kleist P, Ehrlich A, Wieckhorst G, Lucker
Paterson WG, Sadowski D, van Zanten SJ (2005) Canadian PW, Fuder H (1995) Effect of four lansoprazole dose levels and
Consensus Conference on the management of gastroesophageal one dosage regimen of omeprazole on 24-hour intragastric pH in
reflux disease in adults - update 2004. Can J Gastroenterol 19:15– healthy subjects. Methods Find Exp Clin Pharmacol 17:489–495
35 72. Miehlke S, Madisch A, Kirsch C, Lindner F, Kuhlisch E, Laass
56. Caro JJ, Salas M, Ward A (2001) Healing and relapse rates in M, Knoth H, Morgner A, Labenz J (2005) Intragastric acidity
gastroesophageal reflux disease treated with the newer proton- during treatment with esomeprazole 40 mg twice daily or
pump inhibitors lansoprazole, rabeprazole, and pantoprazole pantoprazole 40 mg twice daily-a randomized, two-way crossover
compared with omeprazole, ranitidine, and placebo: evidence study. Aliment Pharmacol Ther 21:963–967
from randomized clinical trials. Clin Ther 23:998–1017 73. Tutuian R, Katz PO, Bochenek W, Castell DO (2002) Dose-
57. Stedman CA, Barclay ML (2000) Review article: comparison of dependent control of intragastric pH by pantoprazole, 10, 20 or
the pharmacokinetics, acid suppression and efficacy of proton 40 mg, in healthy volunteers. Aliment Pharmacol Ther 16:829–
pump inhibitors. Aliment Pharmacol Ther 14:963–978 836
58. Bruley des Varannes S, Gharib H, Bicheler V, Bost R, Bonaz B, 74. Londong W (1994) Effect of pantoprazole on 24-h intragastric pH
Stanescu L, Delchier JC, Bonnot-Marlier S (2004) Effect of low- and serum gastrin in humans. Aliment Pharmacol Ther 8(Suppl 1):
dose rabeprazole and omeprazole on gastric acidity: results of a 39–46
double blind, randomized, placebo-controlled, three-way crossover 75. Reill L, Erhardt F, Fischer R, Huber R, Londong W (1993) Dose-
study in healthy subjects. Aliment Pharmacol Ther 20:899–907 response of pantoprazole 20, 40 and 80 mg on 24-hour intragastric
59. Hurlimann S, Abbuhl B, Inauen W, Halter F (1994) Comparison pH and serum gastrin in man (abstract). Gut 34(suppl 4):F251
of acid inhibition by either oral high-dose ranitidine or omeprazole. 76. Hannan A, Weil J, Broom C, Walt RP (1992) Effects of oral
Aliment Pharmacol Ther 8:193–201 pantoprazole on 24-hour intragastric acidity and plasma gastrin
60. Warrington S, Baisley K, Boyce M, Tejura B, Morocutti A, Miller profiles. Aliment Pharmacol Ther 6:373–380
N (2002) Effects of rabeprazole, 20 mg, or esomeprazole, 20 mg, 77. Ehrlich A, Lucker PW, Wiedemann A, Sander P, Huber R,
on 24-h intragastric pH and serum gastrin in healthy subjects. Mascher H (1999) Comparison of the pharmacodynamics and
Aliment Pharmacol Ther 16:1301–1307 pharmacokinetics of pantoprazole (40 mg) as compared to
61. Norris V, Baisley K, Dunn K, Warrington S, Morocutti A (2007) omeprazole MUPS (20 mg) after repeated oral dose administra-
Combined analysis of three crossover clinical pharmacology studies tion. Methods Find Exp Clin Pharmacol 21:47–51
of effects of rabeprazole and esomeprazole on 24-h intragastric pH in 78. Koop H, Kuly S, Flug M, Eissele R, Monnikes H, Rose K,
healthy volunteers. Aliment Pharmacol Ther 25:501–510 Luhmann R, Schneider A, Fischer R, Arnold R (1996) Intragastric
62. Galmiche JP, Sacher-Huvelin S, Bruley des Varannes S, Vavasseur pH and serum gastrin during administration of different doses of
F, Taccoen A, Fiorentini P, Homerin M (2005) A comparative study pantoprazole in healthy subjects. Eur J Gastroenterol Hepatol
of the early effects of tenatoprazole 40 mg and esomeprazole 40 mg 8:915–918
on intragastric pH in healthy volunteers. Aliment Pharmacol Ther 79. Armbrecht U, Abucar A, Hameeteman W, Schneider A,
21:575–582 Stockbrugger RW (1997) Treatment of reflux oesophagitis of
Eur J Clin Pharmacol (2009) 65:19–31 31

moderate and severe grade with ranitidine or pantoprazole- 86. Katz PO, Castell DO, Chen Y, Andersson T, Sostek MB (2004)
comparison of 24-hour intragastric and oesophageal pH. Intragastric acid suppression and pharmacokinetics of twice-daily
Aliment Pharmacol Ther 11:959–965 esomeprazole: a randomized, three-way crossover study. Aliment
80. Castell D, Bagin R, Goldlust B, Major J, Hepburn B (2005) Pharmacol Ther 20:399–406
Comparison of the effects of immediate-release omeprazole 87. Miner PB Jr, Tutuian R, Castell DO, Liu S, Sostek MB (2006)
powder for oral suspension and pantoprazole delayed-release Intragastric acidity after switching from 5-day treatment with
tablets on nocturnal acid breakthrough in patients with symptomatic intravenous pantoprazole 40 mg/d to 5-day treatment with oral
gastro-oesophageal reflux disease. Aliment Pharmacol Ther esomeprazole 40 mg/d or pantoprazole 40 mg/d: an open-
21:1467–474 label crossover study in healthy adult volunteers. Clin Ther
81. Sanders SW, Tolman KG, Greski PA, Jennings DE, Hoyos PA, 28:725–733
Page JG (1992) The effects of lansoprazole, a new H+,K(+)- 88. Goldstein JL, Miner PB Jr, Schlesinger PK, Liu S, Silberg DG
ATPase inhibitor, on gastric pH and serum gastrin. Aliment (2006) Intragastric acid control in non-steroidal anti-inflammatory
Pharmacol Ther 6:359–372 drug users: comparison of esomeprazole, lansoprazole and
82. Williams MP, Blanshard C, Millson C, Sercombe J, Pounder RE pantoprazole. Aliment Pharmacol Ther 23:1189–1196
(2000) A placebo-controlled study to assess the effects of 7-day 89. Katz PO, Hatlebakk JG, Castell DO (2000) Gastric acidity and
dosing with 10, 20 and 40 mg rabeprazole on 24-h intragastric acid breakthrough with twice-daily omeprazole or lansoprazole.
acidity and plasma gastrin in healthy male subjects. Aliment Aliment Pharmacol Ther 14:709–714
Pharmacol Ther 14:691–699 90. Toruner M, Bektas M, Cetinkaya H, Soykan I, Ozden A (2004) The
83. Eisai Corporation (2001) Clinical investigator’s brochure rabepra- effect of rabeprazole alone or in combination with H2 receptor
zole sodium (E3810, LY307640 sodium). Eisai, Teaneck, NJ blocker on intragastric pH: a pilot study. Turk J Gastroenterol
84. Hatlebakk JG, Katz PO, Kuo B, Castell DO (1998) Nocturnal 15:225–228
gastric acidity and acid breakthrough on different regimens of 91. Lou HY, Chang CC, Sheu MT, Chen YC, Ho HO (2008) Optimal
omeprazole 40 mg daily. Aliment Pharmacol Ther 12:1235–1240 dose regimens of esomeprazole for gastric acid suppression with
85. Katz PO, Koch FK, Ballard ED, Bagin RG, Gautille TC, Checani minimal influence of the CYP2C19 polymorphism. Eur J Clin
GC, Hogan DL, Pratha VS (2007) Comparison of the effects of Pharmacol. doi:10.1007/s00228-008-0552-0
immediate-release omeprazole oral suspension, delayed-release 92. Hunfeld NG, Mathot RA, Touw DJ, van Schaik RH, Mulder PG,
lansoprazole capsules and delayed-release esomeprazole capsules Franck PF, Kuipers EJ, Geus WP (2008) Effect of CYP2C19*2
on nocturnal gastric acidity after bedtime dosing in patients with and *17 mutations on pharmacodynamics and kinetics of proton
night-time GERD symptoms. Aliment Pharmacol Ther 25:197– pump inhibitors in Caucasians. Br J Clin Pharmacol 65:752–760
205 93. Clarke M (2000) The QUORUM statement. Lancet 355:756–757