Adv Ther
DOI 10.1007/s12325-016-0345-2
REVIEW
Characteristics of the Novel Potassium-Competitive
Acid Blocker Vonoprazan Fumarate (TAK-438)
Kazuyoshi Otake . Yuuichi Sakurai . Haruyuki Nishida . Hideo Fukui .
Yoshihiko Tagawa . Hitomi Yamasaki . Masatoshi Karashima .
Keiichi Otsuka . Nobuhiro Inatomi
Received: February 24, 2016
 Springer Healthcare 2016
Abstract: Proton pump inhibitors (PPIs) are
widely prescribed as first-line therapy for the
treatment of acid-related diseases, such as
peptic ulcers and gastro-esophageal reflux
disease, and for the eradication of Helicobacter
pylori. However, the therapeutic efficacy of
conventional PPIs is considered limited
because: (1) they are unstable under acidic
conditions and require an enteric-coated
formulation in clinical use; (2) they show high
interindividual variability in pharmacokinetics
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50CF12A4.
K. Otake (&)
Global Medical Affairs Japan Department, Takeda
Pharmaceutical Co., Ltd., Tokyo, Japan
e-mail: Kazuyoshi.otake@takeda.com
Y. Sakurai
Clinical Science, Takeda Development Center Japan,
Takeda Pharmaceutical Co., Ltd., Osaka, Japan
H. Nishida
Medicinal Chemistry Research Laboratories,
Pharmaceutical Research Division, Takeda
Pharmaceutical Co., Ltd., Kanagawa, Japan
H. Fukui
Drug Safety Research Laboratories, Pharmaceutical
Research Division, Takeda Pharmaceutical Co., Ltd.,
Kanagawa, Japan
due to genetic polymorphisms of cytochrome
P450 (CYP) 2C19 metabolism; (3) they have a
relatively slow onset of pharmacological action
and may require several doses to achieve
optimal acid suppression and symptom relief;
and (4) they often do not provide
stable suppression of gastric acid secretion
over 24 h. Vonoprazan fumarate (TAK-438,
hereinafter referred to as ‘‘vonoprazan’’) is a
new potassium-competitive acid blocker
(P-CAB) developed to resolve the above
limitations of conventional PPIs. Various
physicochemical data have shown that
vonoprazan has a high solubility and stability
Y. Tagawa
H. Yamasaki
Drug Metabolism and Pharmacokinetics Research
Laboratories, Pharmaceutical Research Division,
Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan
M. Karashima
Analytical Development Laboratories, CMC Center,
Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan
K. Otsuka
Analytical Development Laboratories, CMC Center,
Takeda Pharmaceutical Co., Ltd., Osaka, Japan
N. Inatomi
Extra Value Generation Drug Discovery Unit,
Pharmaceutical Research Division, Takeda
Pharmaceutical Co., Ltd., Kanagawa, Japan
 Adv Ther

over a broad pH range in aqueous conditions. In peptic ulcers caused by gastrin-producing

addition, vonoprazan has a more potent and tumors (Zollinger–Ellison syndrome) [1].
longer-lasting acid suppression effect than the Gastric acid is secreted from parietal cells of
conventional PPI, lansoprazole. Preclinical the gastric glands, situated in the mucosa of the
pharmacokinetic studies have shown that gastric fundus and the gastric corpus (Fig. 1).
vonoprazan is accumulated and retained in Histamine, acetylcholine, and gastrin stimulate
the stomach for more than 24 h, even after it gastric acid secretion through histamine (H2)
is eliminated from the plasma. From these receptors, muscarinic (M3) receptors, and
findings, we propose that vonoprazan, which cholecystokinin (CCK2) receptors, respectively,
possesses a novel mode of action, can improve which are present on the basolateral membranes
on the outcomes seen with conventional of parietal cells. Histamine activates adenylate
PPI-based treatments for acid-related diseases. cyclase by binding with H2 receptors, increasing
Funding: This review project, including the the intracellular cyclic adenosine
publication of this article, was funded by monophosphate concentration in cells.
Takeda Pharmaceutical Company Limited. Acetylcholine and gastrin increase intracellular
Ca2? concentration via the inositol
Keywords: Acid-related diseases; phospholipid pathway by binding with M3
Gastroenterology; Helicobacter pylori receptors and CCK2 receptors, respectively.
eradication; Lansoprazole; Stimulation of enterochromaffin-like cells by
Potassium-competitive acid blockers; PPI; gastrin also leads to histamine secretion. These
Proton pump inhibitor; Reflux esophagitis; intracellular messengers ultimately promote
TAK-438; Vonoprazan gastric acid secretion by activating relevant
protein kinases and by phosphorylating
proteins (Fig. 2) [2, 3].
INTRODUCTION: ACID-RELATED In the final step of gastric acid secretion, the
DISEASES AND THERAPEUTIC proton pump, H?,K?-ATPase induces the
STRATEGIES secretion of acid into the inner cavity of the
gastric gland (Fig. 1) [4]. H?,K?-ATPase is a
Acid-related diseases are a family of diseases membrane-bound protein and belongs to the
related to gastric acid, for which clinical effects P-type ATPase family. It forms heterodimers
are generally obtained by suppression of gastric consisting of a subunits and b subunits [5].
acid secretion. While this was previously Using the energy of ATP-hydrolysis, it transports
understood to be centered on peptic ulcers, H? to the inner cavity of the gastric gland against
such as gastric ulcers and duodenal ulcers, a concentration gradient of approximately 1
reflux esophagitis has also come to be million-fold (106), in exchange for K? into the
recognized as a significant pathological cytoplasm of parietal cells [6]. In response to the
condition due to adoption of Western-style movement of H?, HCO3- is transported out of
diet. Suppression of gastric acid secretion has the cytoplasm of the parietal cell by Cl-/HCO3-
become a common therapeutic strategy, as exchangers in the basolateral cell membrane in
evidenced by treatments for gastric mucosal exchange for Cl- into the cytoplasm. Cl- is
injury induced by continuous use of transported to the inner cavity of the gastric
non-steroidal anti-inflammatory drugs or gland through the Cl- channel in the apical
Adv Ther
Fig. 1 Parietal cell and proton pump. Reproduced
with permission from K. Otake, Y. Sakurai, H. Nishida
et al. Vonoprazan fumarate (TAK-438), a new
potassium-competitive acid blocker (P-CAB) with a
membrane of the parietal cell (Fig. 2). Although
the expression of H?,K?-ATPase a subunit mRNA
in humans has been observed in the stomach,
adrenal glands, cerebellum, pancreas, and
kidneys, the expression of the b subunit mRNA
has only been confirmed in the stomach.
Furthermore, with respect to the expression of
protein, both the a subunit and the b subunit
have only been observed in the stomach,
suggesting that the stomach is the only organ
in humans with significant levels of
H?,K?-ATPase [7]. Kraut reported the
H?,K?-ATPase expression in human kidney in
2001 [8]; however, as Herrmann’s investigation
showed that the amount of enzyme expression is
considered to be very small in kidney [7].
The morphology of the parietal cell
conspicuously differs between a resting state
and an active acid-secreting state. During the
resting state, H?,K?-ATPase mainly exists in
cytoplasmic tubulovesicles, but in the active
state, when the tubulovesicles and the secretory
canaliculi fuse, H?,K?-ATPase is exposed on the
novel mode of action—physicochemical properties,
non-clinical data, and a proposed mode of action. Prog
Med 2014;34:2183–2194
apical membrane, and functions as a proton
pump. In the secretory canaliculus,
H?,K?-ATPase is activated, because there is an
adequate supply of K?, but it does not function
as a proton pump in tubulovesicles due to the
lack of K? permeability [9].
It is known that the therapeutic effects for
acid-related diseases are enhanced in proportion
to the rise in intragastric pH. The target pH for
acid secretion suppression varies depending on
the acid-related disease. A meta-analysis showed
that following 24-h pH monitoring and clinical
test results of acid secretion inhibitors, the
optimal conditions for duodenal ulcer healing
are to maintain an intragastric pH of 3 or above
for 18–20 h of the day [10]. In patients with
reflux esophagitis, it has been shown that an
intragastric pH[4 is the target standard for
treatment [11, 12].
There is a long history of drugs used to
suppress gastric acid secretion including
anticholinergic agents and non-selective
muscarinic receptor antagonists, although

Fig. 2 Gastric acid secretion. Adapted with permission
from K. Otake, Y. Sakurai, H. Nishida et al. Vonoprazan
fumarate (TAK-438), a new potassium-competitive
acid blocker (P-CAB) with a novel mode of action—
physicochemical properties, non-clinical data, and a pro-
posed mode of action. Prog Med 2014;34:2183–2194.
cAMP cyclic adenosine monophosphate, CCK2 cholecys-
tokin2 receptor, 106 histamine2 receptor, M3 muscarinic3
receptor, ECL enterochromaffin-like cell
their clinical effects have been unsatisfactory. In
the latter half of the 1970s, the development of
H2 receptor antagonists (H2RA) led to a
dramatic improvement in the management of
peptic ulcer disease, due to their potent acid
secretion inhibitory effect. The introduction of
proton pump inhibitors (PPIs) during the 1990s
revolutionized the treatment of acid-related
diseases. This class of drugs demonstrated
significant therapeutic effects not only for the
treatment of peptic ulcer disease, but also for
reflux esophagitis. Thus, PPIs became the
first-line of therapy for treatment of
acid-related diseases [13].
The significance of Helicobacter pylori (H.
pylori) eradication was recognized when the
Adv Ther
correlation between H. pylori infection and
diseases including gastric cancer was reported.
To demonstrate adequate antimicrobial potency
in H. pylori eradication therapy, it is necessary to
have an environment of pH[5.0 in order to
promote the transition of H. pylori into the
proliferative phase [14]. Regimens including the
combination of an antimicrobial agent such as
clarithromycin and amoxicillin along with a
PPI, is the standard therapy in patients with H.
pylori [15].
However, the limits of treatment with PPIs
have become clear with the accumulation of
clinical experience.
The reflux symptoms are not adequately
controlled after the first dose of a PPI in
approximately two-thirds of symptomatic
gastroesophageal reflux disease (GERD)
patients, and about half of patients still suffer
symptoms even after a few days of initiating
therapies [16]. More than half of patients on
PPIs are dissatisfied with treatment [17]. In
addition, the so-called the nocturnal acid
breakthrough is a significant issue and difficult
to control as it may be receiving PPI twice daily
[18–20]. The ‘‘Japanese Guidelines for Diagnosis
and Treatment of Gastroesophageal Reflux
Disease 2009’’, states that: ‘‘PPIs demonstrate
effects that are superior to H2RA, but they
should still be improved with respect to acid
secretion suppression. In other words, a drug
that inhibits acid secretion promptly after
administration and controls acid secretion
over a 24-h period does not yet exist’’ [21].
For H. pylori eradication therapy, although
an eradication rate of 80% or more is considered
desirable [22], the eradication rate with the
conventional regimens using a PPI has declined
to 70% due to an increase in
antimicrobial-resistant bacteria [23].
This article is based on previously conducted
studies and does not involve any new studies of
Adv Ther
human or animal subjects performed by any of
the authors.
LIMITATIONS OF PPIS
AND DISCOVERY OF POTASSIUM-
COMPETITIVE ACID BLOCKERS
The current known limitations of PPIs are
summarized in the following four points [24]:
(1) since they are acid labile, there is a need for
preparation-related modifications such as
enteric-coated formulations; (2) there are
interindividual variations in pharmacokinetics
as they are mainly metabolized by cytochrome
P450 2C19 (CYP2C19) of the liver
drug-metabolizing enzyme that exhibits
genetic polymorphism; (3) show a slow onset
of action, usually taking 3–5 days for the
manifestation of optimal effects; (4) often a
stable inhibitory effect on acid secretion
cannot be sustained for 24 h, and hence PPIs
fail to adequately suppress nocturnal acid
secretion.
Development of drugs in order to overcome
the limitations of PPIs has long been attempted.
A new class of acid suppressants,
potassium-competitive acid blockers (P-CABs),
inhibit the K?-stimulated ATPase activity by
competing with the binding of K? to
H?,K?-ATPase and prevent K?-stimulated
dephosphorylation [25]. The compound that
was first discovered to block the H?,K?-ATPase
by this mechanism was SCH28080, an
imidazo[1,2a]pyridine derivative [26].
Subsequently, screening was conducted for
? ?
compounds that block H ,K -ATPase by
competitive inhibition of K? binding similar
to SCH28080, resulting in the discovery of
compounds such as pyrimidine derivatives,
imidazonaphthyridine derivatives, and
pyrrolopyridine derivatives. These compounds
are weakly basic, highly lipophilic, and stable at
a low pH. In clinical terms, it is anticipated from
these characteristics that the onset of the acid
secretion inhibitory effect will be rapid and a
near-maximum effect will be obtained from the
first dose. Several pharmaceutical companies
had proceeded with clinical development of
P-CABs, but development was suspended in all
cases due to their insufficient efficacy,
hepatotoxicity, and human Ether-a-go-go
related gene (hERG) channel blockage [27–30].
DISCOVERY OF VONOPRAZAN
FUMARATE
At Takeda Pharmaceutical Company Limited,
we initiated exploratory research with the
objective of discovering ‘‘the ultimate acid
secretion inhibitor’’ to overcome the
limitations of PPIs and eliminate issues of
insufficient efficacy and hepatotoxicity shown
by previously developed P-CABs.
We conducted high-throughput random
screening of our in-house chemical library,
and identified a pyrrole derivative with weak
H?,K?-ATPase inhibitory activity, which was
stable in acidic conditions (Fig. 3, Hit
Compound 1) [31]. This pyrrole derivative is
characterized by a structure having relatively
high basicity wherein a sulfonyl group is at the
1-position, an aromatic ring is at the
5-position, and an ethyl-amino-methyl group
is at the 3-position of the pyrrole ring. In
addition to having the advantages of a low
molecular weight and a large scope for
structural conversion, its chemical structure
was unique and unprecedented for an acid
suppressant.
In order to evaluate the potential of this hit
compound, we synthesized various pyrrole
derivatives, and studied the structure–activity

Fig. 3 Discovery of vonoprazan. Reproduced with
permission from K. Otake, Y. Sakurai, H. Nishida
et al. Vonoprazan fumarate (TAK-438), a new
potassium-competitive acid blocker (P-CAB) with a novel
relationship in detail. As a result, we succeeded
in discovering a novel pyrrole derivative (Fig. 3,
Lead Compound 2) with a more powerful and
sustained action than conventional PPIs [32].
Subsequently, based on this lead compound, we
conducted lead optimization focusing on
factors such as lipophilicity and the effects of
substituents. This process led to the discovery of
vonoprazan fumarate (development code:
TAK-438, hereinafter ‘‘vonoprazan’’), which
had a potent and sustained acid secretion
inhibitory effect combined with an excellent
pharmacokinetic (absorption, distribution,
metabolism, excretion) and toxicological
profiles, leading to the start of its development
(Fig. 3) [33].
Adv Ther
mode of action—physicochemical properties, non-clinical
data, and a proposed mode of action. Prog Med
2014;34:2183–2194
In preclinical testing and chemistry,
manufacturing, and control testing, vonoprazan
exhibited a gastric acid secretion inhibitory effect
that was more potent and sustained than
conventional PPIs and had satisfactory
physicochemical properties. In addition,
vonoprazan had no observable issues of
hepatotoxicity or hERG channel blockage [34].
Phase III clinical trials conducted in Japan for
indications including reflux esophagitis, gastric
ulcers, duodenal ulcers, and H. pylori eradication,
demonstrated potent efficacy and favorable safety
and tolerability [35–38]. An application for
approval of manufacture and sale of vonoprazan
was filed with the Japanese Ministry of Health,
Labor, and Welfare on February 28, 2014.
Adv Ther

CHARACTERISTICS Vonoprazan also exhibits satisfactory solubility

OF VONOPRAZAN
Excellent Physicochemical Properties
Vonoprazan has the following
physicochemical properties, thus, overcoming
the aforementioned limitations of PPIs.
Since the stability of vonoprazan under
acidic conditions is superior to that of
conventional PPIs, it has the major advantage
that it does not require an enteric coating. In an
acidic environment (pH 1*2) within the
stomach, vonoprazan is stable for at least 8 h
(Fig. 4a, internal company data), and exhibits
satisfactory stability even at a neutral pH.
over a wide pH range (Fig. 4b) [34] and has been
confirmed to rapidly dissolve from tablets
(Fig. 4c) [34]. These results have suggested that
vonoprazan has a rapid onset of action and can
superior exhibit a sustained gastric acid secretion
inhibition under the acidic environment of
secretory canaliculi.
Furthermore, vonoprazan is a basic
compound; the pKa (acid dissociation
constant) value of the side chain amino group
portion is 9.3. It exhibits highly satisfactory
membrane permeability in an environment of
pH 7.4, which is similar to the pH of blood. In
contrast, a clear decline in membrane
permeability has been confirmed in lower pH

A B
Time (h) Survival rate (%) pH Solubility (mg/mL)a
(pH 1.2*, 37ºC)
1.2 b 19.0
0 100.0 c
4.5 4.54
2 99.2
6.8 d 5.48
4 98.3 a
37ºC
6 97.2 b
First liquid of Japanese Pharmacopoeia elution
test liquids
8 96.0 c
0.05M acetic acid buffer liquid
d
* First liquid of Japanese Pharmacopoeia elution test Second liquid of Japanese Pharmacopoeia
liquids elution test liquids

C D Membrane
permeability*
Solvent pH (nm/sec)
First liquid of Japanese
Pharmacopoeia elution test 1.2 0
Elution rate (%)

liquids

PrismaTM universal buffer 3.0 0

TM
Prisma universal buffer 5.0 118

PrismaTM universal buffer 7.0 315

* Parallel Artificial Membrane Permeability Assay (PAMPA)

Time (minutes)

Fig. 4 Physicochemical properties of vonoprazan.
a Stability in acidic conditions (pH 1.2). b Solubility at
different pH values. c Elution test at different pH values.
d Membrane permeability at different pH values.
Reproduced with permission from K. Otake, Y. Sakurai,
H. Nishida et al. Vonoprazan fumarate (TAK-438), a new
potassium-competitive acid blocker (P-CAB) with a novel
mode of action—physicochemical properties, non-clinical
data, and a proposed mode of action. Prog Med
2014;34:2183–2194

Fig. 5 Inhibitory activity of vonoprazan and LPZ on
H?, K?-ATPase. Enzyme inhibitory activity was measured
after 40-min incubation of porcine H?, K?-ATPase with
different concentrations of a vonoprazan and b LPZ at pH 6.5
(closed circle) or pH 7.5 (open triangle). Adapted with permission
environments due to a further drop in the
non-ionic form of the compound (Fig. 4d,
internal company data). Based on these
chemical and structural properties, it may be
inferred that vonoprazan can rapidly move into
the acidic secretory canaliculi and remain there
over a long period [39].
The in vitro enzyme inhibitory activity of
the typical PPI, lansoprazole compared with
vonoprazan on isolated and purified porcine
H?,K?-ATPase is shown in Fig. 5. The IC50 of
vonoprazan at pH 6.5 and pH 7.5 were 0.019
and 0.028 lM, respectively. In contrast, the IC50
of lansoprazole at pH 6.5 and pH 7.5 were 6.8
and 66 lM, respectively. These results
demonstrate that vonoprazan has an
? ?
H ,K -ATPase inhibitory activity that is
358–2357 times stronger than that of
lansoprazole in the weakly acidic to neutral
range pH, and is not significantly affected by pH
[40].
Minimal Interindividual Variation
in Pharmacokinetics
Cytochrome P450 2C19 (CYP2C19) and 3A4
(CYP3A4) are the main liver enzymes that
metabolize PPIs. Genetic polymorphisms in
Adv Ther
from K. Otake, Y. Sakurai, H. Nishida et al. Vonoprazan
fumarate (TAK-438), a new potassium-competitive acid blocker
(P-CAB) with a novel mode of action—physicochemical
properties, non-clinical data, and a proposed mode of action.
Prog Med 2014;34:2183–2194
CYP2C19 isoenzymes cause interindividual
variations in the efficacy of PPIs. The genetic
polymorphism of CYP2C19 can be determined
by a single nucleotide polymorphism of exon 4
and exon 5, and is classified into homozygous
extensive metabolizer (homoEM: *1/*1),
heterozygous extensive metabolizer (hetEM:
*1/*2 or *1/*3), and poor metabolizer (PM: *2/
*2 or *2/*3 or *3*3) in the combination of
CYP2C19*2 (*2) and CYP2C19*3 (*3) [41–43]. It
is known that variation in CYP2C19 activity is
greater in Japanese people than in Europeans
and North Americans. The rate of PM
prevalence is 1–2% in Europeans and North
Americans, and approximately 20% in Asians
[44]. In a study which analyzed 300 Japanese
people, the prevalence of homoEM was 35%,
hetEM was 49%, and PM was 16% [45]. In
people with homoEM, PPIs are rapidly
metabolized, leading to a low blood
concentration, whereas in people with PM, the
blood concentration of PPIs is high due to their
low metabolic activity. Interindividual
variation in the pharmacokinetics of PPIs also
affects therapeutic efficacy. Administration of
lansoprazole 30 mg daily over an 8-week period
to Japanese patients with gastroesophageal
reflux disease resulted in cure rates of 45.8,
Adv Ther
67.9, and 84.6% in patients with homoEM,
hetEM, and PM, respectively. These results
suggest a significant correlation between the
therapeutic effects of lansoprazole and
CYP2C19 activity in Japanese patients with
gastroesophageal reflux disease [46].
Vonoprazan is metabolized by multiple
enzymes including CYP3A4 and a to sustain gastric acid secretion inhibitory
non-oxidative enzyme (sulfotransferase).
CYP2C19 partially contributes to the
metabolism of vonoprazan [47], and its
contribution is considered to be small.
Single-dose or repetitive oral administration of
vonoprazan to healthy Japanese adults did not
show any significant correlation of the
CYP2C19 genotype with total drug exposure
(area under the curve from time 0 to infinity;
AUC0-inf) and maximum serum concentration
(Cmax) [48, 49].
Optimal Efficacy can be Expected
from the First Dose
It is known that PPIs require several days to
have a maximum effect. Even when PPIs
migrate into parietal cells, they are not
converted to the active form in the cytoplasm
or in the tubulovesicles, and are thus unable to
inhibit H?,K?-ATPase within the tubulovesicles.
The site where PPIs are activated is the secretory
canaliculus of the parietal cell. They migrate
into the secretory canaliculus, where they are
then converted into the active form
(sulfenamide form) in a strongly acidic
environment. The active form then inhibits
acid production by forming disulfide bonds (S–S
bonds) with the cysteine residue of
H?,K?-ATPase on the secretory canaliculus [50].
However, as active forms of PPIs are easily
decomposed in acid, they are unable to inhibit
? ?
all of the H ,K -ATPase of the secretory
canaliculus. Moreover, the plasma half-life of
PPIs after oral administration is short (1–2 h),
and the concentration of the active form of PPIs
existing in the secretory canaliculus decreases
over a short time [51]. On the other hand, the
half-life of H?,K?-ATPase is approximately 50 h
and 25% of H?,K?-ATPase is newly
biosynthesized each day [52]. PPIs are unable
action against H?,K?-ATPase that is constantly
being produced and supplemented.
Thus, in order to demonstrate their
maximum effect, 3–5 days of repeated
administration of PPIs is required to achieve a
steady-state concentration and consistent
clinical effects [53–56].
In contrast, as already described, vonoprazan
is stable in acid, and non-covalently binds with
H?,K?-ATPase in competition with K? [40].
In vitro studies in HEK293 that express rabbit
H?,K?-ATPase cells showed that non-labeled
vonoprazan (2.5 lg/mL) was able to substitute
half of the [14C] vonoprazan (50 nM) within
4.7 h. The binding was extremely stable and the
dissociation was gradual [57]. This slow
dissociation rate can also be explained from
the structural and biological findings relating to
P-CABs. An electron diffraction analysis of
porcine H?,K?-ATPase and SCH28080, a
prototype of P-CABs, using cryo-electron
microscopy, revealed that a major structural
change is induced over the entirety of the
molecule by inhibitor binding. As a result of
inhibitor binding, the transmembrane helix
constitutes widely open luminal-open
conformations, and the linker that connects
the M2 helix of the transmembrane domain
and the A domain inside the cytoplasm
subsequently forms an a-helix. This structural
change triggers a reconfiguration of the entire
cytoplasm domain, closely resembling the
E2P ground state homologous to sarcoplasmic
reticulum Ca2?-ATPase and other P2-type

Fig. 6 Accumulation of vonoprazan and LPZ in cultured
rabbit fundic glands. Primary cultured rabbit fundic glands
were incubated with different concentrations of a [14C]
vonoprazan and b [14C] LPZ for 15, 30, 60, and 120 min.
Accumulation was measured after washing. Reproduced
with permission from K. Otake, Y. Sakurai, H. Nishida
ATPase families [58]. For this reason,
dissociation of the inhibitor requires a major
conformational change with an orientation that
is the reverse of binding, and with dissociation
rate that is extremely slow.
Vonoprazan can accumulate over a longer
period in the gastric fundic glands than PPIs.
Results of accumulation experiments conducted
with respect to vonoprazan and lansoprazole
using isolated primary cultured rabbit gastric
fundic glands are shown in Fig. 6. Remaining
concentration measurements after conducting
washout following incubation of [14C]
14
vonoprazan and [ C] lansoprazole at various
concentrations (0.01, 0.03, 0.1, 0.3 lM) with
primary cultured rabbit gastric fundic glands for
15, 30, 60, and 120 min, showed that
vonoprazan was accumulated at higher
concentrations than lansoprazole [59]. A study
of the acid secretion inhibitory effect after
incubating rabbit cultured gastric fundic
glands with vonoprazan and lansoprazole for
2 h showed that the acid secretion inhibitory
effect of lansoprazole disappeared immediately
after washout, while the acid secretion
Adv Ther
et al. Vonoprazan fumarate (TAK-438), a new
potassium-competitive acid blocker (P-CAB) with a novel
mode of action—physicochemical properties, non-clinical
data, and a proposed mode of action. Prog Med
2014;34:2183–2194
inhibitory effect of vonoprazan was sustained
even at 8 h after washout [59].
Maximum Effect is Sustained over a Long
Period
A study was performed to demonstrate the
duration of effect of vonoprazan in rats. When
drug concentrations in plasma and the stomach
wall were measured up to 24 h after oral
administration of 2 mg/kg of [14C] vonoprazan
to rats, vonoprazan concentrations in plasma
and the stomach wall at 0.25, 1, 2, and 24 h
after administration were 23, 11, 5, and 0 ng/
ml, respectively, in plasma and 2412, 957, 941,
and 20 ng/g, respectively, in the stomach wall
(Fig. 7). These results show that following oral
administration to rats, vonoprazan rapidly
disappears from plasma, but remains in the
stomach even after 24 h [39].
A study of the inhibitory effect on
histamine-stimulated gastric acid secretion up
to 48 h after oral administration of vonoprazan
and lansoprazole to Heidenhain pouch dogs
showed that when 1 mg/kg of vonoprazan was
Adv Ther
Fig. 7 Concentration of vonoprazan in the plasma and
gastric wall of rats after oral administration. Plasma
concentration (ng/mL) and gastric wall concentration
(ng/g) were measured at 0.25, 1, 2, and 24 h after oral
administration of 2 mg/kg of [14C] vonoprazan to rats.
Reproduced with permission from K. Otake, Y. Sakurai,
H. Nishida et al. Vonoprazan fumarate (TAK-438), a new
potassium-competitive acid blocker (P-CAB) with a novel
mode of action—physicochemical properties, non-clinical
data, and a proposed mode of action. Prog Med
2014;34:2183–2194
administered, an inhibitory effect of
approximately 100, 80, and 60% was sustained
from 1 to 6, 24, and 48 h, respectively. On the
other hand, lansoprazole exhibited an
inhibitory effect of approximately 100% at 1 h
after administration of 3 mg/kg, but the effect
was not sustained, and had almost completely
disappeared at 48 h after administration (Fig. 8)
[39]. Another study showed that inhibitory
effects on histamine-stimulated gastric acid
secretion from 4h after intraperitoneal
administration of vonoprazan (0.7 mg/kg) or
lansoprazole (1 mg/kg) to rats whose gastric pH
had been temporarily raised to near neutral by
intravenous administration of cimetidine
(30 mg/kg), an H2RA, the acid secretion
inhibitory effect of vonoprazan was sustained
and unaffected by pH, while lansoprazole
exhibited an acid secretion inhibitory effect
only under acidic conditions (Fig. 9) [39]. These
results reveal that the gastric acid secretion
inhibitory effect of vonoprazan is more potent
and longer-lasting than that of lansoprazole,
and that its effect is not influenced by gastric
acid secretory conditions.
These results are also supported by clinical
pharmacology testing. In a pH monitoring test
of healthy adults, vonoprazan exhibited a
dose-dependent acid secretion inhibitory
effect. In the vonoprazan 40 mg
administration group, the acid secretion
inhibitory effect (pH[6) was sustained for
almost 24 h [48, 49]. A study of the food-effect
on the pharmacokinetics of vonoprazan showed
that the total drug exposure (area under the
curve from time 0 to 48 h; AUC0–48) and Cmax of
vonoprazan were similar in both fasting and fed
conditions [60]. These results show that the
maximum effect of vonoprazan is sustained for
24 h, and is unaffected by gastric pH or meals.
It is well known that the efficacy of PPIs is
affected by food intake, and it is recommended
that they are prescribed to be taken 30–60 min
before food intake for optimal efficacy [61]. On
the other hand, the efficacy of vonoprazan is
unaffected by food intake, is highly acid stable,
and has an acid secretion inhibitory effect that
is not influenced by gastric acid secretory
conditions [39]. Therefore, vonoprazan is also
superior to PPIs in terms of administration
irrespective of food intake.
THE MECHANISM OF ACTION
OF VONOPRAZAN ESTIMATED
FROM THE DATA
The aforementioned characteristics of
vonoprazan can be explained by the following
mechanism of action in comparison with the
mechanism of action of conventional PPIs.
When PPIs are orally administered, the
enteric-coated formulation is not dissolved in
the stomach. However, since movement inside

Fig. 8 Inhibitory effect of vonoprazan and LPZ on
histamine-stimulated gastric acid secretion in Heidenhain
pouch dogs. Vonoprazan and LPZ were administered orally.
Histamine 2HCl (30 lg/kg) was injected subcutaneously
1 day before and 1, 3, 6, 24 and 48 h after drug and vehicle
administration. Reproduced with permission from K.
Fig. 9 Inhibitory effect of vonoprazan and LPZ on
histamine-stimulated gastric acid secretion in rats after
cimetidine pretreatment. Cimetidine (30 mg/kg) or a
vehicle was injected intravenously, and after 15 min
vonoprazan at 0.7 mg/kg, LPZ at 1 mg/kg, or a vehicle
was administered intraperitoneally. The pylorus was ligated
and histamine (30 mg/kg s.c.) was administered 4 h after
drug or vehicle administration. Gastric contents were
Adv Ther
Otake, Y. Sakurai, H. Nishida et al. Vonoprazan fumarate
(TAK-438), a new potassium-competitive acid blocker
(P-CAB) with a novel mode of action—physicochemical
properties, non-clinical data, and a proposed mode of
action. Prog Med 2014;34:2183–2194
collected 3 h after histamine administration. Reproduced
with permission from K. Otake, Y. Sakurai, H. Nishida
et al. Vonoprazan fumarate (TAK-438), a new
potassium-competitive acid blocker (P-CAB) with a novel
mode of action—physicochemical properties, non-clinical
data, and a proposed mode of action. Prog Med
2014;34:2183–2194
Adv Ther
Fig. 10 Comparison of mechanism of action of vonoprazan
and PPIs (hypothetical). a Suppression of gastric acid
secretion by vonoprazan. b Suppression of gastric acid
secretion by PPIs. Adapted with permission from K. Otake,
Y. Sakurai, H. Nishida et al. Vonoprazan fumarate
the digestive tract is influenced by gastric
peristalsis and gastric emptying, variations
occur in the time required to reach the small
intestine [62]. Furthermore, PPIs, which are
absorbed in the small intestine undergo
hepatic metabolism to differing degrees by the
genetically polymorphic CYP2C19, resulting in
interindividual variations in drug exposure [63].
Vonoprazan, which does not need to be an
enteric-coated formulation, readily dissolves in
the stomach when orally administered, and
moves to the small intestine where it is
absorbed by the mucosa of the small intestine.
Unlike PPIs, vonoprazan is not primarily
metabolized by CYP2C19, and thus, the acid
(TAK-438), a new potassium-competitive acid blocker
(P-CAB) with a novel mode of action—physicochemical
properties, non-clinical data, and a proposed mode of action.
Prog Med 2014;34:2183–2194
secretion inhibitory effects do not differ
significantly among individuals. Vonoprazan,
which is basic, diffuses by passive transport
from the parietal cell cytoplasm into the
secretory canaliculi in high concentrations.
The vonoprazan molecule which has now
migrated into acidic space, and which has
undergone protonation in a strongly acidic
environment, non-covalently binds with
H?,K?-ATPase in a K?-competitive manner,
thereby blocking H? secretion. In a strongly
acidic environment, when the ratio of the
non-ionic type of vonoprazan decreases, and
membrane permeability declines, passive
transport from the acidic space in the parietal

cell to the cytoplasm is inhibited, and it is
retained for a long period inside the parietal
cell. Consequently, vonoprazan is also capable
of exhibiting inhibitory action against
H?,K?-ATPase that is activated by further
stimulation of acid secretion that occurs after
the decline in blood concentration.
On the other hand, when PPIs accumulate in
the secretory canaliculus of the parietal cells,
they are converted to the active form in the
presence of acid. H?,K?-ATPase pumps are
activated primarily by food and the active
form of the PPI blocks secretion of H? by
covalently binding with H?,K?-ATPase.
?
The dissociation rate of vonoprazan from H ,
?
K -ATPase is slow, and it is not decomposed by
acid. Therefore, binding of vonoprazan to
H?,K?-ATPase is maintained even after secretion
stimulus ceases. H?, K?-ATPase on the apical
membrane of the secretory canaliculus is again
taken into the tubulovesicles and migrates into
the parietal cell.
The plasma half-life of PPIs is relatively
short—approximately 1–2 h. Consequently,
after PPIs have been eliminated from the
blood, they no longer exhibit inhibitory action
? ?
against newly activated H ,K -ATPase. The
potent acid inhibitory effect is not
demonstrated after the first dose, and the
amount of inactivated H?, K?-ATPase increases
over repeated administration. Therefore, it is
necessary to repetitively administer PPIs over
3–5 days to reach steady-state inhibition of acid
secretion [64].
The mechanism described above is
schematically represented in Fig. 10.
CONCLUSION
Vonoprazan is an acid secretion inhibitor,
which has overcome the limitations of PPIs
that are currently the first choice among drugs
Adv Ther
for treatment of acid-related diseases, including
GERD, and for H. pylori eradication.
The characteristics of vonoprazan are
summarized as follows.
• It is stable in acid.
• It has satisfactory solubility under acidic to
neutral conditions.
• It has satisfactory membrane permeability
under neutral conditions.
• It has stronger H?,K?-ATPase inhibitory
activity than PPIs under acidic to neutral
conditions, and its activity is minimally
affected by pH.
• CYP2C19 has little effect on its metabolism.
• There is no need for conversion to an active
form.
• Its rate of dissociation from H?,K?-ATPase is
very slow.
• Its retention time in the gastric mucosa is
long (24 h or more).
Vonoprazan non-covalently binds
? ? ?
H ,K -ATPase in a K -competitive manner,
thereby inhibiting its activity. Based on the
aforementioned characteristics of vonoprazan,
it can be expected to not only demonstrate an
adequate clinical effect from the first dose, but
also sustain its maximum effect over a long
period. In that vonoprazan functionally inhibits
H?,K?-ATPase as a result of competing with the
binding of K? ions, it is different from
conventional PPIs that structurally inhibit
H?,K?-ATPase. We believe that it is important
to thoroughly understand the similarities and
differences between vonoprazan and
conventional PPIs in order to effectively and
safely use vonoprazan, and we hope that this
paper is helpful in this regard.
Phase III clinical trials for vonoprazan in
Japan have been completed for indications
including reflux esophagitis, gastric ulcers,
duodenal ulcers, and H. pylori eradication.
Vonoprazan has demonstrated efficacy and
Adv Ther
favorable safety and tolerability profiles
[35–38]. PPIs with a similar inhibitory effect
on acid secretion to vonoprazan are also
reported to increase risk of fracture [65] and
increase risk of gastrointestinal infection with
Clostridium difficile [66]. Given that
vonoprazan blocks gastric acid production by
? ?
inhibiting the same H ,K -ATPase enzyme as a
PPI, it could be hypothesized that vonoprazan
might result in similar risks and may also
increase the degree of elevation in gastrin
levels. Details of these clinical trial results and
safety of vonoprazan will be presented in
future papers.
ACKNOWLEDGMENTS
Sponsorship and article processing charges for
this study were funded by Takeda
Pharmaceutical Company Limited.
We express our thanks to Mr. Masayuki Aboshi
and Mr. Shigeki Okita of the Medical Science
Liaison Group, Medical Affairs Department,
Japan Research Center, Takeda Pharmaceutical
Company Limited, and Mr. Francois Jones of
Quintiles Transnational Japan Co., Ltd. for their
support in drafting this article. We also thank
the Medical Science Liaison Group, Medical
Affairs Department, Japan Research Center,
Takeda Pharmaceutical Company Limited for
providing scientific advice. Dr. Keisuke Ishida of
SunFlare Co., Ltd. provided medical writing
support, which was funded by Takeda
Pharmaceutical Company Limited. Mr.
Yoshitaka Sato of Saikou, provided medical
illustration service, which was funded by
Takeda Pharmaceutical Company Limited.
This article was originally published in
Japanese in the journal Progress in Medicine.
Permission to translate and republish the article
in English was granted by the publisher of
Progress in Medicine. Kazuyoshi Otake, Yuichi
Sakurai, Haruyuki Nishida, Hideo Fukui,
Yoshihiko Tagawa, Hitomi Yamasaki,
Masatoshi Karashima, Keiichi Otsuka,
Nobuhiro Inatomi. Vonoprazan Fumarate
(TAK-438). A New Potassium-Competitive Acid
Blocker (P-CAB) with a Novel Mode of Action—
physicochemical Properties, Non-Clinical Data,
and a Proposed Mode of Action. Progress in
Medicine 2014:34(12):2183–2194. Translation of
the article from Japanese to English was funded
by Takeda Pharmaceuticals USA, Inc. and
performed by a native Japanese-speaking
translator specialized in the life sciences. The
translation was conducted according to rigid
ISO 9001:2008 and EN 15038:2006 certified
quality assurance processes. This article is a
translation of the original Japanese article to
English with updates.
All named authors meet the International
Committee of Medical Journal Editors (ICMJE)
criteria for authorship for this manuscript, take
responsibility for the integrity of the work as a
whole, and have given final approval for the
version to be published.
Disclosures. Kazuyoshi Otake, Yuuichi
Sakurai, Haruyuki Nishida, Hideo Fukui,
Yoshihiko Tagawa, Hitomi Yamasaki,
Masatoshi Karashima, Keiichi Otsuka and
Nobuhiro Inatomi are employees of Takeda
Pharmaceutical Company Limited, and there
are no other applicable matters regarding
conflicts of interest.
Compliance with Ethics Guidelines. This
article is based on previously conducted
studies and does not involve any new studies
of human or animal subjects performed by any
of the authors.

REFERENCES
1. Huang JQ, Hunt RH. pH, healing rate and
symptomatic relief in acid-related diseases. Yale J
Biol Med. 1996;69:159–74.
2. Hirschowitz BI, Keeling D, Lewin M, et al.
Pharmacological aspects of acid secretion. Dig Dis
Sci. 1995;40(2 Suppl):3S–23S.
3. Urushidani T, Nagao T. Calyculin A, a
phosphoprotein phosphatase inhibitor, stimulates
acid secretion in isolated gastric glands. Am J
Physiol. 1996;270(1 Pt 1):G103–12.
4. Forte JG, Ganser A, Beesley R, Forte TM. Unique
enzymes of purified microsomes from pig fundic
mucosa. K?-stimulated adenosine triphosphatase
and K?-stimulated pNPPase. Gastroenterology.
1975;69:175–89.
5. Chow DC, Forte JG. Functional significance of the
beta-subunit for heterodimeric P-type ATPases.
J Exp Biol. 1995;198:1–17.
6. Rabon E, Cuppoletti J, Malinowska D, et al. Proton
secretion by the gastric parietal cell. J Exp Biol.
1983;106:119–33.
7. Herrmann M, Selige J, Raffael S, Sachs G, Brambilla
A, Klein T. Systematic expression profiling of the
gastric H?/K? ATPase in human tissue. Scand J
Gastroenterol. 2007;42:1275–88.
8. Kraut JA, Helander KG, Helander HF, Iroezi ND,
Marcus EA, Sachs G. Detection and localization of
H?-K?-ATPase isoforms in human kidney. Am J
Physiol Renal Physiol. 2001;281(4):F763–8.
9. Forte JG, Hanzel DK, Okamoto C, Chow D,
Urushidani T. Membrane and protein recycling
associated with gastric HCl secretion. J Intern Med
Suppl. 1990;732:17–26.
10. Howden CW, Burget DW, Hunt RH. Appropriate
acid suppression for optimal healing of duodenal
ulcer and gastro-oesophageal reflux disease. Scand J
Gastroenterol Suppl. 1994;201:79–82.
11. Bell NJ, Burget D, Howden CW, Wilkinson J, Hunt
RH. Appropriate acid suppression for the
management of gastro-oesophageal reflux disease.
Digestion. 1992;51(Suppl 1):59–67.
12. Hunt RH. Importance of pH control in the
management of GERD. Arch Intern Med.
1999;159:649–57.
13. Mössner J, Caca K. Developments in the inhibition
of gastric acid secretion. Eur J Clin Invest.
2005;35:469–75.
Adv Ther
14. Sachs G, Meyer-Rosberg K, Scott DR, Melchers K.
Acid, protons and Helicobacter pylori. Yale J Biol
Med. 1996;69:301–16.
15. Asaka M, Kato M, Takahashi S, et al. Guidelines for
the management of H. pylori infections: 2009
revised edition. Helicobacter. 2010;15:1–20.
16. Yuan Y, Wang CC, Yuan YH, et al. The proportion
of patients who are free of reflux symptoms during
the initial days of treatment with proton pump
inhibitors (PPIs) in GERD trials: a meta-analysis.
Gastroenterology. 2008;134(Suppl 1):A174.
17. Hunt RH, Scarpignato C. Potassium-competitive acid
blockers (P-CABs): are they finally ready for prime
time in acid-related disease? Clin Trans Gastroenterol.
2015;6:e119. doi:10.1038/ctg.2015.39.
18. Scarpignato C, Hunt RH. Proton pump inhibitors:
the beginning of the end or the end of the beginning?
Curr Opin Pharmacol. 2008;8(6):677–84.
19. Tytgat GN. Are there unmet needs in acid
suppression? Best Pract Res Clin Gastroenterol.
2004;18(Suppl):67–72.
20. Fass R, Shapiro M, Dekel R, Sewell J. Systematic
review: proton-pump inhibitor failure in
gastro-oesophageal reflux disease - where next?
Aliment Pharmacol Ther. 2005;22(2):79–94.
21. Japanese Society for Gastroenterology. Guidelines
for the management of GERD (2009). http://
minds4.jcqhc.or.jp/minds/GERD/gerd_gl.pdf.
22. Mégraud F. H pylori antibiotic resistance:
prevalence, importance, and advances in testing.
Gut. 2004;53:1374–84.
23. Graham DY, Fischbach L. Helicobacter pylori
treatment in the era of increasing antibiotic
resistance. Gut. 2010;59:1143–53.
24. Ashida K. Notes on features and uses of medications
used for PPI-resistant GERD, drugs under
development and future prospects. Jpn J Med
Pharm Sci. 2014;71:591–6.
25. Stewart B, Wallmark B, Sachs G. The interaction of
H? and K? with the partial reactions of gastric
(H??K?)-ATPase. J Biol Chem. 1981;256:2682–90.
26. Mendlein J, Sachs G. Interaction of a K?
-competitive inhibitor, a substituted
imidazo[1,2a]pyridine, with the phospho- and
dephosphoenzyme forms of H?, K?-ATPase. J Biol
Chem. 1990;265:5030–6.
27. Parsons ME, Keeling DJ. Novel approaches to the
pharmacological blockade of gastric acid secretion.
Expert Opin Investig Drugs. 2005;14:411–21.
Adv Ther
28. Kahrilas PJ, Dent J, Lauritsen K, et al. A randomized,
comparative study of three doses of AZD0865 and
esomeprazole for healing of reflux esophagitis. Clin
Gastroenterol Hepatol. 2007;5:1385–91.
29. Berg AL, Böttcher G, Andersson K, et al. Early
stellate cell activation and veno-occlusive-disease
(VOD)-like hepatotoxicity in dogs treated with
AR-H047108, an imidazopyridine proton pump
inhibitor. Toxicol Pathol. 2008;36:727–37.
30. Dent J, Kahrilas PJ, Hatlebakk J, et al. A randomized,
comparative trial of a potassium-competitive acid
blocker (AZD0865) and esomeprazole for the
treatment of patients with nonerosive reflux
disease. Am J Gastroenterol. 2008;103:20–6.
31. Kondo M, Kawamoto M, Hasuoka A, et al.
High-throughput screening of potassium-
competitive acid blockers. J Biomol Screen.
2012;17:177–82.
32. Nishida H, Hasuoka A, Arikawa Y, et al. Discovery,
synthesis, and biological evaluation of novel
pyrrole derivatives as highly selective
potassium-competitive acid blockers. Bioorg Med
Chem. 2012;20:3925–38.
33. Arikawa Y, Nishida H, Kurasawa O, et al. Discovery
of a novel pyrrole derivative 1-[5-(2-
fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
yl]-N-methylmethanaminefumarate (TAK-438) as a
potassium-competitive acid blocker (P-CAB). J Med
Chem. 2012;55:4446–56.
34. Takeda Takecab (vonoprazan tablets). Japanese
Common Technical Document. Available at:
http://www.pmda.go.jp/drugs/2014/P201400173/
index.html. Accessed 20 Apr 2016.
35. Ashida K, Sakurai Y, Hori T, et al. Randomised clinical
trial: vonoprazan, a novel potassium-competitive
acid blocker, vs. lansoprazole for the healing of
erosive oesophagitis. Aliment Pharmacol Ther.
2016;43(2):240–51.
36. Mizokami Y, Ashida K, Soen S, et al. TAK-438 versus
lansoprazole 15 mg for secondary prevention of
peptic ulcers associated with non-steroidal
anti-inflammatory drug (NSAID) therapy: results
of a phase 3 trial. Gastroenterology.
2014;146(5,Suppl 1):S-739.
37. Kawai T, Ashida K, Mizokami Y, et al. TAK-438
versus lansoprazole 15 mg for secondary prevention
of peptic ulcers associated with low-dose aspirin
therapy: results of a phase 3 trial. Gastroenterology.
2014;146(5,Suppl 1):S-739.
38. Murakami K, Sakurai Y, Shiino M, et al.
Vonoprazan, a novel potassium-competitive
acid blocker, as a component of first-line and
second-line triple therapy for Helicobacter pylori
eradication: a phase III, randomised, double-blind
study. Gut. 2016. doi:10.1136/gutjnl-2015-311304
(Epub ahead of print).
39. Hori Y, Matsukawa J, Takeuchi T, et al. A study
comparing the antisecretory effect of TAK-438, a
novel potassium-competitive acid blocker, with
lansoprazole in animals. J Pharmacol Exp Ther.
2011;337:797–804.
40. Hori Y, Imanishi A, Matsukawa J, et al. 1-[5-(2-
Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-
yl]-N-methylmethanamine monofumarate (TAK-
438), a novel and potent potassium-competitive
acid blocker for the treatment of acid-related
diseases. J Pharmacol Exp Ther. 2010;335:231–8.
41. Adachi K, Katsube T, Kawamura A, et al. CYP2C19
genotype status and intragastric pH during dosing
with lansoprazole or rabeprazole. Aliment
Pharmacol Ther. 2000;14(10):1259–66.
42. Furuta T, Ohashi K, Kosuge K, et al. CYP2C19
genotype status and effect of omeprazole on
intragastric pH in humans. Clin Pharmacol Ther.
1999;65:552–61.
43. Shirai N, Furuta T, Xiao F, et al. Comparison of
lansoprazole and famotidine for gastric acid
inhibition during the daytime and night-time in
different CYP2C19 genotype groups. Aliment
Pharmacol Ther. 2002;16(4):837–46.
44. Yamada S, Onda M, Kato S, et al. Genetic
differences in CYP2C19 single nucleotide
polymorphisms among four Asian populations.
J Gastroenterol. 2001;36:669–72.
45. Furuta T, Shirai N, Kodaira M, et al.
Pharmacogenomics-based tailored versus standard
therapeutic regimen for eradication of H. pylori.
Clin Pharmacol Ther. 2007;81:521–28.
46. Furuta T, Shirai N, Watanabe F, et al. Effect of
cytochrome P4502C19 genotypic differences on
cure rates for gastroesophageal reflux disease by
lansoprazole. Clin Pharmacol Ther.
2002;72:453–60.
47. Kagami T, Sahara S, Ichikawa H, et al. Potent acid
inhibition by vonoprazan in comparison with
esomeprasole, with reference to CYP2C19
genotype. Aliment Pharmacol Ther.
2016;43(10):1048–59.
48. Sakurai Y, Nishimura A, Kennedy G, et al. Safety,
tolerability, pharmacokinetics, and
pharmacodynamics of single rising TAK-438
(vonoprazan) doses in healthy male Japanese/
non-Japanese subjects. Clin Transl Gastroenterol.
2015;25(6):e94.

49. Jenkins H, Sakurai Y, Nishimura A, et al. Randomised
clinical trial: safety, tolerability, pharmacokinetics
and pharmacodynamics of repeated doses of TAK-
438 (vonoprazan), a novel potassium-competitive
acid blocker, in healthy male subjects. Aliment
Pharmacol Ther. 2015;41(7):636–48.
50. Nagaya H, Satoh H, Kubo K, Maki Y. Possible
mechanism for the inhibition of gastric
(H??K?)-adenosine triphosphatase by the proton
pump inhibitor AG-1749. J Pharmacol Exp Ther.
1989;248:799–805.
51. Fock KM, Ang TL, Bee LC, Lee EJ. Proton pump
inhibitors: do differences in pharmacokinetics
translate into differences in clinical outcomes?
Clin Pharmacokinet. 2008;47:1–6.
52. Gedda K, Scott D, Besancon M, Lorentzon P, Sachs
G. Turnover of the gastric H?, K?-adenosine
triphosphatase a subunit and its effect on
inhibition of rat gastric acid secretion.
Gastroenterology. 1995;109:1134–41.
53. Sachs G. Improving on PPI-based therapy of GORD.
Eur J Gastroenterol Hepatol. 2001;13(Suppl 1):
S35–41.
54. Bytzer P, Blum AL. Personal view: rationale and
proposed algorithms for symptom-based proton
pump inhibitor therapy for gastro-oesophageal
reflux disease. Aliment Pharmacol Ther.
2004;20(4):389–98.
55. Sachs G, Shin JM, Howden CW. Review article: the
clinical pharmacology of proton pump inhibitors.
Aliment Pharmacol Ther. 2006;23(Suppl 2):2–8.
56. Tytgat GN. Shortcomings of the first-generation
proton pump inhibitors. Eur J Gastroenterol
Hepatol. 2001;13(Suppl 1):S29–33.
57. Shin JM, Inatomi N, Munson K, et al.
Characterization of a novel potassium-competitive
acid blocker of the gastric H, K-ATPase,
1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-
pyrrol-3-yl]-N-methylmethanamine monofumarate
(TAK-438). J Pharmacol Exp Ther. 2011;339:412–20.
Adv Ther
58. Abe K, Tani K, Fujiyoshi Y. Conformational
rearrangement of gastric H?, K?-ATPase induced
by an acid suppressant. Nat Commun.
2011;2:155–61.
59. Matsukawa J, Hori Y, Nishida H, kajino M, Inatomi
N. A comparative study on the modes of action of
TAK-438, a novel potassium-competitive acid
blocker, and lansoprazole in primary cultured
rabbit gastric glands. Biochem Pharmacol.
2011;81:1145–51.
60. Takeda Takecab (vonoprazan tablets) package
insert. Available at: http://www.pmda.go.jp/
PmdaSearch/iyakuDetail/ResultDataSetPDF/400256_
2329030F1020_1_04. Accessed 20 Apr 2016.
61. Hatlebakk JG, Katz PO, Camacho-Lobato L, Castell
DO. Proton pump inhibitors: better acid
suppression when taken before a meal than
without a meal. Aliment Pharmacol Ther. 2000;
14(10):1267–72.
62. Wada F, Murase K, Isomoto H, et al. Polymorphism
of CYP2C19 and gastric emptying in patients with
proton pump inhibitor-resistant gastric ulcers. J Int
Med Res. 2002;30:413–21.
63. Klotz U. Clinical impact of CYP2C19
polymorphism on the action of proton pump
inhibitors: a review of a special problem. Int J Clin
Pharmacol Ther. 2006;44:297–302.
64. Andersson K, Carlsson E. Potassium-competitive
acid blockade: a new therapeutic strategy in
acid-related diseases. Pharmacol Ther. 2005;108:
294–307.
65. Zhou B, Huang Y, Li H, et al. Proton-pump
inhibitors and risk of fractures: an update
meta-analysis. Osteoporos Int. 2016;27:339–47.
66. Cunningham R, Dial S. Is over-use of proton pump
inhibitors fuelling the current epidemic of
Clostridium difficle-associated diarrhea? J Hosp
Infect. 2008;70:1–6.