Clin Pharmacokinet

DOI 10.1007/s40262-015-0326-7

LEADING ARTICLE

The First-in-Class Potassium-Competitive Acid Blocker,

Vonoprazan Fumarate: Pharmacokinetic and Pharmacodynamic
Considerations
Hirotoshi Echizen1

Ó Springer International Publishing Switzerland 2015

Abstract Vonoprazan fumarate (TakecabÒ) is a first-in- terminal half-life of the drug is approximately 7.7 h in
class potassium-competitive acid blocker that has been healthy adults. Vonoprazan is metabolized to inactive
available in the market in Japan since February 2015. metabolites mainly by cytochrome P450 (CYP)3A4 and to
Vonoprazan is administered orally at 20 mg once daily for some extent by CYP2B6, CYP2C19, CYP2D6, and
the treatment of gastroduodenal ulcer, at 20 and 10 mg SULT2A1. A mass balance study showed that 59 and 8 % of
once daily for the treatment and secondary prevention of the orally administered radioactivity was recovered in urine
reflux esophagitis, respectively, at 10 mg once daily for the as metabolites and in an unchanged form, respectively,
secondary prevention of low-dose aspirin- or non-steroidal indicating extensive metabolism. Genetic polymorphism of
anti-inflammatory drug-induced peptic ulcer, and at 20 mg CYP2C19 may influence drug exposure but only to a clini-
twice daily in combination with clarithromycin and cally insignificant extent (15–29 %), according to the pop-
amoxicillin for the eradication of Helicobacter pylori. It ulation pharmacokinetic study performed in Japanese
inhibits H?,K?-ATPase activities in a reversible and patients. When vonoprazan was co-administered with clar-
potassium-competitive manner with a potency of inhibition ithromycin, the mean AUC from time 0 to time of the next
approximately 350 times higher than the proton pump dose (dosing interval) of vonoprazan and clarithromycin
inhibitor, lansoprazole. Vonoprazan is absorbed rapidly were increased by 1.8 and 1.5 times, respectively, compared
and reaches maximum plasma concentration at 1.5–2.0 h with the corresponding control values, indicating mutual
after oral administration. Food has minimal effect on its metabolic inhibition. The mean area under the curve from
intestinal absorption. Oral bioavailability in humans time zero to infinity obtained from patients with severe liver
remains unknown. The plasma protein binding of vono- and renal dysfunction were elevated by 2.6 and 2.4 times,
prazan is 80 % in healthy subjects. It distributes exten- respectively, compared with healthy subjects, with no sig-
sively into tissues with a mean apparent volume of nificant changes in plasma protein binding. Vonoprazan
distribution of 1050 L. Being a base with pKa of 9.6 and increases intragastric pH above 4.0 as early as 4 h after an
with acid-resistant properties, vonoprazan is highly con- oral dose of 20 mg, and the extensive anti-secretory effect is
centrated in the acidic canaliculi of the gastric parietal cells maintained up to 24 h post-dose. During repeated dosing of
and elicited an acid suppression effect for longer than 24 h 20 mg once daily, the 24-h intragastric pH[4 holding time
after the administration of 20 mg. The mean apparent ratios were 63 and 83 % on days 1 and 7, respectively.
Because vonoprazan elicited a more extensive gastric acid
suppression than the proton pump inhibitor, lansoprazole, it
also gave rise to two to three times greater serum gastrin
concentrations as compared with lansoprazole. In pre-ap-
proval clinical studies for the treatment of acid-related dis-
& Hirotoshi Echizen orders, mild to moderate adverse drug reactions (mostly
[email protected]
constipation or diarrhea) occurred at frequencies of 8–17 %.
1
Department of Pharmacotherapy, Meiji Pharmaceutical Neither severe liver toxicity nor neuroendocrine tumor has
University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan been reported in patients receiving vonoprazan.
 H. Echizen

secretory effects [3]. In addition, PPIs may not be able to

Key Points fully suppress night-time acid breakthrough [4]. As a result,
approximately one-third of patients with gastroesophageal
Vonoprazan is a first-in-class potassium-competitive reflux disease receiving PPIs still need supplemental
blocker. antacids for symptomatic relief or for enduring residual
symptoms [5]. Clinical studies revealed that PPI therapy
It inhibits the H?,K?-ATPase-mediated gastric acid may not be sufficient for the extensive pH control needed
secretion in a reversible and potassium-competitive to prevent rebreeding after endoscopic hemostasis in some
manner. patients [6]. Furthermore, because the pharmacokinetics of
It possesses approximately 350 times more potent many PPIs are subject to the influence of genetic poly-
inhibitory effects than the proton pump inhibitor, morphisms of cytochrome P450 (CYP)2C19, the standard
lansoprazole, in in vitro experiments. dose of PPIs may not provide sufficient anti-secretory
effects in extensive metabolizers of CYP2C19 for the
It increased the gastric pH above 4.0 as early as 4 h
eradication of H. pylori [7]. Finally, PPIs require an acid-
after a single oral dose of 20 mg and maintained the
resistant formulation [3], otherwise they are transformed to
gastric pH above 4.0 until 24 h post-dose.
the active protonated sulfonamides in the gastric lumen
It undergoes substantial metabolic elimination but before reaching the sites of action that are located in the
the influence of a genetic polymorphism is limited. secretory canaliculi of the gastric parietal cells.
An alternative strategy exists for searching an inhibitor
of H?,K?-ATPase. When protons are transported by
H?,K?-ATPase from the cytoplasm to the canalicular
space across the apical membrane of the parietal cell, an
equal amount of K? ions are counter transported into the
1 Introduction cytoplasm of the parietal cells so that the total process is
electrically balanced [8]. As a result, the activity of
Acid-related diseases such as gastroduodenal ulcer and H?,K?-ATPase in the parietal cells is regulated by the
gastroesophageal reflux disease cause substantial morbidity availability of extracellular K?. Studies on the molecular
and are an important public health issue. The mainstay of mechanisms of H?,K?-ATPase led to the discovery of a
treatment for these disorders has been suppression of gas- new class of anti-secretory agent, potassium-competitive
tric acid secretion. Historically, antacids, histamine H2- acid blocker (P-CAB). This class of drugs exhibit their
receptor antagonists, and muscarinic receptor antagonists anti-secretory effects by competitively blocking the avail-
were used until proton pump inhibitors (PPIs) became ability of K? for the H?,K?-ATPase [8]. Following the
available in the late 1980s. Having more potent acid-sup- development of a prototype P-CAB, SCH28080, many
pressing effects and better tolerability than the above- candidate compounds (e.g., TAK-438, BY841, SK&F
named drugs, PPIs have been considered the drug of choice 96067, AZD0865, CS-526, and YH1885) were developed,
for most patients with acid-related disorders in the last two but some of them were withdrawn after clinical trials
decades [1]. In addition, with increasing recognition that owing to the short duration of action or hepatic toxicity [8].
Helicobacter pylori is associated with recurrence of peptic YH1885 (revaprazan) was launched in Korea in 2007 for
ulcer disease and is the etiology of H. pylori-positive, the treatment of gastroduodenal ulcer and gastritis, whereas
mucosa-associated lymphatic tissue lymphoma, immune only limited data are available for its pharmacokinetics and
thrombocytopenia, and possibly gastric adenocarcinoma, details of relevant clinical trials are available only in
eradication therapy of H. pylori has been performed widely Korean [9, 10]. Vonoprazan fumarate (TAK-438, Take-
[2]. One of the PPIs has been included in the combination cabÒ) is another P-CAB that was approved by the Japanese
chemotherapy with amoxicillin and clarithromycin, aiming Ministry of Health, Labour and Welfare in December 2014
to boost the antimicrobial effect against H. pylori [2]. and was launched in February 2015 for the treatment of
Because PPIs revolutionized the pharmacotherapy of acid-related disorders and as an adjunct to H. pylori erad-
acid-related disorders so successfully, many clinicians ication. Vonoprazan is a first-in-class P-CAB of which
doubted whether an anti-secretory drug more powerful than pharmacokinetic and pharmacodynamic data are charac-
PPIs would ever be developed. However, industry terized in Caucasian and Asians [11]. In addition, its effi-
researchers continued their endeavors in the ensuing two cacy and safety for the treatment of acid-related diseases
decades to develop such a drug. Because PPIs have a rel- has been verified as compared to a PPI, lansoprazole, in
atively slow onset of action, three to five dose cycles have well-designed controlled clinical trials. The summarized
to be administered before they exhibit maximum anti- data of individual clinical trials were presented at the
The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate

Digestive Disease Week in 2014 and 2015 and published in 6.5; the half maximal inhibitory concentrations (IC50) were
abstract form subsequently [12–18]. A brief summary of 0.019 nM, 0.14 nM, and 7.6 lM, respectively [24]. In
therapeutic trials of vonoprazan was reported recently [19], addition, the rate of dissociation of vonopazan from iso-
but more detailed information is available at this moment lated ATPase is slower (half-life: 7.5 h in 20 mM KCL,
only in Japanese [20–22]. The present article is the first close to physiological concentrations in stimulated gastric
review article on the pharmacokinetics and pharmacody- juice at pH 7.0) than other P-CABs (2 min for SCH28080
namics of vonoprazan using information published as of in 10 mM KCL). These in vitro pharmacological properties
July, 2015 in English or Japanese. may account for the more potent and longer lasting anti-
secretory effects of vonopazan than lansoprazole observed
in in vivo animal experiments [25].
2 Physicochemical Characteristics and Relevant
Pharmacologic Properties
3 Pharmacokinetics
Vonoprazan is an acid-resistant pyrrole derivative 1-[5-(2-
fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N- 3.1 Healthy Subjects
methylmethanamine fumarate (TAK-438) developed by
Takeda Pharmaceutical Company Ltd. as a P-CAB [23] 3.1.1 Absorption
(Fig. 1). Because vonoprazan has a greater point-positive
charge (pKa 9.06) than other P-CABs with different Being acid resistant, vonoprazan can be given as a rapid-
chemical structures (such as SCH28080 with pKa 5.6), it is release formulation. The pharmacokinetics of the drug after
accumulated at higher concentrations in the canalicular oral administration were studied in Japan (n = 60) and the
space of the gastric parietal cells compared with the pre- UK (n = 48) [11]. While no model-based pharmacokinetic
vious P-CABs [24]. The drug is bound to H?,K?-ATPase analysis has been performed on the data, the intestinal
in a strictly K?-competitive and reversible manner with a absorption of vonoprazan appears rapid. After single oral
Ki of 10 nM at pH 7.0 [24]. Vonoprazan is 10 and 350 doses of the drug at 10, 15, 20, 30, and 40 mg under fasting
times more potent in H?,K?-ATPase inhibitory activity conditions, the maximum plasma concentration (Cmax)
than a prototype P-CAB, SCH28080, and a PPI, lanso- increased from approximately 10 to 60 ng/mL in a largely
prazole, respectively, in porcine gastric microsomes at pH dose-proportional manner in both study populations, with
time to reach Cmax of 1.5–2.0 h [11]. The data obtained
during repeated oral dosing of the drug at 10, 15, 20, 30,
and 40 mg once daily for 7 days showed that the drug
accumulation was almost completed by the third day with
accumulation factors for Cmax and area under the curve
from time zero to infinity (AUC0–inf) at the respective doses
ranging from 1.14 to 1.32 [11]. Dose proportionality for
Cmax and AUC0–inf was observed on the first day and
seventh day in both study populations.

3.1.1.1 Bioavailability The oral bioavailability of vono-

prazan in humans remains unknown because no intra-
venous pharmacokinetic study has been performed.
Nevertheless, a mass balance study performed in healthy
subjects after a single oral dose of 15 mg 14C-vonoprazan
demonstrated that 67 and 31 % of the total radioactivity
administered was recovered by 168 h post-dose in urine
and feces, respectively [20]. In addition, the unchanged
form of the drug recovered in urine and feces accounted for
only 8 and 1 %, respectively, of the total radioactivity
administered. Furthermore, the plasma AUC attributable to
the unchanged form accounted for only 13 % of the total
radioactivity. These data suggest that intestinal absorption
Fig. 1 Chemical structure of vonoprazan (reproduced from [9] with of the drug is fair ([67 %) and the drug undergoes
permission from the publisher, Adis International Ltd.) extensive metabolism. As the oral bioavailability of
 H. Echizen

vonoprazan is unknown, it remains unclear whether the intravenous dose [20]. As described above, vonoprazan is
drug is subject to a substantial first-pass elimination in accumulated in the secretory canaliculi more extensively
either the liver or the gut, or combination thereof, in than other P-CABs because it has a greater point-positive
humans. The pharmacokinetics of 14C-vonoprazan after charge [24].
intravenous and oral administration were studied in rats
and dogs. The oral bioavailability was 10 % in rats and 3.1.2.1 Plasma Protein Binding The unbound fractions
52 % in dogs, despite gastrointestinal absorption being of vonoprazan in human plasma spiked with the drug to
[80 % in both species. These data indicate the presence of concentrations of 0.1, 1, and 10 lg/mL were 14, 15, and
substantial to moderate first-pass metabolism in these 12 %, respectively [20, 22]. Because plasma vonoprazan
species [20]. Whether substantial metabolism takes place in concentrations attained after an oral dose approved for
the intestinal wall and contributes significantly to the first- the treatment of acid-related diseases (10 or 20 mg once
pass metabolism remains unclear in these species. How- daily) are less than 50 ng/mL [22], plasma protein
ever, an absorption study performed with perfused jejunum binding of the drug is unlikely to be saturated even at
loops of rats showed that 42 % of 14C-vonoprazan concentrations well above the therapeutic range. In
administered into the loop was recovered in the portal addition, the drug is bound to both albumin and a1-acid
blood within 2 h, mainly in the unchanged form ([89 %). glycoprotein [20].
These findings imply that the gut may not be involved
in the substantial metabolism of vonoprazan, at least in 3.1.3 Elimination
rats [20].
3.1.3.1 Clearance The mean (±SD) oral clearance of
3.1.1.2 Effects of Food Ingestion on Gastrointestinal vonoprazan after an oral dose of 20 mg in healthy subjects
Absorption The effects of a meal on the pharmacokinet- under fasting conditions was 97.5 ± 30.1 L/h (1.63 ± 0.50
ics of vonoprazan were examined in a randomized cross- L/min) [20]. Because the oral bioavailability of vonoprazan
over trial. Twelve healthy subjects took an oral dose of is unknown, its systemic clearance cannot be calculated.
vonoprazan 20 mg before breakfast (fasting) in one study The blood to plasma concentration ratio of the drug was
and after breakfast in the other, separated by a washout shown to be 0.93–0.93 [20]. The mean apparent terminal
period of 7 days [20–22]. The ratios of geometric means half-life obtained from healthy subjects after a single oral
for Cmax and area under the curve from time zero to 48 h dose under fasting conditions was 7.7 h, irrespective of the
(AUC0–48h) obtained after a meal to those obtained under administration under fasting or after a meal [22].
fasting conditions were 1.09 [90 % confidence interval (CI)
0.94–1.26] and 1.12 (90 % CI 1.01–1.14), respectively, 3.1.3.2 Metabolism In vitro studies on the metabolism
indicating that the effect of a meal on intestinal absorption of vonoprazan using human liver microsomes revealed
of the drug, if any, is clinically insignificant. that the drug is metabolized mainly by CYP3A4 and to
some extent by CYP2B6, CYP2C19, CYP2D6, and
3.1.2 Distribution SULT2A1 [20–22]. None of the metabolites are phar-
macologically active. Vonoprazan has been shown to
Because no plasma concentration–time data after an have a direct inhibitory effect on CYP2B6 and CYP3A4/
intravenous administration of vonoprazan are available, 5, with IC50 of 16 and 29 lmol/L, respectively. In
only apparent volume of distribution for the drug is addition, vonoprazan is known to inhibit the activities of
available at present. In a study performed with 12 healthy CYP2B6, CYP2C19, and CYP3A4/5 in a time-dependent
men, the mean (±standard deviation [SD]) volume of manner, with IC50 of 3, 13, 10, and 10 lmol/L, respec-
distribution was 1056 ± 263 L after an oral dose of 20 mg tively [20]. Because the maximum plasma concentrations
vonoprazan under fasting conditions [20]. Because the of the drug after therapeutic oral doses are approximately
bioavailability of vonoprazan is theoretically no less than 100–200 nmol/L, which are far lower than the above
8 % (see Sect. 3.1.1.1), the true Vd is estimated to be 84 L IC50 values, vonoprazan may be less likely to have
or greater. Because vonoprazan is a base with pKa [9.0 clinically significant inhibitory effects on these CYP
[21], it is accumulated in the acidic or neutral secretory isozymes in clinical situations [20]. In addition, the drug
canaliculi of the gastric parietal cells in much higher has been shown to inhibit the transporter activity of
concentrations than in plasma. An experiment performed P-glycoprotein (P-gp), with an IC50 of 50 lmol/L.
using rats demonstrated that the mean gastric wall con- According to the guidelines of drug interaction for
centrations of vonoprazan was more than 1000 times industries issued by the US Food and Drug Adminis-
greater than plasma concentrations at 5 h after an tration and the European Medicines Agency [26, 27],
The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate

industries are requested to conduct clinical studies of the 3.2.2 Renal Disease
drug under development, if maximum drug concentra-
tions in the intestinal lumen are estimated to be 10 times A pharmacokinetic study was performed in patients with
higher than the IC50 for P-gp observed in in vitro mild, moderate, and severe renal dysfunction as well as
experiments. The maximum concentrations of vono- those with end-stage renal disease (ESRD) having an esti-
prazan in the intestinal lumen are approximately mated glomerular filtration rate (eGFR) of 60–89, 30–59,
230 lmol/L, which exceeds the IC50 for P-gp by only 15–29 (n = 8 each), and \15 mL/min/1.73 m2 (n = 3),
five times. Therefore, it is considered, at least theoreti- respectively, compared with healthy subjects having an
cally, that vonoprazan may be less likely to elicit a eGFR of[90 mL/min/1.73 m2 (n = 13), after a single oral
clinically significant inhibitory effect on P-gp [20]. dose of 20 mg vonoprazan [20, 22]. The geometric mean of
However, further clinical studies are required to confirm Cmax and AUC0–inf obtained from patients with mild,
the theoretical considerations for the drug interaction via moderate, and severe renal dysfunction, and ESRD were
the inhibition of drug metabolism and P-gp. greater than the corresponding values obtained from healthy
controls by 2.3 and 1.7, 1.2 and 1.3, and 2.8 and 2.4, and 1.2
3.1.3.3 Renal Excretion The mean renal clearance of and 1.3 times, respectively. The mean renal clearance (L/h)
vonoprazan is 6.4 L/h (107 mL/min) in healthy subjects in patients with mild, moderate, severe, and end-stage renal
(n = 13) and only 4 % of the oral dose is recovered in urine dysfunction were 5.4, 4.6, 1.8, and 0.5 L/h, respectively,
as the unchanged form [21]. Because the systemic clearance compared with 6.4 L/h in healthy subjects. In addition, the
of the drug remains unclear, it may be difficult to conclude mean percentages of vonoprazan excreted into urine as an
whether renal elimination contributes substantially to sys- unchanged form obtained from the corresponding groups of
temic clearance of the drug based only on the pharma- patients were reduced in association with their renal func-
cokinetics of healthy subjects. However, it is obvious that tion to 5.4, 3.6, 2.8, and 0.4 %, respectively, compared with
an active transport mechanism is involved in renal elimi- 4.0 % for healthy subjects. Mean plasma unbound fractions
nation of vonoprazan, because renal clearance for the of vonoprazan in healthy subjects and patients with mild,
unbound drug (approximately 700 mL/min) apparently far moderate, severe, and end-stage renal dysfunction were 21,
exceeds the glomerular filtration rate (120 mL/min). 21, 23, and 20 %, respectively, with no significant differ-
ences between groups. The reason why the AUC of the drug
3.2 Special Populations was increased in patients with renal dysfunction despite
only less than 5 % of the unchanged form of the drug
3.2.1 Liver Disease eliminated into urine remains to be studied. The clinical
implications of these data remain to be determined. At
A clinical study was performed to investigate the influence present, the prescribing information contains no specific
of liver disease on the pharmacokinetics of vonoprazan recommendations for dosage reduction in patients with
after a single oral dose of 20 mg in patients with mild, severe liver dysfunction [22].
moderate, and severe liver dysfunction classified as Child–
Pugh classes A, B, and C (n = 8 in each group), respec- 3.2.3 Sex
tively, compared with healthy subjects (n = 8) [20–22].
The geometric means for Cmax and AUC0–inf obtained from A pharmacokinetic study performed in healthy men and
patients with Child–Pugh classes A, B, and C were greater women (n = 12 each) after a single oral dose of 20 mg
than the corresponding values obtained from healthy sub- demonstrated that the female/male ratio for the geometric
jects by 1.2 and 1.2, 1.8 and 2.4, and 1.8 and 2.6 times, means (95 % CI) of Cmax and AUC0–inf were 0.78
respectively. No data were available for changes in the (0.52–1.17) and 0.84 (0.54–1.31), respectively [20]. While
half-life. The mean plasma unbound fractions of vono- there is a trend towards greater oral clearance in women
prazan obtained from patients with mild, moderate, and than in men, the difference did not reach a significant level.
severe liver dysfunction and healthy controls were 19, 24, Supplemental data for sex difference in the pharmacoki-
23, and 21 %, respectively, with no significant differences netics of the drug are provided in the following section.
between groups. Collectively, these data are compatible
with the idea that the metabolic elimination is substantially 3.2.4 CYP2C19 Polymorphism
involved in the systemic clearance of the drug. The clinical
implications of these data remain to be verified. At present, An exploratory study was performed to measure plasma
the prescribing information contains no specific recom- concentrations of vonoprazan in 60 Japanese patients whose
mendations for dosage reduction in patients with severe genotypes of CYP2C19 were identified [11]. These subjects
liver dysfunction [22]. took 10–40 mg of vonoprazan once daily for 7 days. No
 H. Echizen

appreciable correlation was found between CYP2C19 daily for 7 days alters the pharmacokinetics of the drugs
genotypes (*1/*1, *1/*2, *1/*3, and *2*2) and mean dose- compared with the respective drugs when used alone
normalized AUC from time 0 to time of the next dose (control values) [20–22]. This study demonstrated that
(dosing interval) (AUC0–tau) at steady state. In contrast, a mean Cmax and area under the curve from time zero to 12 h
population pharmacokinetic modeling analysis using the (AUC0–12) for vonoprazan increased by 1.9 and 1.8 times
non-linear mixed-effect model software performed on 1751 on the seventh day, and those for clarithromycin also
plasma samples obtained from 592 patients with reflux increased by 1.6 and 1.5 times compared with the respec-
esophagitis who participated in phase II dose-finding stud- tive control values. In contrast, no changes were observed
ies revealed that among the variables examined, dose, sex, in mean Cmax and AUC0–12 for amoxicillin. In addition, the
age, and CYP2C19 were significantly associated with the pharmacokinetics of vonoprazan after an oral dose of
inter-individual variability of oral clearance of vonoprazan 40 mg once daily was studied before and after co-admin-
[20]. Specifically, the median values of oral clearance for istration of oral clarithromycin 500 mg twice daily for 7
women obtained by individual post hoc estimation at dif- consecutive days [20]. Co-administration of clarithromycin
ferent doses were 5–24 % greater than the corresponding increased mean Cmax and AUC0–inf of vonoprazan by 1.6
values for men. The values obtained from patients aged and 1.4 times compared with when vonoprazan was
from 65 to 75 years and those aged [75 years were lower administered alone. These data suggest that vonoprazan
than those aged \65 years by 18–25 % and 19–35 %, and clarithromycin mutually inhibit the metabolism of each
respectively. The values obtained from patients with other to a similar extent, probably via inhibition of
CYP2C19 genotypes associated with the poor metabolizer CYP3A4. These data appear to offer contradicting evi-
phenotype were 15–29 % lower than those associated with dence against the considerations based upon the in vitro
the extensive metabolizer phenotype. Because the magni- drug interaction experiments (Sect. 3.1.3.2). Further clini-
tudes of the effect caused by these covariates were less than cal studies are required to study whether the co-adminis-
35 % compared with the population mean, these variables tration of vonoprazan with other CYP3A substrate drugs
may exert only clinically insignificant influence on the alters their pharmacokinetics.
overall exposure of vonoprazan. Oral administration of 10 mg vonoprazan once daily has
been approved for the prevention of relapse after healing of
3.3 Drug Interaction aspirin- or non-steroidal anti-inflammatory drug-induced
gastric or duodenal ulcer [22]. Pharmacokinetic studies
3.3.1 Absorption were performed to investigate whether oral administration
of low-dose aspirin (100 mg), loxoprofen sodium hydrate
Theoretically, vonoprazan may attenuate the bioavailabil- (60 mg), diclofenac sodium (25 mg), or meloxicam
ity of drugs of which gastrointestinal absorption is sus- (10 mg) alters the pharmacokinetics of vonoprazan [20,
ceptible to changes in gastric pH. Indeed, PPIs have been 22]. These studies detected no changes in the pharma-
shown to reduce the mean Cmax and AUC0–24 of atazanavir cokinetics of vonoprazan.
by 94 and 91 %, respectively, compared with the corre-
sponding values observed for atazanavir alone (for review
see [28]). There is a possibility that vonoprazan also 4 Pharmacodynamics
interferes with the bioavailability of those drugs to a sim-
ilar extent as PPIs. At present, no data are available to 4.1 Mechanism of H1,K1-ATPase Inhibition
negate or support such a theoretical concern. by Vonoprazan

3.3.2 Metabolism The discovery of the role of H?,K?-ATPase in the final step
of gastric acid secretion fueled intensive research to find the
As was discussed in Sect. 3.1.3.2, vonoprazan is a substrate ultimate anti-secretory agents. Historically, PPI was the
and may be an inhibitor of CYP3A4 and some other CYP first-in-class agent targeting this enzyme [8]. When H?,K?-
isoforms [20]. Because the drug has an approved indication ATPase is activated and the canalicular space is strongly
for the eradication of H. pylori by co-administration with acidic, PPI is converted non-catalytically to the active pro-
clarithromycin, a strong CYP3A inhibitor [26], there is a tonated sulfonamide, then forming a covalent disulfide bond
concern over whether there is a significant drug interaction with a cysteine residue on the H?,K?-ATPase leading to the
between vonoprazan and clarithromycin. In this context, a inactivation of the enzyme [3]. Accordingly, PPIs inhibit
clinical study was performed in healthy subjects to inves- mainly activated H?,K?-ATPase.
tigate whether co-administration of vonoprazan (20 mg), An alternative approach to inhibit H?,K?-ATPase
clarithromycin (400 mg), and amoxicillin (750 mg) twice activity is to reduce the availability of K? for the enzyme.
The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate

Because H?,K?-ATPase counter transports equal amounts 4.1.1 Pharmacodynamics of Vonoprazan in Relation
of H? and K? to maintain an electrical balance through bi- to Plasma Concentrations in Humans
directional ion transport, the availability of K? for the
enzyme is essential to maintain its activity [8]. P-CABs Pharmacokinetic and pharmacodynamics profiles of vono-
interfere with the binding of K? to the enzyme in a com- prazan were investigated in two phase I studies conducted
petitive and reversible manner. Briefly, the H?,K?-ATPase in healthy subjects in Japan and the UK, who were given
localized at the apical membrane of the parietal cells is in five different oral doses of vonoprazan or placebo once
E1 conformation and possesses a high-affinity H? binding daily for 7 consecutive days [11]. Pharmacodynamic
site on the cytoplasm side. Upon binding H?, the enzyme effects were measured by continuous intragastric pH
undergoes ATP-driven three-directional conformation monitoring. The onset of action measured by the increase
changes to the phosphorylated E2 conformation (E2P), in intragastric pH was rapid after oral dosing: the mean
which possesses a high-affinity K? binding site on the side intragastric pH rose above 4 as early as 4 h after the first
of the extracellular canalicular space. Binding of K? to E2P oral dose on day 1. Plasma concentrations of the drug
promotes dephosphorylation of the enzyme, which reverts reached the Cmax at 1.5–2.0 h post-dose, indicating that
to the E1 conformation and releases K? into the cytoplasm. there was little time lag between the elevation of plasma
As the cycle is repeated, acid secretion continues [8]. concentrations and the increase in intragastric pH. The
Because P-CABs have higher pKa values than PPIs and are anti-secretory effect persisted throughout the 24-h interval
stable under low pH conditions, they are accumulated in before the next dose, in an apparently dose-dependent
the secretory canaliculi at higher concentrations than PPIs manner. With the recommended therapeutic dosage of
and act on the H?,K?-ATPase irrespective of its status of 20 mg once daily, 24-h intragastric pH [4 holding time
activity [24, 25]. ratio (%HTR) on days 1 and 7 were 63 and 83 %,
Subsequent molecular studies on the H?,K?-ATPase respectively, in Japanese patients and 63 and 85 % in UK
have revealed that there is a single, high-affinity K? patients. No population differences were observed in the
binding site in the transmembrane helix [8]. P-CABs dose–response relationship of vonoprazan. The night-time
have been designed to bind at the vicinity of the K? fall in intragastric pH was more attenuated in subjects
binding site. Differences in potency and duration of given vonoprazan than in those given placebo, also in an
action among P-CABs may be associated with their apparently dose-dependent manner.
affinity and/or dissociation constant for the binding sites When the plasma concentration–effect relationship of
on H?,K?-ATPase. For instance, vonoprazan has Ki the drug was evaluated based on plasma AUC0–tau and 24-h
values of 10 nmol/L at pH 7 [24] and 3 nmol/L at pH intragastric pH [4 %HTR, the concentration-effect curves
6.5 [25], respectively. In addition, the IC50 for acid obtained from Japanese and UK patients were almost
secretion is 17–19 nmol/L in porcine microsomes in superimposable, indicating that there were little population
in vitro studies [24]. In addition, the rate of dissociation differences in the pharmacodynamics of vonoprazan
of vonoprazan from isolated ATPase is slower than other between the two populations (Fig. 2). In addition, there
P-CABs: the dissociation half-life of vonoprazan was was no attenuation in anti-secretory response based on the
7.5 h in the presence of 20 mM KCL (near physiological relationship between plasma AUC0–tau and 24-h intragas-
concentration in stimulated gastric juice) as compared tric pH [4 %HTR during administration of the drug over 7
with \2 min for SCH28080 at 10 mH KCL [24]. The consecutive days. Nevertheless, further studies are required
accumulation and clearance of vonoprazan from the to determine whether attenuation of an anti-secretory effect
gastric glands were studied by Matsukawa et al. using would emerge over a long period of use as observed for H2
cultured rabbit gastric glands and compared with lanso- receptor antagonists [30] (Fig. 2).
prazole [29]. They demonstrated that the amounts of Assuming that the inhibition kinetics for H?,K?-
[14C]vonoprazan accumulated in the cultured rabbit gas- ATPase obtained from in vitro studies using animal gastric
tric glands after a 2-h incubation were four and two vesicles [24, 25] can largely be extrapolated to humans, the
times higher than those of lansoprazole at resting and mean plasma concentrations of unbound vonoprazan at
forskolin-stimulated conditions, respectively. In addition, Cmax after an oral dose of 20 mg is approximately
they studied the clearance of the two drugs from the 20–25 ng/mL (equivalent to 23–30 nmol/L), which would
glands by measuring the remaining radioactivity in the be comparable to the IC50 of H?,K?-ATPase. Given the
glands over a 24-h washout period. They found that the competitive nature of inhibition, the achievement of almost
mean radioactivity of vonoprazan measured after wash- complete suppression of acid secretion throughout the
out was approximately seven and three times greater dosing interval of 24 h may be explained by accumulation
than those of lansoprazole at resting and forskolin-stim- of the drug in the secretory canaliculi of the parietal cells
ulated conditions, respectively. owing to its high pKa (9.06) as discussed in the previous
 H. Echizen

Day 1 Day 7 gastrin has trophic effects on the epithelial cells of the
stomach and intestine, sustained hypergastrinemia may
have a role in the development of gastrointestinal malig-
24-h pH >4 HTR(%)

nancies. In preclinical toxicological studies, the adminis-

tration of vonoprazan orally to male and female mice over
2 years was associated with the development of hyper-
Japan study
plasia of neuroendocrine cells (enterochromaffin-like cells)
UK study or malignant carcinoid tumors at doses of 6 mg/kg/day or
greater [20, 21]. A similar results were obtained with male
and female rats at doses greater than 5 mg/kg/day or
Plasma AUC(0-tau) of vonoprazan (ng*h/mL) greater [20, 21]. A pharmacokinetic study performed with
rats showed that plasma AUCs observed after the admin-
Fig. 2 The relationships between plasma AUC0–tau of vonoprazan istration of vonoparazan associated with gastric tumors
and 24-h in gastric pH [4 holding-time ratio (HTR) in healthy men
(n = 60 and 48 for Japan and UK studies, respectively). The data are (i.e., 6 mg/kg) were largely comparable to those seen after
shown as the mean ± standard deviation. The figures were drawn a single oral dose of 40 mg in humans [20, 22]. It is
based upon the data given in [11] uncertain whether the association between tumorigenesis
and hypergastrinemia observed in rodents might be
Sect. (3.1.2) and slow dissociation from the enzyme [24]. extrapolated into humans. A long-term administration of
Further studies are required to examine whether other PPIs accompanying hypergastrinemia has not been
demographic or pathophysiological factors are associated demonstrated to increase the risk of developing carcinoid
with the intra- or inter-individual variability in the anti- tumor owing probably to species differences in gastric
secretory effects of vonoprazan. physiology and enterochromaffin-like cells [31, 32]. Nev-
ertheless, vigilant post-marketing surveillance should be
undertaken until such theoretical concerns are negated by
5 Safety and Tolerability pharmacoepidemiological studies because vonoprazan was
shown to elevate serum gastrin levels two to three times
Because most of the clinical trials performed during the greater than PPIs [20–22].
pre-approval period were reported only as abstracts [for
review see 9, 13–19] and a summary of drug approval
review [20], a detailed profile of adverse drug reactions 6 Clinical Implications
cannot be evaluated at present. Although no studies have
been undertaken or powered to assess this, vonoprazan Vonoprazan as monotherapy was approved for the treat-
appears to be well tolerated compared with PPIs. Among ment of gastroduodenal ulcer and reflux esophagitis, and
2271 patients who received 10 or 20 mg of the drug for the the secondary prevention of low-dose aspirin or NSAID-
treatment of acid-related disorders, 186 (8.2 %) developed induced gastric mucosal damages, and the prevention of
adverse drug reactions including asymptomatic abnormal- relapse for reflux esophagitis. In addition, the drug was
ities in laboratory data. Among the reported clinical events, approved for the eradication of H. pylori as one of the first-
gastrointestinal symptoms of constipation (3.3 %), diarrhea line therapies in combination with clarithromycin and
(0.7 %), and flatulence (0.4 %) were the three most fre- amoxicillin and as a second-line therapy in combination
quent symptoms. Because development of the prototype with amoxicillin and metronidazole [22].
P-CAB SCH28080 was discontinued owing to hepatotox- Briefly, a phase III, randomized, double-blind clinical
icity [8], it is important to monitor the adverse drug reac- study was conducted in Japanese patients having endo-
tion for newer P-CABs. Reversible abnormal liver function scopically confirmed gastric ulcer [20, 21]. Two hundred
tests were observed in 0.2 % of the patients who received and forty-four and 238 patients were allocated to receive
vonoprazan in pre-approval clinical studies: all events were either vonoprazan or lansoprazole at 20 and 30 mg once
reversible and most were associated with elevation of peak daily orally, respectively, for 8 weeks. Results demon-
serum alanine transaminase or aspartate transaminase to strated that the endoscopically confirmed healing was
\200 IU/L, while some were associated with elevation to observed within 8 weeks in 93.5 % of patients receiving
[500 IU/L [20]. Because of the limited number of patients vonoprazan and 93.8 % of those receiving lansoprazole
studied, a continuous post-marketing pharmacovigilance (95 % CI of the difference -4.8 to 4.2), indicating non-
program for hepatotoxicity is required. inferiority of vonoprazan as compared with lansoprazole,
Another important safety issue of vonoprazan is assuming the non-inferiority margin would be -8 %. In
hypochlorhydria-induced hypergastrinemia. Because addition, another phase III, randomized, double-blind,
The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate

clinical study was conducted for evaluating the efficacy of thromboembolic diseases despite having endoscopically
vonoprazan as compared with lansoprazole for the treat- confirmed healed peptic ulcers [14, 20]. Two hundred and
ment of duodenal ulcer [20, 21]. One hundred and eighty- two patients and 202 patients were allocated to low and
three and 185 Japanese patients were allocated to receive high doses of vonoparazan and 217 patients were allocated
either vonoprazan or lansoprazole at 20 and 30 mg once to lansoprazole, and the clinical course was monitored for
daily, respectively, for 6 weeks. Results demonstrated that 24 weeks. Results showed that the relapsing rates of peptic
the endoscopically confirmed healing was observed within ulcer in those given the low and high doses of vonoprazan
6 weeks in 95.5 % of patients receiving vonoprazan and in (0.5 and 1.5 %, respectively) appeared lower than those
98.3 % of those received lansoprazole (95 % CI of the given lansoprazole (2.8 %) and the 95 % CI for the dif-
difference -6.4 to 0.7). Non-inferiority of vonoprazan as ferences between the low-dose vonoprazan vs. lansopra-
compared with lansoprazole failed to be confirmed, zole and the high-dose vonoprazan vs. lansoprazole were
assuming the non-inferiority margin would be -6 %. (-4.7 to 0.1) and (-4.1 to 1.5), respectively. As a result,
A phase III, randomized, double-blind, multicenter the low and high doses of vonoprazan was considered non-
study was conducted for evaluating the efficacy and safety inferior to lansoprazole assuming the non-inferiority mar-
of vonoprazan (20 mg once daily) as compared with gin of 8.7 %. Based upon these data, 10 mg vonoprazan
lansoprazole (30 mg once daily) in Japanese patients with was approved for clinical use. Another phase III study was
endoscopically diagnosed reflux esophagitis [16, 20, 21]. conducted with a similar protocol for evaluating the effi-
Two hundred and seven and 202 patients were allocated cacy of vonoprazan as compared with lansoprazole for the
to vonoprazan and lansoprazole, respectively, and the secondary prevention of gastroduodenal ulcers in Japanese
primary endpoint, endoscopically confirmed healing of patients who needed non-steroidal anti-inflammatory drugs
esophagitis, was assessed at 2, 4, and 8 weeks after the for pain control of rheumatoid arthritis, osteoarthritis, and
beginning of the treatment. Results demonstrated that the other orthopedic diseases despite having endoscopically
healing rates by 8 weeks for vonoprazan and lansoprazole confirmed healed peptic ulcers [13, 20–22]. Two hundred
were 99.0 and 95.5 % (95 % CI of the difference and eighteen and 212 patients were allocated to low and
0.3–6.7), respectively, indicating the non-inferiority of high doses (10 and 20 mg, respectively) of vonoparazan
vonoprazan as compared with lansoprazole, assuming the and 210 patients were allocated to lansoprazole, and the
non-inferiority margin would be -6 % and superiority of clinical course was monitored for 24 weeks. Results
vonoprazan. showed that the relapsing rates of peptic ulcer in those
As for the efficacy of vonoprazan for the eradication of given the low and high doses of vonoprazan (3.3 and
H. pylori, a phase III, randomized, double-blind, multi- 3.4 %, respectively) appeared lower than that in those
center study was performed in Japanese patients with given lansoprazole (5.5 %). In addition, the 95 % CI for
active H. pylori infection confirmed by [13C]-urea breath the difference in relapsing rate between low-dose vono-
test and endoscopically confirmed gastroduodenal ulcer prazan vs. lansoprazole was -6.2 to 1.8 and for high-dose
scars [15, 20–22]. Three hundred and twenty-nine patients vonoprazan vs. lansoprazole was -6.1 to 2.0. As a result,
and 321 patients were allocated to receive either vono- the low and high doses of vonoprazan were considered
prazan (20 mg twice daily) or lansoprazole (30 mg twice non-inferior to lansoprazole assuming the non-inferiority
daily) with amoxicillin (750 mg twice daily) and clar- margin of 8.3 %.
ithromycin (200 mg or 400 mg twice daily) for 7 days. Collectively, the efficacy of vonoprazan seems largely
Eradication of H. pylori was assessed by the urea breath non-inferior to lansoprazole in various clinical indications.
test 4 weeks after the completion of the eradication ther- Vonoprazan may have some advantages over PPIs in terms
apy. Results demonstrated that the eradication rates for of the pharmacokinetic profile: more rapid onset of action,
vonoprazan and lansoprazole were 92.6 and 75.9 %, more powerful acid suppression particularly during night-
respectively (95 % CI for the difference 11.2–22.1), indi- time, and no influence of the CYP2C19 polymorphism on
cating the non-inferiority of vonoprazan as compared with drug exposure. Regarding the pharmacodynamics profile,
lansoprazole assuming the non-inferiority margin of vonoprazan may be preferred to PPIs as maintenance
-10 % and superiority of vonoprazan to lansoprazole. A therapy for reflux esophagitis and for eradication of H.
phase III, randomized, double-blind study was conducted pylori because of its stronger anti-secretory effect com-
for evaluating the efficacy of vonoprazan (either 10 or pared with PPIs [24].
20 mg once daily orally) as compared with lansoprazole
Compliance with Ethical Standards
(15 mg once daily orally) for the secondary prevention of
peptic ulcers in Japanese patients who needed a low-dose Conflict of interest The author declares no conflict of interest
aspirin (81–324 mg daily) therapy for prevention of regarding the present article.
 H. Echizen

References potassium-competitive acid blocker, vonoprazan, compared with

esomeprazole or rabeprazole. Gastroenterology. 2015;148:S-620.
1. Soll AH, Achord JL, Bozymski G, Brooks S, Lanza F, Lyon D, 18. Mizokami Y, Oda K, Saito K, et al. A phase 3, lansoprazole-
Meyer G, Reinus J, Schuster M, Achord J, Ofman J, Glassman P, controlled, long-term extension study to evaluate the safety and
efficacy of vonoprazan (10 mg or 20 mg) for prevention of
Laine L, Tytgat G, Walsh JH, Graham DY, Peterson WL. Med-
ical treatment of peptic ulcer disease: practice guidelines. JAMA. recurrent peptic ulcers during long-term therapy with non-ster-
1996;275:622–9. oidal anti-inflammatory drug (NSAID). Gastroenterology.
2. Axon A. Helicobacter pylori and public health. Helicobacter. 2015;148:S-88–S-89.
19. Garnock-Jones KP. Vonoprazan: first global approval. Drugs.
2014;19(Suppl 1):68–73.
3. Fock KM, Ang TL, Bee LC, Lee EJD. Proton pump inhibitors. 2015;75:439–43.
Clin Pharmacokinet. 2008;47:1–6. 20. Drug approval review for vonoprazan fumarate (in Japanese), the
4. Katz PO, Hatlebakk JG, Gstell DO. Gastric acidity and acid Pharmaceuticals and Medical Devices Agency of Japan. 2014.
breakthrough with twice-daily omeprazole or lansoprazole. Ali- https://www.pmda.go.jp/. Accessed 28 May 2015.
ment Pharmacol Ther. 2000;14:709–14. 21. The interview form for vonoprazan fumarate (TakecabÒ tablets
5. Shaw MJ, Crawley JA. Improving health-related quality of life in 10 mg and 20 mg) ver. 3, (in Japanese). Takeda Pharmaceutical
gastro-oesophageal reflux disease. Drugs. 2003;63:2307–16. Company Limited. 2015. http://www.takeda.co.jp/. Accessed 28
6. Cheng HC, Sheu BS. Intravenous proton pump inhibitors in the May 2015.
management for peptic ulcer bleeding: clinical benefits and lim- 22. Prescribing information of TakecabÒ tablets 10 mg and 20 mg
its. World J Gastrointest Endosc. 2011;3:49–56. ver. 2 (in Japanese). 2015. http://www.takeda.co.jp/. Accessed 28
May 2015.
7. Furuta T, Sugimoto M, Shirai N. Individualized therapy for
gastroesophageal reflux disease: potential impact of pharmaco- 23. Arikawa Y, Nishida H, Kurasawa O, Hasuoka A, Hirase K,
genetic testing based on CYP2C19. Mol Diagn Ther. Inatomi N, Hori Y, Matsukawa J, Imanishi A, Kondo M, Tarui N,
2012;16:223–34. Hamada T, Takagi T, Takeuchi T, Kajino M. Discovery of a
8. Parsons ME, Keeling DJ. Novel approaches to the pharmaco- novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-
logical blockade of gastric acid secretion. Expert Opin Investig sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate
Drugs. 2005;14:411–21. (TAK-438) as a potassium-competitive acid blocker (P-CAB).
9. Chung IS, Choi MG, Park SH, et al. Revaprazan (RevanexÒ), a J Med Chem. 2012;55:4446–56.
novel acid pump antagonist, for duodenal ulcer: results of a 24. Shin JM, Inatomi N, Munson K, Strugatsky D, Tokhtaeva E,
double-blind, randomized, parallel, multi-center phase III clinical Vagin O, Sachs G. Characterization of a novel potassium-com-
trial. Korean J Gastrointest Endosc. 2005;31(1):17–24. petitive acid blocker of the gastric H, K-ATPase, 1-[5-(2-fluo-
rophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methyl-
10. Chang R, Chung IS, Park SH, et al. Phase III clinical trial of
revaprazan (RevanexÒ) for gastric ulcer. Korean J Gastrointest methanamine monofumarate (TAK-438). J Pharmacol Exp Ther.
Endosc. 2007;34(6):312–9. 2011;339:412–20.
11. Jenkins H, Sakurai Y, Nishimura A, Okamoto H, Hibberd M, 25. Hori Y, Imanishi A, Matsukawa J, Tsukimi Y, Nishida H, Ari-
kawa Y, Hirase K, Kajino M, Inatomi N. 1-[5-(2-Fluorophenyl)-
Jenkins R, Yoneyama T, Ashida K, Ogama Y, Warrington S.
Randomised clinical trial: safety, tolerability, pharmacokinetics 1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine
and pharmacodynamics of repeated doses of TAK-438 (vono- monofumarate (TAK-438), a novel and potent potassium-com-
prazan), a novel potassium-competitive acid blocker, in healthy petitive acid blocker for the treatment of acid-related diseases.
male subjects. Aliment Pharmacol Ther. 2015;41:636–48. J Pharmacol Exp Ther. 2010;335:231–8.
12. Umegaki E, Iwakiri K, Hiramatsu N, et al. A phase 3, random- 26. US Department of Health and Human Services, Food and Drug
ized, double-blind, multicenter study to evaluate the efficacy and Administration, Center for Drug Evaluation and Research
safety of TAK-438 (10 mg or 20 mg once-daily) compared to (CDER). Guidance for industry, drug interaction studies: study
lansoprazole (15 mg once-daily) in a 24-week maintenance design, data analysis, implications for dosing, and labeling rec-
treatment for healed erosive esophagitis. Gastroenterology. ommendations. 2012. http://www.fda.gov/downloads/Drugs/
2014;146:S-738. GuidanceComplianceRegulatoryInformation/Guidances/
UCM292362.pdf. Accessed 26 Aug 2015.
13. Mizokami Y, Ashida K, Soen S, et al. TAK-438 versus lanso-
prazole 15 mg for secondary prevention of peptic ulcers associ- 27. European Medicine Agency (EMA), Committee for Human
ated with non-steroidal anti-inflammatory drug (NSAID) therapy: Medicinal Products (CHMP). Guideline on the investigation of
results of a phase 3 trial. Gastroenterology. 2014;146:S-739. drug interactions. 2012. http://www.ema.europa.eu/docs/en_GB/
14. Kawai T, Ashida K, Mizokami Y, et al. TAK-438 versus lanso- document_library/Scientific_guideline/2012/07/WC500129606.
prazole 15 mg for secondary prevention of peptic ulcers associ- pdf. Accessed 26 Aug 2015.
ated with low-dose aspirin therapy: results of a phase 3 trial. 28. Ogawa R, Echizen H. Drug-drug interaction profiles of proton
Gastroenterology. 2014;146:S-739. pump inhibitors. Clin Pharmacokinet. 2010;49:509–33.
15. Murakami K, Sakurai Y, Shiino M, et al. A phase 3, double-blind 29. Matsukawa J, Hori Y, Nishida H, Kajino M, Inatomi N. A com-
study of a triple therapy with TAK-438, amoxicillin, and clar- parative study on the modes of action of TAK-438, a novel potas-
ithromycin as first line eradication of H. pylori and a triple sium-competitive acid blocker, and lansoprazole in primary cultured
rabbit gastric glands. Biochem Pharmacol. 2011;81:1145–51.
therapy with TAK-438, amoxicillin, and metronidazole as second
line eradication of H. pylori. Gastroenterology. 2014;146:S-740. 30. Sandvik AK, Brenna E, Waldum HL. Review article: the phar-
16. Iwakiri K, Umegaki E, Hiramatsu N, et al. A phase 3, random- macological inhibition of gastric acid secretion-tolerance and
ized, double-blind, multicenter study to evaluate the efficacy and rebound. Aliment Pharmacol Ther. 1997;11:1013–8.
31. Freston JW. Omeprazole, hypergastrinemia, and gastric carcinoid
safety of TAK-438 (20 mg once-daily) compared to lansoprazole
(30 mg once-daily) in patients with erosive esophagitis. Gas- tumors. Ann Intern Med. 1994;121:232–3.
troenterology. 2014;146:S-741. 32. Klinkenberg-Knol EC, et al. Long-term omeprazole treatment in
17. Sakurai Y, Mori Y, Okamoto H, et al. A crossover study to resistant gastroesophageal reflux disease: efficacy, safety, and
evaluate the acid-inhibitory effect of a newly developed influence on gastric mucosa. Gastroenterology. 2000;118:661–9.