JNM 25 006
JNM 25 006
JNM 25 006
Proton pump inhibitors are commonly utilized for the treatment of gastric acid-related diseases, such as gastroesophageal reflux
disease, peptic ulcer disease, and Helicobacter pylori infection, and for the prevention of low-dose aspirin or nonsteroidal anti-
inflammatory drug-induced peptic ulcers. Vonoprazan is a first-in-class potassium-competitive acid blocker, which has distinct
advantages compared to other conventional proton pump inhibitors in terms of the efficacy for acid suppression. Due to its strong
gastric acid suppression capabilities, vonoprazan serves as an effective drug for the treatment of gastroesophageal reflux disease and
H. pylori infection.
(J Neurogastroenterol Motil 2019;25:6-14)
Key Words
Gastroesophageal reflux; Helicobacter pylori ; Peptic ulcer; Potassium; Proton pump inhibitors
Received: August 7, 2018 Revised: September 27, 2018 Accepted: October 25, 2018
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.
org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work
is properly cited.
*Correspondence: Hidekazu Suzuki, MD, PhD, FACG, AGAF, RFF
Fellowship Training Center and Medical Education Center, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan
Tel: +81-3-5363-3914, Fax: +81-3-5363-3967, E-mail: hsuzuki1201@gmail.com
nists (H2RAs).7 PPIs are metabolized and inactivated by a num- quire acid protection. In addition, vonoprazan has a higher value of
ber of cytochrome P450 (CYP) enzymes (CYP2C9, CYP2C8, alkaline pKa (> 9) than PPIs, and previous P-CABs can be easily
CYP2C18, CYP2C19, CYPA3/4, CYP3A1A2, and CYP3A4), protonated and accumulated at high concentrations in the intracel-
mainly CYP2C19 and CYP3A4.9 The distribution of CYP2C19 lular canaliculi of parietal cells.6,8 As such, vonoprazan is more stable
phenotypes was divided into 4 phenotypes: extensive metabolizers in an acidic environment than PPIs.27 In addition, vonoprazan is
(EM), intermediate metabolizers, ultra-rapid metabolizers, and shown to have consistent acid suppression capabilities irrespective
poor metabolizers.10 CYP2C19 is responsible for > 80% of the of CYP2C19. It is metabolized to its inactive form mainly by CY-
metabolism of omeprazole, lansoprazole, and pantoprazole metabo- P3A4, and partially also by CYP2B6, CYP2C19, CYP2D6, and
lism.11 Esomeprazole, the S-isomer of omeprazole, is metabolized SULT2A1, whereas most PPIs are mainly metabolized by CY-
to a less extent by CYP2C19 than omeprazole.12 Rabeprazole is P2C19.28 Therefore, vonoprazan showed quite rapid, strong, and
mainly metabolized via a non-enzymatic reduction to rabeprazole continuous gastric acid suppression when compared to conventional
thioether.9 Therefore, the effectiveness of omeprazole and lansopra- PPIs. Tegoprazan is another potent and highly selective inhibitor of
zole is sometimes insufficient in EM and ultra-rapid metabolizers.13 gastric H+/K+-ATPase. Interestingly, tegoprazan evoked a gastric
Another issue with PPIs is that the effect on gastric acid secretion phase III contraction of the migrating motor complex in a canine
is slow and reaches a plateau in 3-5 days because several doses are model.19 YH4808 had a faster onset than esomeprazole and can
required to inhibit newly synthesized proton pumps and achieve maintain an intra-gastric acidity of pH > 4 for a longer time dur-
maximal acid-inhibition.14-16 ing both day and night in healthy volunteers.20 DWP14012 showed
rapid and sustained suppression of gastric acid secretion in healthy
volunteers.22 KFP-H008 showed a more effective, potent, and
Pharmacology of Potassium-competitive longer-lasting inhibitory action than lansoprazole in a rat model.23
Acid Blockers However, there are no reports about the usefulness of tegoprazan,
P-CAB is a class of drug that competitively blocks the potassi- YH4808, DWP14012, and KFP-H008 in actual clinical practice.
um-binding site of the gastric H+/K+-ATPase.6 The first P-CAB
used in clinical practice was revaprazan, which has been available
in South Korea and India since 2007. Revaprazan showed an early
Gastroesophageal Reflux Disease
effect on acid suppression.17 However, the effect was not superior For most patients with GERD, PPIs are the first choice
to conventional PPIs for the treatment of endoscopic submucosal of treatment.24 A recent Japanese guideline for GERD recom-
dissection-induced ulcers18 and there are no reports that revaprazan mended the use of PPIs as first-line and maintenance treatments
is more effective than PPIs for the other gastric acid-related condi- (Fig. 1A).29 PPIs were shown to be superior to H2RAs in healing
tions. In 2015, vonoprazan became the second P-CAB available in erosive esophagitis and decreasing relapse rates.30-32 A randomized
the Japanese market, and it is now available in the Philippines, Sin- study suggested that esomeprazole has a more rapid effect against
gapore, and Thailand. Tegoprazan was approved as a treatment for heartburn and reflux symptoms than omeprazole, lansoprazole, and
GERD in South Korea since July 2018. Other P-CABs (YH4808, pantoprazole; however, there was no significant difference in the
DWP14012, and KFP-H008) are still in clinical trials.19-23 rate of endoscopic healing of reflux esophagitis at 8 weeks.33 Despite
Vonoprazan was significantly effective in the treatment of H. this, most studies determined that there is no notable difference in
pylori infection, GERD, and LDA-induced peptic ulcers.6,24 There effect among PPIs in terms of short-term symptom management.34
are several advantages to using vonoprazan than conventional PPIs Vonoprazan could be the first-line drug in the future. In
from a pharmacological point of view. It is rapidly absorbed in the CYP2C19 EM patients with erosive esophagitis, 90.0% treated
small intestine where it accumulated in the canalicular membranes with vonoprazan (20 mg/day) achieved mucosal healing at 2 weeks
of parietal cells25 and it shows a greater acid-inhibitory effect than compared with the 79.3% that were treated with lansoprazole (P <
those of esomeprazole and rabeprazole, as observed from the first 0.01).35 Similarly, at 4 and 8 weeks, the proportion of patients with
day of administration.26 It also has a longer duration of action. The healed erosive esophagitis tended to be higher in the vonoprazan
pH 4 holding time ratios of vonoprazan were significantly longer group than in the lansoprazole group (at 4 weeks 96.1% vs 90.9%,
than those of esomeprazole and rabeprazole.26 It does not require P < 0.05; at 8 weeks 98.9% vs 94.5%, P < 0.03).35 Moreover,
acid activation, whereas PPIs are acid-activated prodrugs that re- vonoprazan was more effective for severe erosive esophagitis (Los
A GERD
Initial therapy
Maintenance therapy
B GERD
Initial therapy
Maintenance therapy
Surgery
Figure 1. Strategy of gastroesophageal reflux disease (GERD) treatment. (A) Conventional strategy of GERD treatment (an abridged edition
of the Evidence-based Clinical Practice Guidelines for GERD 2015 published by the Japanese Society of Gastroenterology).29 Initial treatment is
administration of proton pump inhibitor (PPI) standard dose for 8 weeks. Then, maintenance treatment is administration of PPI half dose daily.
If incomplete healing occurs, maintenance with continuous PPI standard dose is permissible. On-demand PPI treatment is alternative manage-
ment strategy. (B) The authors propose a new strategy of GERD treatment considering the effectiveness of potassium-competitive acid blocker (P-
CAB). Initial treatment is 4-week treatment with P-CAB standard dose for severe erosive esophagitis. Four-week treatment with P-CAB or 8-week
treatment with PPI are recommended as an initial therapy for mild erosive esophagitis or non-erosive reflux disease (NERD). Then, maintenance
treatment is administration of P-CAB half dose daily. If incomplete healing, maintenance with continuous P-CAB standard dose is permissible.
Continuous PPI standard or half dose daily is one of the options. On-demand P-CAB treatment is a workable alternative management strategy.
The severity of reflux esophagitis is classified according to the Los Angeles classification. EE, erosive esophagitis.
Angeles classification grades C/D) than lansoprazole (at 8 weeks Even in whole patients, vonoprazan is more effective than lanso-
98.7% vs 87.5%, P < 0.01) and had more rapid effectiveness (at prazole at each time point (at 2 weeks 90.7% vs 81.9%, P < 0.01;
2 weeks 88.0% vs 63.9%, P < 0.01; at 4 weeks 96.0% vs 80.6%, at 4 weeks 96.6% vs 92.5%, P < 0.01; at 8 weeks 99.0% vs 95.5%,
P < 0.03).35 Therefore, vonoprazan is highly effective for patients P < 0.01). On the other contrary, no data showed that P-CAB was
with more severe erosive esophagitis and CYP2C19 EM patients. effective to relieve the symptoms of mild esophagitis and NERD.
resistant strains (82.0% vs 40.0%, P < 0.01).53 In CYP2C19 EM noprazan (or other P-CABs)-based concomitant therapy; therefore,
patients, the eradication rate of vonoprazan-based triple therapy was studies on this regard are expected (Fig. 3B). Currently, a phase III
significantly higher than that of lansoprazole-based triple therapy clinical trial for H. pylori eradication is being conducted in Korea to
(92.9% vs 75.0%, P < 0.01).53 In CYP2C19 PM patients, there compare tegoprazan-amoxicillin-clarithromycin triple regimen with
was no significant difference, but the rate of vonoprazan-based tri- lansoprazole-amoxicillin-clarithromycin triple regimen.
ple therapy was high compared with the rate of lansoprazole-based
triple therapy (90.9% vs 81.3%, P = NS). Conversely, the rate of
the second-line metronidazole and amoxicillin-based triple therapy
Low-dose Aspirin or Nonsteroidal
did not differ significantly between the PPI and vonoprazan groups
Anti-inflammatory Drug–induced
(96.8% vs 90.5%, P = NS).54 A meta-analysis showed that vono-
Peptic Ulcers
prazan- and conventional PPI-based therapies are similarly effective The use of LDA in the prevention of atherothrombosis is
in eradicating clarithromycin-susceptible H. pylori strains (95.4% frequently associated with a development of erosions or ulcerations
vs 92.8%, P = 0.230), and that vonoprazan-based triple therapy in the upper gastrointestinal tract. Compared to controls, PPIs re-
was significantly superior to PPI-based therapy in treating patients duced the risk of LDA-induced peptic ulcers but did not increase
infected with clarithromycin-resistant H. pylori strains (82.0% vs the risk of mortality.59,60 Another meta-analysis showed that PPIs
40.0%, P < 0.01).55 Ono et al56 showed that a clarithromycin-met- were superior to H2RAs for prevention of LDA-induced peptic
ronidazole-vonoprazan regimen had greater efficacy than clarithro- ulcers.5 PPIs are also effective and safe in preventing NSAID-
mycin-metronidazole-PPI regimen for penicillin allergy patients induced peptic ulcers when compared to placebos and H2RAs.61,62
(92.9% vs 54.6%, P < 0.01). There is geographic distribution of Recently, vonoprazan showed an equivalent efficacy to that of lanso-
resistance to clarithromycin and metronidazole in H. pylori . High prazole in preventing LDA-induced ulcer recurrence (Farrington
resistance to clarithromycin and low resistance to metronidazole are and Manning test: margin 8.7%, significance level 2.5%). At the
found in Japan.57 Further studies are needed to evaluate the efficacy same time, peptic ulcer recurrence rates were significantly lower
of vonoprazan-based therapy because vonoprazan has been ap- with vonoprazan 10 mg than with lansoprazole 15 mg, as shown by
proved only in Japan, Philippines, Singapore, and Thailand at this the results of the post hoc analyses of the extension study (log-rank
time. The Maastricht V/Florence Consensus Report recommended test, P = 0.039).63 The 24-week peptic ulcer recurrence rate was
that the optimal regimen should be selected with the prevalence of 2.8% and 0.5% in the lansoprazole (15 mg) and vonoprazan (10 mg)
antibiotic resistance rates (Fig. 3A).58 Amoxicillin-clarithromycin- groups, respectively. With regard to NSAID-induced peptic ulcers,
PPI triple therapy without prior susceptibility testing should be vonoprazan showed better efficacy.64 The proportion of patients
abandoned when the clarithromycin resistance rate in the region is with endoscopically confirmed recurrent NSAID-induced peptic
more than 15%.58 In the area with high resistance to clarithromycin ulcers within 24 weeks was 3.3%, 3.4%, and 5.5%, for vonoprazan
and low resistance to metronidazole, amoxicillin-metronidazole-PPI (10 mg, 20 mg) and lansoprazole (15 mg), respectively.64
triple regimen is recommended.58 In the area with dual resistance
to clarithromycin and metronidazole, bismuth quadruple therapy is
recommended. As a rescue treatment, bismuth quadruple therapy
Complications
or quinolone-containing therapy is recommended.58 In the area with The long-term use of PPIs could cause the development of
low resistance to clarithromycin, we recommend the amoxicillin- fundic gland polyps, carcinoid tumors, increase the risk of com-
clarithromycin-vonoprazan triple regimen. If antimicrobial suscepti- munity acquired pneumonia, iron and vitamin B12 deficiencies,
bility testing is available, amoxicillin-clarithromycin-PPI triple regi- Clostridium difficile -associated diarrhea, dementia, and chronic
men can be an alternative choice. In the area with high resistance kidney disease.25,65-72 Clinical trials evaluating the safety and toler-
to clarithromycin and low resistance to metronidazole, amoxicillin- ability of vonoprazan revealed that most of treatment-emergent ad-
metronidazole-vonoprazan or PPI triple regimen is recommended verse events with vonoprazan were mild in intensity and there was
because there is no evidence of the amoxicillin-metronidazole- no obvious trend towards an increase in incidence over time up to
vonoprazan triple regimen being more effective than the amoxicil- 52 weeks of treatment.35,63 In these trials, hepatotoxicity was rarely
lin-metronidazole-PPI triple regimen. Little has been reported on observed. One differential characteristic of vonoprazan is that it is a
bismuth quadruple therapy, quinolone-containing therapy, and vo- pyrrole derivate, whereas previous P-CABs are imidazole-pyridine
A H. pylori infection
Low CAM resistance (< 15%) High CAM resistance (> 15%) High CAM resistance (> 15%)
Low MTZ resistance (< 15%) High MTZ resistance (> 15%)
Bismuth Quinolone
quadruple therapy containing therapy
containing PPI containing PPI
B H. pylori infection
Low CAM resistance (< 15%) High CAM resistance (> 15%) High CAM resistance (> 15%)
Low MTZ resistance (< 15%) High MTZ resistance (> 15%)
Figure 3. Strategy of proton pump inhibitor (PPI)-resistant Helicobacter pylori (H. pylori) eradication treatment. (A) Conventional strategy of H.
pylori eradication treatment (an abridged edition of Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report
published by the European Helicobacter and Microbiota Study Group).58 In areas of low clarithromycin (CAM) resistance (< 15%), amoxicillin
(AMX), CAM, and PPI triple therapy is the recommended first-line treatment. In areas of high CAM resistance (> 15%) and low metronida-
zole (MTZ) resistance (< 15%), AMX, MTZ, and PPI triple therapy is recommended. In areas of dual resistance, bismuth quadruple therapy is
recommended. Quinolone containing therapy and bismuth quadruple therapy are recommended as rescue therapy. (B) The authors propose a new
strategy of H. pylori eradication treatment. AMX, CAM, and potassium-competitive acid blocker (P-CAB) triple therapy is sufficient treatment
even for CAM resistant strains. AMX, MTZ, P-CAB, or PPI triple therapy, quinolone containing therapy and bismuth quadruple therapy may
be recommended as rescue therapy.
derivates, which might cause the hepatotoxicity of previous P-CABs docrine tumors remained. Bone fracture, hypomagnesemia, pneu-
(SCH 28080 and AZD 0865) and subsequent termination of their monia, and C. difficile -associated diarrhea may also be caused by
clinical development.73,74 Serum gastrin levels tended to be higher strong inhibition of gastric acid by continuous P-CABs treatment.6
in the vonoprazan group than in the PPI group.75,76 Although In addition, parietal cell protrusion and dilated oxyntic glands can
there is no evidence that hypergastrinemia induced by PPIs or P- be observed after vonoprazan treatment.77 Vonoprazan treatment
CABs causes neuroendocrine tumors in humans, P-CAB-induced reduced the value of urea breath test in patients infected with H.
stimulation of enterochromaffin cells and increased risk of neuroen- pylori .78 The long-term (5 years) effect of vonoprazan is currently
under examination in patients receiving maintenance treatment for 5. Mo C, Sun G, Wang YZ, Lu ML, Yang YS. PPI versus histamine H2
healed erosive esophagitis, and complications of long-term vonopra- receptor antagonists for prevention of upper gastrointestinal injury associ-
ated with low-dose aspirin: systematic review and meta-analysis. PLoS
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Financial support: This work was supported by a Grant-in-Aid dolf L. Stereoselective metabolism of omeprazole by human cytochrome
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Conflicts of interest: Hidekazu Suzuki received scholarship 16036.
funds for the research from Daiichi-Sankyo, EA Pharma, Otsuka 14. Junghard O, Hassan-Alin M, Hasselgren G. The effect of the area
Pharmaceutical, and Tsumura, and received service honoraria from under the plasma concentration vs time curve and the maximum plasma
Astellas, AstraZeneca, Daiichi-Sankyo, Otsuka Pharmaceutical, concentration of esomeprazole on intragastric pH. Eur J Clin Pharmacol
2002;58:453-458.
Mylan EPD, Takeda Pharmaceutical, and Tsumura.
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16. Sachs G, Shin JM, Munson K, et al. Review article: the control of gas-
zuki wrote the manuscript; Hideki Mori made the Figures; and
tric acid and Helicobacter pylori eradication. Aliment Pharmacol Ther
Hidekazu Suzuki supervised the all preparation of this article. 2000;14:1383-1401.
17. Yu KS, Bae KS, Shon JH, et al. Pharmacokinetic and pharmacodynamic
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