Alimentary Pharmacology and Therapeutics

Potent acid inhibition by vonoprazan in comparison with

esomeprazole, with reference to CYP2C19 genotype
T. Kagami*, S. Sahara*, H. Ichikawa*, T. Uotani*, M. Yamade*, M. Sugimoto*, Y. Hamaya†, M. Iwaizumi*, S. Osawa‡,
K. Sugimoto*, H. Miyajima* & T. Furuta§

*First Department of Medicine, SUMMARY

Hamamatsu University School of
Medicine, Hamamatsu, Japan.
†
Department of Clinical Oncology,
Background
Hamamatsu University School of Acid inhibitory effects of proton pump inhibitors (PPIs) are influenced by
Medicine, Hamamatsu, Japan. CYP2C19 genotype. In contrast, the potent acid inhibition of vonoprazan is
‡
Department of Endoscopic and not influenced by CYP2C19 genotype.
Photodynamic Medicine, Hamamatsu
University School of Medicine,
Hamamatsu, Japan. Aim
§
Center for Clinical Research, To compare the acid inhibitory effects of vonoprazan and esomeprazole in
Hamamatsu University School of relation to CYP2C19 genotype.
Medicine, Hamamatsu, Japan.
Methods
Correspondence to: Twenty-eight healthy Japanese volunteers [7 CYP2C19 poor metabolisers
Dr T. Furuta, Center for Clinical (PMs), 11 intermediate metabolisers (IMs) and 10 rapid metabolisers
Research, Hamamatsu University (RMs)] received four different regimens in a randomised crossover manner:
School of Medicine, 1-20-1, (i) vonoprazan 20 mg twice daily (b.d.), (ii) vonoprazan 20 mg daily, (iii)
Handayama, Higashi-ku, Hamamatsu
431-3192, Japan.
esomeprazole 20 mg b.d. and (iv) esomeprazole 20 mg daily. The timing of
E-mail: [email protected] each dosing was 1 h before a meal. Twenty-four-hour intragastric pH mon-
itoring was performed on day 7 on each regimen.
Publication data Results
Submitted 20 December 2015
In the overall genotype group, pH ≥4 holding time ratios (pH 4 HTRs)
First decision 8 January 2016
Resubmitted 10 February 2016 with vonoprazan b.d., vonoprazan daily, esomeprazole b.d. and esomepra-
Accepted 26 February 2016 zole daily were 100%, 95%, 91%, and 68% respectively. pH 5 HTRs were
EV Pub Online 18 March 2016 99%, 91%, 84% and 54% respectively. Vonoprazan b.d. potently suppressed
acid for 24 h, and was significantly superior to other regimens irrespective
This article was accepted for publication
after full peer-review.
of CYP2C19 genotype. Vonoprazan daily was equivalent to esomeprazole
b.d. in IMs and PMs, but superior in RMs. CYP2C19 genotype-dependent
differences were observed in esomeprazole daily but not in vonoprazan b.d.
or daily.

Conclusion
Vonoprazan 20 mg b.d. inhibits acid irrespective of CYP2C19 genotype,
more potently than esomeprazole 20 mg b.d., pH 4 and 5 holding time
ratios reached 100% and 99%, respectively.

Aliment Pharmacol Ther 2016; 43: 1048–1059

1048 ª 2016 John Wiley & Sons Ltd

doi:10.1111/apt.13588
 Comparison of vonoprazan with esomeprazole

INTRODUCTION lansoprazole 30 mg b.d. and rabeprazole 10 mg b.d.,

Acid suppression is an important part of therapy for with the result that esomeprazole was relatively effective
gastro-oesophageal reflux disease (GERD) and peptic even in RMs.24 Nevertheless, esomeprazole still showed
ulcer. Proton pump inhibitors (PPIs) are widely used as CYP2C19 genotype-dependent differences in acid inhibi-
first-line drugs in such acid-related diseases,1 and are also tion, and the acid inhibition by esomeprazole in RMs
used in the eradication of Helicobacter pylori with antibi- was inferior to that in PMs and IMs.
otics.2–4 In Japan, GERD is typically treated with single The novel drug, vonoprazan, belongs to a new class of
daily administration of a PPI (i.e. omeprazole 20 mg, lan- acid secretion inhibitors called potassium-competitive acid
soprazole 30 mg, rabeprazole 10 mg or esomeprazole blockers. Vonoprazan competitively inhibits the binding
20 mg), while H. pylori is treated by twice daily dosing. of potassium ion to H+, K+-ATPase (proton pump) in the
Proton pump inhibitors are mainly metabolised by final step of acid secretion in gastric parietal cells.25 It has
CYP2C19 in the liver.5–8 This enzyme shows a wide been clinically available in Japan since February 2015, and
range of genetically determined inter-individual differ- is administered under the Japanese health insurance sys-
ence.9, 10 CYP2C19 genotypes are classified into four tem at 20 mg daily for GERD; 20 mg daily or 10 mg daily
groups, namely poor metaboliser (PM), intermediate for the secondary prevention of GERD and 20 mg b.d.
metaboliser (IM), rapid metaboliser (RM) and ultra rapid with antibiotics for eradication of H. pylori.26–28 Vono-
metaboliser (URM).9–11 The population frequency of prazan binds selectively to parietal cells, independently of
URM in the Japanese is extremely low, and the clinical acid secretion. It has slow dissociation from the H(+),K(+)
relevance of URM in PPI use is unclear.12 For PPI use, -ATPase and long-lasting inhibition.29 Unlike PPIs, which
therefore, CYP2C19 genotypes are classified into three need drug accumulation and acid activation,30 vono-
groups, namely PM, IM and RM (including URM). prazan, therefore, acts on both active and resting proton
The population frequency of PMs, IMs and RMs in Japa- pumps. Its inhibition of proton pump activity is 400-fold
nese are 18.8%, 43.8% and 35.5% respectively.13 The phar- more potent than that of lansoprazole (CH50 = 0.019 and
macokinetics and pharmacodynamics of a PPI are affected 7.600 lmol/L for vonoprazan and lansoprazole, respec-
by CYP2C19 polymorphism9, 14, 15: metabolism and elimi- tively, at pH 6.6).31 The plasma half-life of a single dose of
nation from the systemic circulation are more rapid in RMs vonoprazan 20 mg is 7.7 h,27 and is accordingly superior
than PMs and IMs, and acid inhibition by a PPI is less effec- to the typical 1–2 h of other PPIs. Vonoprazan is metabo-
tive in RMs than in PMs and IMs.16, 17 Consistent with lised to its inactive form mainly by CYP3A4, and partially
these findings, cure rates of GERD (i.e. erosive reflux also by CYP2B6 and CYP2C19, CYP2D6 and
esophagitis) with a PPI and successful eradication rates of SULT2A1.26–28 This plurality means that the plasma con-
H. pylori with a PPI-based regimen were reportedly lower centrations and acid inhibition induced by vonoprazan are
in RMs than in PMs and IMs.3, 18–21 Insufficient acid inhi- less affected by polymorphism in drug metabolising
bition with standard doses of a PPI in RMs remains an enzymes, such as CYP2C19, than those of other PPIs.
important clinical problem.22 Here, we investigated the potency of acid inhibition
Of the four PPIs now available in Japan (omeprazole, with vonoprazan and esomeprazole in relation to
lansoprazole, rabeprazole and esomeprazole), omeprazole CYP2C19 genotype in H. pylori-negative healthy Japa-
and lansoprazole are mainly metabolised by CYP2C19 in nese volunteers.
the liver.11 Serum concentrations of omeprazole and lan-
soprazole are significantly affected by CYP2C19 poly- METHODS
morphism, with the result that their acid inhibition in
RMs is inferior to that in PMs and IMs. Institutional Review Board approval
Esomeprazole is the S-isomer of omeprazole. Com- Approval for the study protocol was obtained in advance
pared with omeprazole, esomeprazole undergoes less first from the Ethics Committee of Hamamatsu University
pass metabolism by CYP2C19 in the liver, and therefore School of Medicine (approval no. RG14-283).
has a superior AUC (area under the concentration-time
curve) to omeprazole23 and yields more potent acid inhi- Clinical trial registry
bition. We previously reported that the acid inhibition of This study was registered in the University hospital
esomeprazole 20 mg b.d. was less affected by CYP2C19 Medical Information Network (UMIN) Clinical Trials
polymorphism than that of omeprazole 20 mg b.d., Registry System (UMIN000019890).

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T. Kagami et al.

Subjects The primary endpoint was acid inhibition with the

From February to April 2015, 40 healthy Japanese volun- four regimens of vonoprazan 20 mg b.d., vonoprazan
teers were consecutively recruited from among medical 20 mg daily, esomeprazole 20 mg b.d. and esomeprazole
and nursing students of Hamamatsu University School 20 mg daily, as assessed by 24-h intragastric pH moni-
of Medicine (Figure 1). After written informed consent toring. Intragastric pH ≥4 and pH ≥5 are reportedly
was obtained, fasting blood samples were collected from important for the treatment of GERD and the eradica-
all subjects, and serum antibodies to H. pylori and tion of H. pylori respectively.32–36 We therefore examined
CYP2C19 polymorphism were analysed. pH 4 and 5 HTR as indices of the gastric acid inhibition
Exclusion criteria were any underlying disease, smok- effect. The secondary endpoint was a descriptive estima-
ing habit, past or present H. pylori infection, and habit- tion of the influence of CYP2C19 genotypes. We also
ual use of any medicine. Of 40 volunteers, 9 (22.5%), 16 measured fasting serum gastrin concentration on day 7
(40%) and 15 (37.5%) were PMs, IMs and RMs of of each regimen.
CYP2C19 respectively. These ratios were compatible with
those in our previous report.21 Eight subjects were then Serum antibody to H. pylori
excluded, four with serum antibody to H. pylori, two Serum antibody to H. pylori was analysed with a com-
who used habitual medicines and two who declined to mercially available kit (E-plate Eiken H. pylori antibody;
participate during the run-in period. The remaining 32 Eiken Chemical Co. Ltd, Tokyo, Japan). Volunteers with
participants (7 PMs, 12 IMs and 13 RMs) agreed to par- titres of <10 U/mL were diagnosed as H. pylori negative.
ticipate in the study. It was decided in advance that par-
ticipants who dropped out during the follow-up period Serum gastrin concentration
would be excluded from the analysis. Four participants All blood samples were collected in the fasting state, at
dropped out, finally leaving 28 subjects (7 PMs, 11 IMs least 4 h after the last oral intake of food or drink.
and 10 RMs) to complete the study. Baseline gastrin concentration was determined as the
median of five samples collected at the beginning
Assessed for eligibility (n = 40, PMs: 9, IMs: 16, RMs: 15)
(17:30 hours) of the control study and the four different
dosing studies. Washout interval between regimens was
Excluded (n = 8, PMs: 2, IMs: 4, RMs: 2) at least 2 weeks, and no carry-over effects in serum
Met exclusion criteria (n = 6) gastrin concentration were observed. Serum gastrin con-
Declined to participate (n = 2)
centration was analysed at 17:30 hours (before adminis-
tration in the evening) on day 7 in each regimen.
Enrolled (n = 32, PMs: 7, IMs: 12, RMs: 13)
Concentrations were analysed by a commercial laboratory
company (BML Inc., Tokyo, Japan: ISO 15189, certifica-
tion number: RML00010) using commercial kits (Gastrin
Underwent control study: RIA kit II; Fuji Rebio Inc., Tokyo, Japan). The antibody
24-h pH monitoring without medication
used in the kit was specific to both G-17 and G-34. The
binding sites are the 12th tyrosine and the 15th methion-
ine of G-17. G-34 has an identical amino acid sequence
Underwent crossover study: as G-17 on its carboxyl-terminal side, and the antibody
24-h pH monitoring with medication therefore has cross-reactivity to G-17 and G-34.37
Accordingly, we measured the total of G-17 and G-34.
Dropped out (n = 4, PM: 0, IM: 1, RMs: 3)

CYP2C19 polymorphism
Completed study (n = 28,PMs: 7, IMs: 11, RMs: 10) DNA was isolated from white blood cells with a com-
mercially available kit (Wizard Genomic DNA Purifica-
Figure 1 | Study flow outline. Includes data on the tion Kit; Promega, Madison, WI, USA). Polymorphic
number of participants enrolled and the number of analyses of CYP2C19 were performed with an automated
participants who completed the study. PMs, poor gene analyzer (Genecube; Toyobo Co. Ltd, Osaka,
metabolisers of CYP2C19; IMs, intermediate Japan).38 The volunteers were then classified into three
metabolisers of CYP2C19; RMs, rapid metabolisers of
genotype groups by (*2) and (*3) polymorphism, namely
CYP2C19.

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 Comparison of vonoprazan with esomeprazole

PMs (*2/*2, *3/*3, *2/*3), IMs (*1/*2 or *1/*3) and 24-h intragastric pH monitoring
RMs (*1/*1). Day 1 Day 7

Intragastric pH monitoring
Twenty-four-hour intragastric pH monitoring was per- VPZ 20 mg b.d.
formed using pH catheters (one-channel crystal anti-
mony multi-use pH catheter; Synectics Medical,
Barcarena, Portugal) and a catheter-based ambulatory
VPZ 20 mg daily
pH monitoring system (Digitrapper pH400; Sierra Scien-
tific Instruments, Los Angeles, CA, USA). Before each
24-h intragastric pH monitoring, the pH catheter and
EPZ 20 mg b.d.
catheter-based ambulatory pH monitoring system were
calibrated using standard buffer solutions (Buffer solu-
tion pH 1.07 and Buffer solution pH 7.01; Given Imag-
ing, Duluth, GA, USA). EPZ 20 mg daily
The pH catheter was inserted trans-nasally and placed
about 5 cm below the lower oesophageal sphincter under Figure 2 | Schematic demonstration of the study
fluoroscopy guidance at 18:00 hours. Twenty-four-hour protocol. Participants with different CYP2C19
intragastric pH monitoring was started soon after inser- genotypes received four regimens in a randomised
tion. Three standard meals were then provided at 19:00, crossover manner: (i) vonoprazan (VPZ) 20 mg twice
8:00 and 12:00 hours. Bottled water was allowed ad libi- daily (b.d.) for 7 days; (ii) VPZ 20 mg daily for 7 days;
(iii) esomeprazole (EPZ) 20 mg b.d. for 7 days and (iv)
tum, but other beverages were not permitted.
EPZ 20 mg daily for 7 days. The timing of each dosing
was 1 h before a meal (18:00 hours for daily; 7:00 and
Study protocol 18:00 hours for b.d.). Twenty-four-hour intragastric pH
Volunteers first underwent 24-h intragastric pH monitor- monitoring was performed on day 7 in each regimen.
ing without medication. We then tested four different regi- Washout period between regimens was at least 2 weeks.
mens in a crossover manner for 7 days as follows
(Figure 2): (i) vonoprazan 20 mg b.d., (ii) vonoprazan
20 mg daily, (iii) esomeprazole 20 mg b.d. and (iv) 20.3. The 10% extra effect on pH 4 HTR (delta = 7.69)
esomeprazole 20 mg daily The order of the four regimens was considered to be sufficient to show the superiority of
was randomised. A clinical research coordinator (M. K.) vonoprazan b.d. to esomeprazole b.d. When alpha = 0.05
managed the dosing schedule of each subject. The washout and 1-beta = 0.8, the appropriate sample size was calcu-
period between the different regimens was at least lated with the paired t-test (two-tailed) as eight per
2 weeks. The timing of each dosing was 1 h before a meal CYP2C19 genotype group.
(18:00 hours for daily; 7:00 and 18:00 hours for b.d.). The number of IM and RM subjects would reach 12
Compliance was confirmed by sending a reminder e-mail each if the expected dropout rate due to follow-up loss
every morning and evening and by receiving a response or protocol violation was fixed at 20–30%. A smaller
from each participant confirming their completion of their number of PMs was permitted because the population
drug protocol for the day. In each regimen, 24-h intragas- ratio of PMs was far lower than that of IMs and RMs.
tric pH monitoring was performed on day 7. Sample powers were calculated with IBM SPSS Sample
Power 3.0.1 (IBM, Madison Ave, NC, USA).
Sample power
The primary endpoint was the superiority of vonoprazan Statistical analysis
20 mg b.d. over esomeprazole 20 mg b.d. In our previ- Statistically significant differences in median pH profiles,
ous data, the median pH 4 HTR attained with b.d. dos- median pH 4 and 5 HTRs, and median serum gastrin
ing of esomeprazole 20 mg on day 7 in the overall concentrations among the four regimens were deter-
genotype group (10 PMs, 15 IMs and 15 RMs) was mined using the Freidman test followed by the Wilcoxon
79.6%, and standard deviation (s.d.) was 10.3.24 The pH signed-rank test. Statistically significant differences in
4 HTR with vonoprazan 40 mg/day on day 7 was median pHs, median pH 4 and 5 HTRs, and median
99.9%.27 Therefore, the mean difference could be set as serum gastrin concentrations among the three CYP2C19

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T. Kagami et al.

genotypes were determined using the Kruskal–Wallis test Median of 24-h intragastric pH profiles
followed by the Mann–Whitney U test. Statistical differ- Median 24-h intragastric pH with vonoprazan b.d. was
ences in age, height and weight among the CYP2C19 the highest of the four regimens, followed in order by
three genotype groups were assessed by one-way vonoprazan daily, esomeprazole b.d. and esomeprazole
ANOVA (analysis of variance). Statistical calculations daily as the lowest of the four regimens (Figure 4).
were performed with StatView 5.0 (SAS Institute, Cary, In the comparison between vonoprazan and
NC, USA). All P values were two-tailed, and P < 0.05 esomeprazole, median 24-h intragastric pH profiles with
indicated statistical significance. vonoprazan b.d. were significantly higher than those with
esomeprazole b.d., irrespective of CYP2C19 genotype
RESULTS [6.9 vs. 6.3 (P = 0.018) for PMs, 6.7 vs. 6.4 (P = 0.013)
for IMs and 6.9 vs. 6.1 (P = 0.009) for RMs: Figure S1a].
Demographic data and clinical characteristics of Median pH with vonoprazan daily was higher than
subjects that with esomeprazole b.d. in the overall genotype
Twenty-eight volunteers (7 PMs, 11 IMs and 10 RMs) group [6.5 vs. 6.2 (P = 0.049): Figure 4]. The same ten-
completed the study from February to September 2015. dency was observed in each genotype, albeit without sta-
Four subjects dropped out during the study and were tistical significance [6.4 vs. 6.3 (P = 0.398) for PMs, 6.5
excluded from analysis, giving a follow-up rate of 87% vs. 6.4 (P = 0.110) for IMs, and 6.6 vs. 6.1 (P = 0.066)
(28/32). No severe adverse event was recognised during for RMs: Figure S1a]. In other words, median pH with
the study period. There was no significant difference in vonoprazan daily was equivalent to or slightly superior
demographic or clinical characteristics among the three to that with esomeprazole b.d. On the other hand, med-
genotype groups (Table 1). Drug compliance was 100% ian pH with vonoprazan daily was higher than that with
in each genotype group, as confirmed by the daily esomeprazole daily in the overall genotype group [6.5 vs.
receipt of emails during the period of each regimen. 4.8 (P < 0.001): Figure 4]. The same difference was
observed in each genotype group [6.4 vs. 4.8 (P = 0.018)
24-h intragastric pH-time curves for PMs, 6.5 vs. 5.1 (P = 0.005) for IMs, and 6.6 vs. 4.6
pH profiles (median with range) of the 28 volunteers on (P = 0.005) for RMs: Figure S1a]. Namely, median pH
day 7 in each of the four different regimens are shown with vonoprazan daily was superior to that with
in Figure 3a–d. The pH-time curve with vonoprazan b.d. esomeprazole daily irrespective of CYP2C19 genotype.
was highest in the overall genotype group, followed by As shown in Figure S1b, median pH among CYP2C19
vonoprazan daily and then esomeprazole b.d (Figure 3a). genotypes did not differ among vonoprazan b.d., vono-
The same tendency was observed in each genotype group prazan daily or esomeprazole b.d. In other words, these
(Figure 3b–d for PMs, IMs and RMs respectively). regimens overcame the difference in CYP2C19 polymor-
The lowest pH-time curves were seen for esomepra- phism. In contrast, median pH attained with esomepra-
zole daily irrespective of CYP2C19 genotype. zole daily was influenced by CYP2C19 genotype.

Table 1 | Demographic data and clinical characteristics of Helicobacter pylori-negative healthy volunteers with
different CYP2C19 genotypes

PMs (n = 7) IMs (n = 11) RMs (n = 10) P value

Sex (M/F) 2/5 5/6 3/7 0.412*
Age (median with range) 21 (20–24) 21 (19–30) 21 (19–28) 0.947‡
Height (cm; mean  s.d.) 161.6 (11.4) 164.4 (8.0) 164.0 (8.0) 0.798‡
Weight (kg; mean  s.d.) 53.9 (8.1) 59.1 (8.0) 56.8 (9.1) 0.460‡
Control median intragastric pH (median with range) 2.4 (1.3–3.5) 2.1 (1.4–3.1) 1.7 (1.2–3.1) 0.210†
Baseline serum gastrin (pg/mL: median with range) 113 (82–133) 116 (85–145) 105 (89–125) 0.473†

PMs, poor metabolisers of CYP2C19; IMs, intermediate metabolisers of CYP2C19; RMs, rapid metabolisers of CYP2C19.
* Chi-squared test.
† Kruskal–Wallis test.
‡ One-way ANOVA.

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 Comparison of vonoprazan with esomeprazole

VPZ 20 mg b.d. EPZ 20 mg b.d.

VPZ 20 mg daily EPZ 20 mg daily

(a) Overall
(n = 28) pH
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
18 20 22 24 2 4 6 8 10 12 14 16 Time

(b) PMs
(n = 7) pH
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
18 20 22 24 2 4 6 8 10 12 14 16 Time
(c) IMs
(n = 11) pH

Figure 3 | (a) Intragastric pH 9.0

profiles with vonoprazan 8.0
7.0
(VPZ) 20 mg b.d. and daily, 6.0
and esomeprazole (EPZ) 5.0
20 mg b.d. and daily on day 7 4.0
in the overall genotype group. 3.0
2.0
(b) Particpants with the poor 1.0
metaboliser genotype of 0.0
CYP2C19 (PMs). (c) 18 20 22 24 2 4 6 8 10 12 14 16 Time
Participants with the (d) RMs
intermediate metaboliser (n = 10) pH
genotype of CYP2C19 (IMs).
9.0
(d) Participants with the rapid 8.0
metaboliser genotype of 7.0
CYP2C19 (RMs). The plot and 6.0
error bar show the median 5.0
4.0
and range. The two kinds of 3.0
arrow indicate the timing of 2.0
b.d. and daily dosing of VPZ 1.0
20 mg or EPZ 20 mg. 0.0
18 20 22 24 2 4 6 8 10 12 14 16 Time

Comparison of median pH 4 and 5 HTRs Median (range) pH 4 HTRs in the overall genotype
The median (range) pH 4 and 5 HTRs in the overall group with vonoprazan b.d., vonoprazan daily,
genotype group with vonoprazan b.d., vonoprazan daily, esomeprazole b.d. and esomeprazole daily were 100.0%
esomeprazole b.d. and esomeprazole daily are shown in (85–100%), 95% (79–100%), 91% (62–100%) and 68%
Figure 5. (39–78%) respectively (Figure 5 pH ≥ 4).

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T. Kagami et al.

On comparison of vonoprazan and esomeprazole, CYP2C19 genotype group [100% vs. 90% (P = 0.018) for
median pH 4 HTR with vonoprazan b.d. was signifi- PMs, 100% vs. 93% (P = 0.003) for IMs and 100% vs.
cantly higher than that with esomeprazole b.d. in each 89% (P = 0.005) for RMs: Figure S2a–c pH ≥ 4].
Median pH 4 HTR with vonoprazan daily was higher
than that with esomeprazole b.d. in the overall genotype
P < 0.001
group [95% vs. 91% (P = 0.019): Figure 5 pH ≥ 4]. The
<0.001
<0.001 same tendency was observed in each genotype [99% vs.
0.001 90% (P = 0.237) for PMs, 95% vs. 93% (P = 0.075) for
<0.001 IMs and 95% vs. 89% (P = 0.241) for RMs: Figure S2a–c
<0.001 pH ≥ 4].
0.049
Similarly, median (range) pH 5 HTRs in the overall
<0.001 genotype group with vonoprazan b.d., vonoprazan daily,
<0.001
esomeprazole b.d. and esomeprazole daily were 99%
<0.001
pH (82–100%), 91% (57–100%), 84% (48–98%) and 54%
8.0 6.8 6.5 6.2 4.8 1.8 (20–74%) respectively (Figure 5 pH ≥ 5).
7.0 Median pH 5 HTR with vonoprazan b.d. was signifi-
6.0
cantly higher than that with esomeprazole b.d. in each
5.0
4.0 CYP2C19 genotype group [100% vs. 79% (P = 0.018) for
3.0 PMs, 98% vs. 89% (P = 0.003) for IMs and 100% vs.
2.0
1.0 83% (P = 0.005) for RMs: Figure S2a–c pH ≥ 5].
0.0 Median pH 5 HTR with vonoprazan daily was
VPZ b.d.

EPZ b.d.

Baseline
VPZ daily

EPZ daily

higher than that with esomeprazole b.d. in the overall

genotype group [91% vs. 84% (p = 0.003): Figure 5
pH ≥ 5]. The same tendency was observed in each
Overall (n = 28 for each) genotype [92% vs. 79% (P = 0.091) for RMs, 88% vs.
89% (P = 0.155) for IMs and 91% vs. 83% (P = 0.047)
Figure 4 | Whisker box plots of median intragastric pH for RMs: Figure S2a–c pH ≥ 5]. These findings show
profiles in the overall genotype group on day 7 of each that vonoprazan daily was equivalent to esomeprazole
of the four regimens. VPZ, vonoprazan; EPZ, b.d. in median pH 5 HTR for IMs and PMs, but
esomeprazole; b.d., twice daily.
superior in RMs.

Overall P < 0.001 <0.001

<0.001 <0.001
(n = 28)
<0.001 <0.001

<0.001 <0.001
0.019 0.003

<0.001 <0.001

% 100 95 91 68 99 91 84 54
100
80
60
40
20
0
b.d. Daily b.d. Daily b.d. Daily b.d. Daily
VPZ E PZ VPZ E PZ

pH ≥ 4 pH ≥ 5

Figure 5 | Comparison of median pH ≥4 and pH ≥5 holding time ratios with the four different regimens in the overall
genotype group. VPZ, vonoprazan; EPZ, esomeprazole; b.d., twice daily.

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 Comparison of vonoprazan with esomeprazole

Comparison of serum gastrin concentrations pg/mL (P = 0.004) for IMs and 477 pg/mL vs. 268 pg/
There was the moderate correlation between fasting mL (P = 0.037) for RMs: Figure S3a]. Namely, we noted
serum gastrin concentration and pH 5 HTR for the over- that vonoprazan tended to induce higher serum gastrin
all regimen (q = 0.560, P < 0.001: Figure S4). In the concentrations than those induced with esomeprazole,
overall genotype group, median (range) serum gastrin irrespective of CYP2C19 genotype.
concentrations on day 7 of vonoprazan b.d., vonoprazan As shown in Figure S3b, on administration of vono-
daily, esomeprazole b.d. and esomeprazole daily were prazan b.d. in each CYP2C19 genotype group, serum
664 pg/mL (133–1377 pg/mL), 529 pg/mL (130–909 gastrin concentration was significantly higher in PMs
pg/mL), 258 pg/mL (95–711 pg/mL) and 206 pg/mL than RMs [806 pg/mL vs. 536 pg/mL (P = 0.011)]. The
(113–556 pg/mL) respectively (Figure 6). same tendency was observed with vonoprazan daily
When stratified based on CYP2C19 genotype, median [699 pg/mL vs. 477 pg/mL (P = 0.143)].
serum gastrin concentrations with vonoprazan b.d. were
significantly higher than those with esomeprazole b.d., DISCUSSION
irrespective of CYP2C19 genotype [806 pg/mL vs. In this study of intragastric pH profiles under four gas-
373 pg/mL (P = 0.028) for PMs, 708 pg/mL vs. 208 tric acid suppression regimens, we found that vono-
pg/mL (P = 0.003) for IMs and 536 pg/mL vs. 268 pg/ prazan 20 mg b.d. provided potent acid inhibition in 28
mL (P = 0.028) for RMs: Figure S3a]. healthy Japanese volunteers. Vonoprazan caused sus-
Moreover, serum gastrin concentration with vono- tained acid inhibition throughout the 24-h dosing inter-
prazan daily was significantly higher than that with val, and was well tolerated. These results are consistent
esomeprazole b.d. in the overall genotype group [529 pg/ with previous reports.39, 40 The acid suppression with
mL vs. 258 pg/mL (P < 0.001): Figure 6]. The same ten- this regimen was superior to that with esomeprazole
dency was observed for each genotype [699 pg/mL vs. 20 mg b.d. irrespective of CYP2C19 genotype. Further,
373 pg/mL (P = 0.116) for PMs, 513 pg/mL vs. 208 suppression with vonoprazan 20 mg daily was equivalent
to that with esomeprazole 20 mg b.d. in IMs and PMs,
P < 0.001
but superior in RMs. These findings suggest the useful-
<0.001 ness of vonoprazan in eradication therapy for H. pylori
<0.001 and the treatment of GERD.
<0.001 The main role of PPIs in H. pylori eradication therapy
<0.001
<0.001 is to increase the bioavailability and stability of antimi-
crobial agents in the stomach.41, 42 Amoxicillin and clar-
<0.001
0.022 ithromycin are easily degraded in acidic conditions.43
<0.001 Moreover, the sensitivity of H. pylori to antimicrobial
pg/mL agents such as amoxicillin and clarithromycin increases
1400 664 529 258 206 113 at pH ≥ 5.32–35 Therefore, sufficient acid inhibition is a
1200 key factor in H. pylori eradication therapy.
1000 In the present study, median pH 5 HTR with vono-
800
prazan b.d. reached 99%, even in H. pylori-negative sub-
600
400 jects with active gastric acid secretion. We therefore
200 expect that b.d. dosing of vonoprazan will induce
0 sufficient acid inhibition to eradicate H. pylori, and that
Baseline
VPZ b.d.

EPZ b.d.
VPZ daily

EPZ daily

eradication rates with vonoprazan-based regimens will

accordingly be superior to those with PPI-based
regimens.
In Japan, first-line eradication was limited until Jan-
Overall (n = 28 for each) uary 2015 to 1-week treatment with b.d. dosing of a PPI
(i.e. omeprazole 20 mg, lansoprazole 30 mg, rabeprazole
Figure 6 | Comparison of median serum gastrin values 10 mg and esomeprazole 20 mg), amoxicillin and clar-
with the four different regimens in the overall genotype ithromycin. However, eradication rate with this regimen
group. VPZ, vonoprazan; EPZ, esomeprazole; b.d., twice
was reported to be lower in RMs than in PMs and
daily.
IMs,3, 21 because sufficient acid inhibition for H. pylori

Aliment Pharmacol Ther 2016; 43: 1048–1059 1055

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T. Kagami et al.

eradication could not always be achieved by b.d. dosing PPI was associated with the hyperplasia of ECL cells
of a PPI at the standard dose in RMs. This was an and carcinoid.50–54 These findings raised concerns
important clinical problem. about the possibility of the same association with PPI-
Vonoprazan became available in Japan under the induced hypergastrinaemia and gastric carcinoid in
Japanese health insurance system in February 2015. An humans, but this association has not been proved in
unpublished phase III parallel-group trial in Japan had a humans.55–59 Although a few case reports on gastric
successful H. pylori eradication rate of 92.6% (324/300) carcinoid and gastric neuroendocrine carcinoma with
with 1-week b.d. dosing with vonoprazan 20 mg, amoxi- long-term PPI treatment have appeared,60–62 these
cillin 750 mg and clarithromycin 200 or 400 mg as first- reports did not provide evidence for a causal relation-
line regimen. This was superior to that of a PPI-based ship between long-term PPI treatment and neuroen-
regimen with lansoprazole 30 mg b.d. and the same docrine tumours. Rodents treated with vonoprazan in
doses of amoxicillin and clarithromycin, at 75.9% (243/ pre-clinical toxicity testing for 2 years at a dosage
320).26–28, 44–46 The potent acid inhibition with a vono- equivalent to 20 mg daily in humans developed hyper-
prazan-based regimen yielded higher eradication rates plasia of ECL cells and gastric carcinoid.27, 28 However,
than that with a lansoprazole-based regimen. it is unknown whether these results can be applied to
A previous study with oesophageal pH monitoring humans.
reported that frequent gastro-oesophageal reflux, particu- Our data suggest that standard dosing of vonoprazan
larly at night-time, is closely related to the pathogenesis tended to induce higher serum gastrin concentrations
of GERD.47 Intra-oesophageal pH is correlated with the than those induced with esomeprazole. The safety of
cure rate of GERD and is correlated with intragastric vonoprazan in long-term administration should be veri-
pH.36 The reported pH 4 HTR in the stomach needed fied in future clinical studies.
for GERD treatment is 83–91% (20–22 h/day).36 With In the present study, CYP2C19 genotype-dependent
regard to esomeprazole, the Japanese health insurance difference in serum gastrin concentrations was observed
system limits treatment of GERD to esomeprazole 20 mg when vonoprazan 20 mg b.d. was dosed. The same ten-
daily. In the present study, however, median (range) pH dency was observed when vonoprazan 20 mg daily was
4 HTR with esomeprazole 20 mg daily was insufficient dosed. We therefore hypothesised that serum gastrin
irrespective of CYP2C19 genotype, at 64% (58–71%), concentration with vonoprazan showed a degree of
73% (53–78%) and 62% (39–76%) in PMs, IMs and RMs inter-individual variation according to CYP2C19 geno-
respectively. On the other hand, even in RMs, median type. On this basis, high-dose administration of vono-
(range) pH 4 HTRs with vonoprazan 20 mg daily and prazan should be done with consideration to
esomeprazole b.d. were 95% (79–100%) and 89% (72– hypergastrinaemia, particularly in PMs.
100%) respectively. We therefore expect that vonoprazan The mechanism of hypergastrinaemia in this study is
20 mg daily and esomeprazole 20 mg b.d. will be able to thought to be the reciprocal reaction through the feed-
induce the acid inhibition required for GERD treatment back to hypoacidity. However, CYP2C19 genotypic dif-
even in RMs. Indeed, in their dose-ranging study of ferences were not seen in the pH data of vonoprazan, as
vonoprazan in Japan, Ashida et al. recommended vono- described previously. This result appears to contradict
prazan 20 mg daily as a clinical dose for the treatment the CYP2C19 genotype-dependent difference in serum
of erosive oesophagitis.48 Our present data support this gastrin concentrations.
recommendation. Twenty-four-hour intragastric pH monitoring is a use-
As suggested by the present study, we consider that ful indicator of acid inhibition. However, it is not clear
esomeprazole 20 mg for GERD treatment in Japan is whether 24-h intragastric pH monitoring can detect
better given by twice daily administration. Moreover, in small differences in acid output under the potent acid
those western counties with a larger proportion of RMs inhibition provided by vonoprazan.
than Japan, vonoprazan 20 mg daily will be useful Vonoprazan is metabolised to its inactive form
because single daily dosing of vonoprazan 20 mg is mainly by CYP3A4, and partially also by CYP2C19. It
equivalent to or superior to esomeprazole 20 mg b.d. is therefore possible that the acid inhibition of vono-
Hypergastrinaemia has a trophic effect on gastric prazan is influenced by CYP2C19 genotypic differences.
mucosal cells, including enterochromaffin-like cells However, the acid inhibition attained with vonoprazan
(ECL cells), and increases cell proliferation.49 In rats, is so potent that a CYP2C19 genotype-dependent differ-
hypergastrinaemia on long-term administration of a ence in acid inhibition cannot be always detected by

1056 Aliment Pharmacol Ther 2016; 43: 1048–1059

ª 2016 John Wiley & Sons Ltd
 Comparison of vonoprazan with esomeprazole

24-h intragastric pH monitoring, because at median pH SUPPORTING INFORMATION

around 7 (i.e. pH 5 HTR close to 100%), pH monitor- Additional Supporting Information may be found in the
ing results are influenced by alkalinity, such as reflux of online version of this article:
bile juice. Figure S1. (a) Whisker box plots of median intragas-
On the other hand, serum gastrin is secreted from G tric pH profiles among the four different regimens for
cells of the gastric antrum which is rich in acid sensors, each genotype of CYP2C19. (b) Whisker box plots of
such as D cells (somatostatin-secreting cells) and GRP- median intragastric pH profiles among the three different
secreting cells. Therefore, serum gastrin is a sensitive genotypes of CYP2C19 with each regimen. PMs, poor
marker of H+ concentration at the gastric lumen and is metabolisers of CYP2C19; IMs, intermediate metabolisers
assumed to express slight differences in gastric acid out- of CYP2C19; RMs, rapid metabolisers of CYP2C19;
put around pH 7 which cannot be detected by 24-h VPZ,vonoprazan; EPZ, esomeprazole; b.d., twice daily.
intragastric pH monitoring. As shown in Figure S4, a Figure S2. Whisker box plots of pH ≥4 and pH ≥5
significant correlation was observed between intragastric holding time ratios (pH 4 and 5 HTRs) by four different
pH and serum gastrin concentrations in the overall regimens in each CYP2C19 genotype group. (a) pH 4
analysis, whereas no such correlation was observed and 5 HTRs by different four regimens for poor
when the data were limited to vonoprazan 20 mg b.d., metabolisers of CYP2C19 (PMs). (b) Those for interme-
where median pH levels were around 7 (e.g. the pH 5 diate metabolisers of CYP2C19 (IMs) and (c) the rapid
HTRs were close to 100%) [(q = 0.042, P = 0.836): Fig- metaboliser genotype of CYP2C19 (RMs). VPZ, vono-
ure S5]. prazan; EPZ, esomeprazole; b.d., twice daily.
Lastly, these results should be interpreted within sev- Figure S3. Subanalyses of serum gastrin concentrations
eral limitations of the study. First, all participants were with different CYP2C19 genotypes or different regimens. (a)
H. pylori-negative healthy volunteers who had neither Comparison of median serum gastrin values with the four
H. pylori infection nor GERD. The clinical relevance of different regimens in each genotype of CYP2C19. (b) Com-
vonoprazan 20 mg b.d. and daily should be verified in parison of median serum gastrin values of the three different
clinical studies. Second, the observation period was genotypes of CYP2C19 with each regimen. PMs, poor
1 week, and it is unknown whether the pH profiles of metabolisers of CYP2C19; IMs, intermediate metabolisers of
vonoprazan 20 mg b.d. and daily can be applied to CYP2C19; RMs, rapid metabolisers of CYP2C19; VPZ,
patients who require long-term administration. Third, vonoprazan; EPZ, esomeprazole; b.d., twice daily.
the subjects in the present study were all Japanese. A Figure S4. Scatter plot of fasting serum gastrin concentra-
recent study indicated the presence of ethnic differences tions on day 7 and pH ≥5 holding time ratios (pH 5 HTRs)
in CYP2C19 RM activity, such as between Koreans and with the four different regimens. There was a statistically sig-
Caucasians.63 It is therefore unclear whether our study nificant correlation between serum gastrin concentration
results can be extrapolated to Caucasians. Finally we and pH 5 HTR for the overall regimen. q, Spearman rank-
did not measure plasma vonoprazan and esomeprazole order correlation coefficient, VPZ, vonoprazan; EPZ,
(S-isomer of omeprazole) concentrations, and the rela- esomeprazole; b.d., twice daily.
tionship of the AUCs of the two agents with intragas- Figure S5. Scatter plot of fasting serum gastrin concentra-
tric pH and serum gastrin concentrations could not be tions on day 7 and pH ≥5 holding time ratios (pH 5 HTRs)
evaluated. when vonoprazan (VPZ) 20 mg was dosed twice daily
Allowing for these limitations, the efficacy of vono- (b.d.). There was no statistically significant correlation
prazan on single and twice daily administration at between serum gastrin concentration and pH 5 HTR. q,
20 mg in short-term use appears clear. Acid inhibition Spearman rank-order correlation coefficient.
with vonoprazan 20 mg b.d. was significantly superior to
that with esomeprazole 20 mg b.d. Further, vonoprazan AUTHORSHIP
20 mg daily was effective and equivalent to or superior Guarantor of the article: Takahisa Furuta.
to esomeprazole 20 mg b.d. Given that not all acid- Author contributions: Takama Kagami contributed towards acquisi-
tion of data of pH monitoring, statistical analysis and interpretation
related disorders require strong acid inhibition, the clini- of data, drafting of the manuscript. Shu Sahara, Hitomi Ichikawa,
cal relevance of these regimens awaits verification in Takahiro Uotani, Mihoko Yamade, Mistushige Sugimoto, Yasushi
large-scale clinical studies. The optimal treatment of Hamaya, Moriya Iwaizumi, Satoshi Osawa and Ken Sugimoto con-
tributed towards acquisition of data of pH monitoring. Hiroaki
acid-related disorders requires the optimal selection of Miyajima was involved in study supervision. Takahisa Furuta con-
acid inhibitors suitable for individual conditions. tributed towards study concept and design, analysis and interpreta-

Aliment Pharmacol Ther 2016; 43: 1048–1059 1057

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T. Kagami et al.

tion of data, drafting of the manuscript, critical revision of the Declaration of personal interests: The First Department of Medicine
manuscript for important intellectual content and obtained funding. and the Center for Clinical Research at Hamamatsu University
School of Medicine have received grants from Takeda Pharmaceuti-
ACKNOWLEDGEMENTS cal Co., Ltd., AstraZeneca KK, Eisai Co., Ltd. and Daiichi-Sankyo
This work was supported by a grant-in-aid from the Ministry of Co. Ltd. The authors have no other conflicts of interest that are
Education, Culture, Sports, Science and Technology of Japan directly relevant to the content of this article.
(20590718). Declaration of funding interests: None.

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