Xenobiotica

the fate of foreign compounds in biological systems

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Pharmacokinetics and pharmacodynamics of

intravenous ilaprazole in healthy subjects after
single ascending doses

Hongyun Wang, Ning Ou, Liwei Lang, Ruihua Shi, Pei Hu & Ji Jiang

To cite this article: Hongyun Wang, Ning Ou, Liwei Lang, Ruihua Shi, Pei Hu & Ji Jiang (2016):
Pharmacokinetics and pharmacodynamics of intravenous ilaprazole in healthy subjects after
single ascending doses, Xenobiotica, DOI: 10.3109/00498254.2016.1156185

To link to this article: http://dx.doi.org/10.3109/00498254.2016.1156185

Published online: 21 Mar 2016.

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ISSN: 0049-8254 (print), 1366-5928 (electronic)

Xenobiotica, Early Online: 1–9

! 2016 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.3109/00498254.2016.1156185

RESEARCH ARTICLE

Pharmacokinetics and pharmacodynamics of intravenous ilaprazole in

healthy subjects after single ascending doses

Hongyun Wang1, Ning Ou2, Liwei Lang1, Ruihua Shi2, Pei Hu1, and Ji Jiang1
1
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing, China and 2Jiangsu Province Hospital, Nanjing,
Jiangsu, China

Abstract Keywords
1. Ilaprazole is a novel proton pump inhibitor and this is the first study to investigate the Ilaprazole, intravenous, pharmacodynamics,
pharmacokinetics, pharmacodynamics and safety of intravenous ilaprazole in healthy pharmacolinetics, proton pump inhibitor
volunteers.
2. In this open-label, single-dose, randomized and four-period crossover study, 16 healthy History
Chinese subjects received ilaprazole 5, 10 or 20 mg intravenously, or 10 mg orally. Serial
blood and urine samples were collected and intragastric pH was recorded within 24 h. The Received 2 January 2016
percentage time of intragastric pH > 6 was the major index. Safety was assessed throughout Revised 15 February 2016
the study. Accepted 16 February 2016
3. Plasma exposure of intravenous ilaprazole increased proportionally over the dose of Published online 17 March 2016
5–20 mg. Clearance and volume of distribution were independent of dose. Ilaprazole was
not eliminated through urine and the absolute bioavailability was 55.2%. For the
intravenous dose of 5, 10, 20 mg, and oral dose of 10 mg, the mean percentages time of
intragastric pH > 6 were 47.3%, 52.8%, 68.2% and 47.5%, respectively.
4. Ilaprazole showed linear pharmacokinetics over the dose of 5–20 mg. Intravenous ilaprazole
provided rapid onset of action and the potency of effect were exhibited in a dose-
dependent manner. Intravenous ilaprazole was safe and well tolerated except for elevated
activated partial thromboplastin time (APTT) and prothrombin time (PT).

Introduction
Proton pump inhibitors (PPIs) are a mainstay for the treatment
of all known acid-related diseases, including gastro-esopha-
geal reflux disease (GERD), peptic ulcer disease, Zollinger
Ellison syndrome and Helicobacter pylori infection
(Robinson, 2004; Sachs et al., 2006; Shi & Klotz, 2008).
Although the available PPIs such as omeprazole, lansoprazole
and esomeprazole are generally safe and effective, a number
of challenges remain in the treatment, including high
individual variability and short duration of acid inhibition.
Current studies are being focused on development of the
third-generation of PPIs, which should be more rapid, potent
and prolonged in their intragastric acid inhibition activity
(Carmelo & Richard, 2008).
Ilaprazole is a novel PPI that was synthesized by Il-Yang
Pharmacy Co. (Seoul, Korea) and is currently developed by
Livzon Pharmaceutical Co., Ltd. (Zhuhai, China). Oral
ilaprazole has been approved for the treatment of gastric
and duodenal ulcer, as well as erosive oesophagitis in China
Address for correspondence: Ji Jiang, MD, Professor, Clinical
Pharmacology Research Center, Peking Union Medical College
Hospital, Beijing 100730, China. Tel: +8610 69158357. Fax: +8610
69158364. E-mail: jiangjipumch@sohu.com
and South Korea. Ilaprazole belongs to a class of substituted
benzimidazole molecules, chemically related to omeprazole
(Kim et al., 2001; Kwon et al., 2001). At variance with
conventional PPIs, ilaprazole was predominantly metabolized
by CYP3A and partly by CYP 2C19 (Myung et al., 1999; Seo
et al., 2012; Zhou et al., 2010). As a consequence the
pharmacokinetics and pharmacodynamics of ilaprazole were
not significantly influenced by CYP 2C19 polymorphism
(Cho et al., 2012; Li et al., 2008). Of note, ilaprazole displays
a t1/2 (4–10 h) (Cho et al., 2012; Shin et al., 2014) longer than
the first- and second generation PPIs (0.5–2 h) (de Bortoli
et al., 2013). These features of ilaprazole resulted in lower
inter-subject variability and long lasting acid inhibition. In a
clinical study in 12 healthy subjects, ilaprazole at the oral
dose 20 mg provided significantly higher mean 24-h pH than
omeprazole at the same dose (Du et al., 2012). A comparative
study in patients with GERD indicated that, a 5-mg dose of
ilaprazole was comparable to a 20-mg dose of omeprazole in
gastric pH control, and at doses of 10 and 20 mg it provided a
more potent and prolonged suppression of gastric acid
(Periclou et al., 2000). Recently, a study comparing ilaprazole
versus esomeprazole showed that ilaprazole 20 and 40 mg
exhibited much better pH control over 24 h and during
2 H. Wang et al.
evening and overnight compared with esomeprazole 40 mg in
healthy volunteers (Shin et al., 2014).
Although oral administration has been widely used in
clinic, intravenous PPI therapy is critical for the patients
unable to take the oral medications, or for some emergent
situations such as non-variceal upper gastrointestinal bleed-
ing, in which a rapid onset of action is desired (Freston et al.,
2004; Sung et al., 2014; Taubel et al., 2001; Yüksel et al.,
2008; Wang et al., 2009). The rapid attainment of increased
and sustainable intragastric pH would offer great clinical
benefits for patients. Current guidelines have recommend
high-dose intravenous PPI as the adjuvant therapy for peptic
ulcer bleeding (Holster & Kuipers, 2011; Laine & Jensen,
2012; Sung et al., 2011). Despite some PPIs have long been
used intravenously, the PPI ilaprazole is only available in oral
formulation in clinic. Currently intravenous ilaprazole is
being evaluated in phase I clinical trials in China. This open-
label, randomized and four-period cross-over study was
conducted to evaluate the pharmacokinetics, pharmaco-
dynamics and safety profiles of intravenous ilaprazole, to
compare the intragastric pH control of intravenous with oral
administration, to assess the absolute bioavailability of
ilaprazole in healthy Chinese volunteers. Meanwhile, the
gender effect on the pharmacokinetics and pharmacodynam-
ics of ilaprazole was investigated in this study.
Methods and materials
Chemicals and study medications
Chemical standards of ilaprazole (purity 99.7%) and d2-
ilaprazole (purity 99.1%) were provided by Livzon
Pharmaceutical Group Inc. (Zhuhai, Guangdong, China).
HPLC-grade acetonitrile was purchased from Thermo-Fisher
(Fair Lawn, NJ). Other reagents used were all of analytical
grade and distilled water was produced by Milli-Q system
(Millipore, Bedford, MA).
Ilaprazole enteric coated tablets (5 mg/tablet) and lyophi-
lized powder (10 mg/vial) were provided by Livzon
Pharmaceutical Co., Ltd. (Zhuhai, China). For intravenous
administration, the lyophilized powder was freshly reconsti-
tuted with saline solution (0.9% NaCl) to produce ilaprazole
solution at the concentration of 0.1 mg/mL. Within 4 h after
reconstitution, the solution (0.1 mg mL1) was given to the
subjects using a calibrated infusion pump and the infusion
time was 45 min. Three intravenous dosing regimens were
designed: (A) 5 mg: 50 mL of ilaprazole solution
(0.1 mg mL1); (B) 10 mg: 100 mL of ilaprazole solution
(0.1 mg/mL); (C) 20 mg: 200 mL of ilaprazole solution.
Subjects
This study was conducted in accordance with Good Clinical
Practice regulations, the ethical principles stated in the
Declaration of Helsinki. This study was registered at Center
for Drug Evaluation (CFDA) of China (No. CTR20132848).
Approval of the study was obtained from the Ethical
Committee of the Peking Union Medical College Hospital
(Beijing, China) prior to subject enrollment. All the subjects
provided written informed consent after the nature of the
study was fully explained.
Xenobiotica, Early Online: 1–9
The subjects were enrolled based on the following
inclusion criteria: men and women of Chinese ethnicity
between 18 and 45 years of age with a body mass index of 19–
25 kg/m2; no evidence of clinically significant abnormalities
in cardiac, hepatic, renal, pulmonary, neurological, gastro-
intestinal, hematological and psychiatric function as deter-
mined by medical history, physical examination and
laboratory screens; H. pylori-negative as determined by C13
urea breath test. Pregnant and lactating women were excluded
from the study. Female subjects were required to be surgically
incapable of pregnancy, or practice effective double-barrier
birth control methods. Exclusion criteria included a history of
allergy to drugs; participation in a clinical drug study or blood
donation within a period of three months; positive test results
for hepatitis B virus (HBV), hepatitis C virus (HCV), or
human immunodeficiency virus (HIV); positive for drugs
abuse; a history of alcohol abuse; or administration of any
prescription or over-the-counter medication within 14 days
prior to the study.
Study design
This open-label, single-dose and four-period cross over study
consisted of three phases: the screening phase (three weeks
prior to the first dose), a treatment phase (four 2-day periods
with three 7-day washout intervals), and the safety follow-up
phase (14 days after the last treatment).
Sixteen eligible Chinese subjects were enrolled and
randomized to one of four treatment groups. The subjects
received a single oral dose of 10 mg (with 200 mL of water) or
intravenous infusion of 5, 10 or 20 mg at 8:00 am after an
overnight fasting. Drinking water was not allowed until 2 h
after dose and standard meals were provided at 4 and 10 h on
each study day.
Serial blood samples (3 mL) were drawn at the following
time points: (i) for intravenous administration: 0 (pre-dose),
15, 30, 45, 50 min, 1, 2, 3, 4, 5, 8, 12, 16 and 24 h; (ii) for oral
administration: 0 (pre-dose), 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12,
24, 34 and 48 h. The blood samples were collected into
EDTA-K2 vacutainers and immediately placed on ice. After
being centrifuged at 1500 g for 10 min at 4  C, the plasma was
collected and stored at 80  C until analysis. Following
intravenous infusion of 5, 10, or 20 mg ilaprazole, fractio-
nated urine samples were collected at the following time
intervals: 0 (pre-dose), 0–3, 3–6, 6–9, 9–12 and 12–24 h.
Each subject underwent intragastric pH monitoring for
24 h on day-1 (baseline) and during the treatment. A
calibrated pH microelectrode (Orion II, MMS, the
Netherlands) was inserted transnasally into the stomach,
fixed approximately 10 cm below the lower esophageal
sphincter, and connected to a pH data recorder (Orion II,
MMS, the Netherlands). The electrodes were calibrated with
standard buffers (pH 1.07 and 7.01) prior to each recording.
Intragastric pH was automatically recorded every 4 s during
the 24-h recording period.
Bioanalysis
The concentrations of ilaprazole in human plasma and urine
were determined using a validated ultra-performance liquid
chromatography-tandem mass spectrometry (UPLC-MS/MS)
DOI: 10.3109/00498254.2016.1156185
method. Each plasma (0.05 mL) or urine (0.1 mL) sample was
extracted with 10 fold-volume of ethyl acetate (5% isopropyl
alcohol) after addition of 0.01 mL of internal standard
(omeprazole-d2, 1 mg mL1). The analytes were then chro-
matographed on Acquity UPLC BEH C18 column (1.7 mm,
50  2.1 mm id) (Waters, Milford, MA) with acetonitrile-
10 mM ammonium acetate (0.08% ammonium hydroxide,
pH = 9.0) (55:45, v/v) as mobile phase. The samples were
delivered at a flow rate of 0.4 mL min1. The analytical run
time was 2.0 min for each sample. Detection was performed
on Xevo-TQS tandem mass spectrometer using an electro-
spray ionization (ESI) source (Waters, Milford, MA). The
standard curves of ilaprazole in plasma and urine samples
were 1–1000 ng mL1 and 0.01–10 ng mL 1, respectively.
Lower limit of quantitation (LLOQ) for plasma and urine
assay was 1 and 0.01 ng mL1, respectively. Low, medium
and high quality control (QC) samples (3, 75, 750 ng mL1
for plasma; 0.03, 0.75, 7.5 ng mL1 for urine) were analyzed
with the study samples to ensure the quality of analysis. For
plasma assay, the accuracy (% bias) ranged from 3.6% to
6.6%, and precision (CV%) ranged from 2.6% to 5.6%. For
urine assay, the accuracy (% bias) ranged from 6.1% to
8.1%, and precision (CV%) ranged from 3.3% to 9.8%.
Pharmacokinetic and pharmacodynamic analysis
Pharmacokinetic parameters of ilaprazole were calculated
using non-compartmental analysis with validated WinNonlin
version 6.3 (Pharsight, St Louis, MO). Cmax was the
maximum plasma concentration in a profile and tmax was
the time to Cmax. The elimination half-life (t1/2) was estimated
by linear regression of log-transformed concentration–time
data. The area under the plasma concentration–time curve
from time zero to t (AUC0t), where t was the time of last
measurable sample, was calculated according to the linear
trapezoidal rule. The AUC from time zero to infinity
(AUC01) was estimated as AUC0t +Ct/lz, where Ct was
the plasma concentration of the last measurable sample.
Apparent total clearance (CL) was calculated as Dose/
AUC01 and apparent total volume of distribution (V) as
calculated as CL/lz. Renal clearance (CLr) was estimated as
Au0t/AUC0t, where Au0t was the cumulative amount of
drug excreted in urine from time 0 to t (24 h) and AUC0t was
area under the plasma concentration–time curve over the
same time interval. The absolute bioavailability of ilaprazole
was calculated as AUC01,oral 10 mg/AUC01,iv.10 mg.
For pharmacodynamic analysis, the intragastric pH of each
subject over 24 h, percentages of time intragastric pH >4, >5
and >6, as well as the nighttime pH (20:00–8:00 next day)
were recorded. The first time to reach pH > 6 and maintained
for over 0.25 h after dosing was also recorded.
Statistical analysis
Statistical analysis was performed using the SAS version 9.1.3
(SAS Institute, Cary, NC). For each dose regimen, mean
intragastric pH over 24 h, mean percentage of time intragas-
tric pH >4, >5 and >6, as well as the mean nighttime pH
(20:00–8:00 next day) were summarized using descriptive
statistics. Analysis of variance (ANOVA) or the paired-t test
PK and PD of intravenous ilaprazole 3
was used to assess the differences and p value50.05 was
considered statistically significant.
Dose proportionality of intravenous ilaprazole over the
range of 5 to 20 mg was assessed using the power model:
ln(y) = 0 + 1ln (dose), where y represents the AUC and
Cmax (Hummel et al., 2009; Smith et al., 2000). The mean
slope of the ln-transformed parameter against ln dose was
estimated and the corresponding 90% confidence interval
(CI) was constructed. Dose proportionality was concluded
if the mean slope ( 1) was not statistically different from
unity, and 90% CI fall within 0.8–1.25 for AUC and 0.7–
1.43 for Cmax.
Safety evaluation
Safety and tolerance were evaluated based on occurrence,
frequency and severity of adverse events (AEs). Routine
clinical laboratory tests (biochemistry, hematology and urin-
alysis), 12-electrocardiograms (ECG), physical examinations
and vital sign (blood pressure, pulse rate and body tempera-
ture) were performed at scheduled time points. AEs were
monitored throughout the study, from the initial administra-
tion to a follow-up phase of 14 days after last treatment. The
AEs were assessed by the investigators with regard to severity
(mild, moderate, severe and life-threatening) and the rela-
tionship to study treatment (reasonably or possibly related,
not reasonably or not possibly related).
Results
Subject demographics
Sixteen Chinese subjects (half of men and women) were
enrolled in the study. The demographics were as follows
(mean ± SD, range): age, 24.9 ± 4.1 (19–34) y; weight,
62.6 ± 8.0 (52.0–79.0) kg; height, 1.69 ± 0.08 (1.57–1.85)
m; body mass index, 21.7 ± 1.3 (19.8–24.0) kg m2. All the
16 subjects received at least one dose of the study drug; 15
subjects completed the study and one male subject withdrew
due to elevated PT after receiving intravenous infusion of
10 mg ilaprazole on period one of the study. All the subjects
were included in the safety analysis, and 15 of them were
included in the pharmacokinetic and pharmacodynamics
analysis (Table 1).
Pharmacokinetics
Mean plasma concentration–time curves of ilaprazole in 15
Chinese subjects after intravenous dose of 5, 10 or 20 mg, as
well as oral dose of 10 mg were shown in Figure 1. The
pharmacokinetic parameters were shown in Table 2 After 45-
min intravenous infusion, mean Cmax increased from
482.2 ng/mL for the 5-mg dose to 1718.9 ng/mL for the 20-
mg dose; mean AUC0t and AUC01 increased from 1736.3
and 1754.8 h ng mL1 for the 5-mg dose to 6988.4 and
7056.6 h ng mL1 L for the 20-mg dose. The percentage of
AUC extrapolated from t to infinity was around 1%,
indicating that the sampling time was long enough. The
point estimate and 90% CI for the ratio of dose-normalized,
geometric mean values of Cmax, AUC0t and AUC01 were
0.893 (0.831–0.96), 1.016 (0.96–1.075), and 1.015 (0.957–
1.076), respectively. The results demonstrated that there was
4 H. Wang et al. Xenobiotica, Early Online: 1–9

Table 1. Subject demographics. After oral administration of 10 mg of ilaprazole enteric

coated tablet, mean Cmax and AUC01 were 347.9 ng mL 1
Subject Height Weight Body mass
ID Gender Age (y) (cm) (kg) index (kg/m2)
and 1970.2 h ng mL 1, respectively. Ilaprazole was elimi-
nated rapidly with a mean t1/2 of 3.5 h. Mean oral CL and V
1 Male 23 169 61 21.4 were 5.9 L h  1 and 29.1 L, respectively. The mean absolute
2 Male 33 173 65 21.7
3 Female 21 164 64 23.8 bioavailability of ilaprazole was 55.2% (range, 29.1%–83.3%).
4 Female 25 168 61 21.6 Following intravenous infusion of 5, 10 or 20 mg, cumu-
5 Male 22 175 64 20.9 lative urinary excretion of ilaprazole were 330.6, 838.2 and
6 Male 25 178 69 21.8
1599.9 ng, representing 0.007%, 0.008% and 0.008% of the
7 Female 34 160 52 20.3
8 Female 23 157 53 21.5 corresponding doses, respectively. The mean estimated CLR
9 Male 28 172 71 24 of ilaprazole was 0.2 L h  1 (range, 0.1–0.6 L h1). The
10 Male 25 180 70 21.6 results demonstrated that renal excretion was not the elimin-
11 Female 24 171 70 24
12 Female 28 158 52 20.8
ation way of ilaprazole.
13 Male 19 185 79 23.1
14 Male 24 174 60 19.8 Pharmacodynamics
15 Female 23 166 58 21
16 Female 22 160 52 20.3 Mean 24-h intragastric pH-time profiles of 15 healthy
Mean 24.9 169.4 62.6 21.7 Chinese subjects before and after intravenous infusion of 5,
SD 4.1 8.2 8.0 1.3 10 or 20 mg, as well as oral administration of 10 mg
ilaprazole, were shown in Figure 2. The mean percentages
of time intragastric pH > 4, pH > 5 and pH > 6, mean
nighttime pH (20:00–8:00 next day), and the first time to
reach pH > 6 and maintained for over 0.25 h were summar-
ized in Table 3.
The circadian rhythm of gastric acid secretion and food
effect were observed in the baseline 24-h pH-time profile
(day-1 of the first dose). All the treatment groups displayed
significant intragastric pH inhibition compared with baseline.
The potency and onset of action were closely related to the
dose. The mean percentages time of intragastric pH >6 were
47.3%, 52.8% and 68.2% for the intravenous does of 5, 10 and
20 mg, respectively. There was statistical difference among
the three dose cohorts (p50.05). Likewise, the mean
percentages time of intragastric pH >4 and pH >5 were
also increased as dose escalation. During the nighttime
(20:00–8:00 next day), the mean pH value was 5.0, 5.2 and
6.1 for the 5-, 10- and 20-mg dose cohorts, respectively.
Furthermore, the fastest onset of action was observed in the
20-mg dose group, and the first time to reach pH >6 and
maintained for over 0.25 h was 1.2 h (range 0.9–2.8 h) after
dosing.
Compared with oral administration, intravenous infusion
of ilaprazole provided much better pH control (Figure 2). The
first time to reach pH > 6 was 2.4 h (intravenous 10 mg)
versus 4.5 h (oral 10 mg). Intravenous 5 mg of ilaprazole was
comparable to oral 10 mg in gastric pH control, and at the
dose of 10 mg it provided a more potent and prolonged
suppression of gastric acid in terms of percentages of time
pH > 4, pH > 5 and pH > 6 (Table 3).

Gender effect on the pharmacokinetics and

Figure 1. Mean plasma concentration–time curves of ilaprazole in
healthy Chinese subjects after intravenous infusion of 5, 10 or 20 mg, as
well as oral administration of 10 mg (n = 15): (a) normal scale; (b) semi-
log scale.
dose-proportionality over the dose range of 5–20 mg.
The disposition of ilaprazole was rapid and monophasic
with a mean t1/2 of 3.3 h. Mean CL and V were 3.0–3.1 L/h
and 13.6–14.0 L/h, respectively.
pharmacodynamics of ilaprazole
In this study, we found that plasma exposure (AUC0t,
AUC01 and Cmax) of female subjects were much higher than
those of males (p50.05) (Table 4). However, there was no
statistical difference in terms of CL, V and t1/2 (p > 0.05). In
order to confirm the gender effect, the differences were
further assessed by means of bioequivalence test.
‘‘Bioequivalence’’ was to be concluded if the 90% CI of
the ratios of dose-normalized, geometric mean values of
DOI: 10.3109/00498254.2016.1156185 PK and PD of intravenous ilaprazole 5
Table 2. Mean pharmacokinetic parameters of ilaprazole in healthy subjects after intravenous infusion of 5, 10, or 20 mg,
and oral administration of 10 mg (mean ± SD).

IV 5 mg IV 10 mg IV 20 mg Oral 10 mg
Parameter (n = 15) (n = 15) (n = 15) (n = 15)
t1/2 (h) 3.3 ± 0.90 3.4 ± 0.9 3.3 ± 0.8 3.5 ± 0.8
tmax (h) 0.8 ± 0.03 0.8 ± 0.07 0.8 ± 0.04 3.8 ± 1.08
Cmax (ng/mL) 482.2 ± 65.8 834.3 ± 101.2 1718.9 ± 255.1 347.9 ± 176.3
AUC0t (ng h/mL) 1736.3 ± 501.7 3520.9 ± 915.3 6988.4 ± 1782.5 1970.2 ± 834.7
AUC01 (ng h/mL) 1754.8 ± 511.3 3562.6 ± 947.8 7056.6 ± 1833.2 1984.2 ± 836.6
Vz (L) 13.7 ± 2.6 14.0 ± 2.2 13.6 ± 1.8 29.1 ± 12.2*
CL (L/h) 3.1 ± 0.9 3.0 ± 0.9 3.0 ± 0.8 5.9 ± 2.5*

*CL/F and V/F for oral administration, where F was absolute bioavailability.

Figure 2. Mean 24-h intragastric pH-time

profiles of healthy Chinese subjects before
and after intravenous infusion of 5, 10 or
20 mg, as well as single oral administration of
10 mg (n = 15).

Table 3. Mean pharmacodynamics parameters of ilaprazole according to dose regimens (mean ± SD).

Baseline IV 5 mg IV 10 mg IV 20 mg Oral 10 mg
Mean 24-h pH 2.1 ± 0.9 5.1 ± 1.5 5.5 ± 1.1 6.3 ± 1.0 5.1 ± 1.4
Mean nighttime pH 1.8 ± 0.9 5.0 ± 1.9 5.2 ± 1.4 6.1 ± 1.3 5.4 ± 1.8
pH >4 (%) 14.7 ± 12.9 68.1 ± 23.9* 79.9 ± 17.8* 89.4 ± 13.1* 71.3 ± 27.1
pH >5 (%) 10.6 ± 10.1 63.3 ± 28.2* 72.2 ± 21.9* 82.2 ± 18.7* 62.9 ± 31.1
pH >6 (%) 6.6 ± 3.1* 47.3 ± 29.5* 52.8 ± 25.3* 68.2 ± 25.1* 47.5 ± 30.4
First time to pH >6 (h)a 4.1 ± 3.4 2.4 ± 1.9 1.2 ± 1.0 4.5 ± 3.0
a
First time to reach pH > 6 and maintained over 0.25 h.
*p50.05, comparison among the intravenous dose 5, 10 and 20 mg.

log-transformed AUC and Cmax of female versus male
subjects were within 0.7–1.43 for Cmax and 0.8–1.25 for
AUC. The final point estimate and 90% CI for Cmax, AUC0t
and AUC01 were 1.09 (1.0–1.18), 1.29 (1.05–1.57), 1.29
(1.06–1.58), respectively. The results demonstrated that the
Cmax was ‘‘bioequivalent’’, while AUC differed significantly.
Mean 24-h intragastric pH-time profiles of male and
female subjects before and after dosing were shown in
Figure 3. During the 24-h pH monitoring period, the mean pH
of female subjects (n = 7) was higher than that of males
(n = 8) at 5- and 10-mg dose cohorts. However, for the 20-mg
dose, the mean pH-time profile of the females appeared
comparable to that of males except for the nighttime. For each
dose level, the differences were further analyzed using paired
t-test in terms of mean 24-h intragastric pH, and percentages
of time pH > 4, pH > 5 and pH > 6. It was indicated the male
and female subjects differed significantly at 5- and 10-mg
dose level (p50.05), whereas the difference was not statis-
tically significant for 20-mg group (p > 0.05).
Safety
A total number of 6 (37.5%) subjects experienced AEs
that were considered by the investigator to be possibly
6 H. Wang et al. Xenobiotica, Early Online: 1–9

Table 4. Comparison of pharmacokinetic parameters between male and female subjects (mean ± SD).

IV 5 mg IV 10 mg IV 20 mg
Parameter Female Male Female Male Female Male
a
t1/2 (h) 3.56 ± 0.97 2.93 ± 0.73 3.63 ± 0.98 3.22 ± 0.74 3.36 ± 0.74 2.89 ± 0.60
V (L)a 12.79 ± 2.11 14.63 ± 2.84 13.32 ± 1.61 14.74 ± 2.56 13.14 ± 1.75 14.21 ± 1.87
CL (L/h)a 2.64 ± 0.74 3.63 ± 0.99 2.74 ± 0.91 3.31 ± 0.95 2.59 ± 0.58 3.53 ± 0.84
Cmax (ng/mL)b 497.90 ± 77.55 464.25 ± 48.90 844.01 ± 102.87 824.62 ± 105.47 1848.90 ± 224.14 1570.48 ± 212.03
AUC0tb 1985.48 ± 476.74 1451.59 ± 380.58 3881.90 ± 1036.48 3159.83 ± 650.35 7943.80 ± 1601.20 5896.54 ± 1347.14
AUC01b 2010.60 ± 487.53 1462.49 ± 381.84 3940.26 ± 1083.84 3184.85 ± 651.19 8042.04 ± 1633.21 5930.34 ± 1356.41
a
p > 0.05.
b
p50.05.

drug-related. One subject withdrew due to elevated PT after
intravenous infusion of 10 mg ilaprazole and was recovered
soon without any medication. The AEs observed in the study
included toothache (one subject, 6.7%), diarrhea (one subject,
6.7%), and increase in activated partial thromboplastin time
(APTT) (six subjects, 37.5%) and PT (two subjects, 12.5%).
Most AEs were mild and transient in nature with no pattern of
dose-related, and were recovered without any medication-
treatment. There were no serious AEs and deaths reported in
the study. Except for high incidence of elevated APTT and
PT, there were no clinically significant changes in all subjects
of the physical examination, laboratory test and ECG reports
before and after the administration of ilaprazole.
Discussion
Intravenous PPI therapy is critical for the patients unable to
take the oral formulation or for emergent situations such as
peptic ulcer bleeding. This study, to the best of our
knowledge, was the first study to investigate the pharmaco-
kinetics, pharmacodynamics, and safety of intravenous infu-
sion of ilaprazole in human subjects. Following 45 min-
infusion of 5, 10 or 20 mg ilaprazole, Cmax, AUC0t and
AUC01 were proportionally increased as dose escalation.
The CL, V and t1/2 were not statistically different among the
three dose cohorts. It was concluded that intravenous
ilaprazole displayed linear pharmacokinetics, which was
comparable to that when ilaprazole was orally administered
(de Bortoli et al., 2013; Shin et al., 2014). Urinary excretion
of ilaprazole was less than 0.01% of the administered dose
indicating renal excretion was not the elimination way of
ilaprazole.
Currently oral ilaprazole is available and prescribed for the
treatment of peptic ulcers and erosive oesophagiti; however
the bioavailability remains unclear. In this study, the absolute
bioavailability (BA) of ilaprazole in healthy subjects was
assessed and the value was 55.2% (29.1%–83.3%). It
was indicated that half of the oral dose was lost and there
was large inter-subject variability in the absorption of
illaprazole. Previous studies suggested that ilaprazole was
predominantly metabolized by CYP3A (Myung et al., 1999;
Seo et al., 2012; Zhou et al., 2010), thereby the loss might be
the contribution of first-pass effect caused by gut wall or
hepatic metabolism of CYP3A4. Besides the high inter-
subject variability of CYP3A abundance might result in the
large BA variability. Of note, the presence of efflux
transporters (e.g. P-glycoprotein) might also contribute to
the reduced systemic absorption. Further studies, such as
concurrent administration of inhibitors of the CYP3A or P-
glycoprotein would resolve this problem.
Since intragastric acid secretion shows a circadian rhythm,
and is modified by buffering meals and nocturnal duodeno-
gastric reflux (Saitoh et al., 2001; van Herwaarden et al.,
1999), it is important to consider these factors when
evaluating the pharmacodynamics of PPIs. In the current
study, 24-h baseline pH-time profiles were acquired for each
subject. Compared with basal pH profile, the intravenous
ilaprazole exhibited significant acid inhibition in a dose-
dependent manner. The potency and onset of action was
closely related to the dose. Ilaprazole at intravenous dose of
20 mg (45 min infusion) provided the most significant effect
in terms of mean 24-h intragastric pH, nighttime pH,
percentages of time pH > 4, pH > 5 and pH > 6, as well as
onset of action. Moreover, t high dose of ilaprazole did not
bring more AEs compared with other dose regimens.
Therefore, the 45 min-infusion of 20 mg ilaprazole would be
recommended for the phase II and III study.
It is generally believed that intravenous PPI is a faster way
to achieve gastric acid suppression than oral administration.
However, things are not always as they seem. A clinical study
in patients with erosive esophagitis indicated that both
intravenous and oral administration of 40 mg of esomeprazole
resulted in similar safety and efficacy profiles (Schneider
et al., 2004). Therefore, it is necessary to compare the effect
with oral administration when developing an intravenous PPI.
Previously, in a study comparing the gastro-protective effects
of intravenous and enteral ilaprazole in rat, intravenous
ilaprazole exhibited faster and longer effect of acid inhibition
than oral ilaprazole (Yu et al., 2014). The superiority of
intravenous relative to oral administration of ilaprazole was
confirmed by the present study. Compared with oral admin-
istration of 10 mg, the intravenous infusion of 10 mg
ilaprazole produced much better pH control in terms of
intensity and onset of action.
The gender effect on the pharmacokinetics and pharma-
codynamics of ilaprazole has never been identified. In this
study, we found that plasma exposure (AUC and Cmax) of
female subjects were higher than those of males. Since
ilaprazole was predominantly metabolized by CYP3A, we
assumed the observed difference might result from the
difference in CYP3A hepatic activity between men and
women. It was reported that women showed significantly
greater hepatic CYP3A activity than men (Chen et al., 2006;
Hu & Zhao, 2010). However, this assumption was not
 DOI: 10.3109/00498254.2016.1156185

Figure 3. Mean 24-h intragastric pH-time profiles of male and female subjects before and after intravenous infusion of ilaprazole: (a) baseline; (b) 5 mg; (c) 10 mg; (d) 20 mg.
PK and PD of intravenous ilaprazole
7
8 H. Wang et al.
supported by the fact that clearance of the female sub-
jects was not statistically different from that of the males
(Table 3). Reasons are still not clear and the variability of
individual and study period may also contribute to the
differences. Since the intragastric acid inhibition of PPIs is
generally related to systemic exposure (e.g. AUC), it was
not surprising that the female subjects exhibited higher
mean pH values (at 5- and 10-mg, Figure 3). However, this
difference was not observed at high dose of 20 mg. Overall
it is still difficult to make conclusion regarding the gender
effect; however it deserves special attention in the follow-
ing clinical studies.
To date, information on the safety profile of intravenous
ilaprazole is very scarce. When reviewing previous studies,
this drug was generally safe and well tolerated both in
healthy subject and patients after oral administration (Ho
et al., 2009; Wang et al., 2012). Likewise, intravenous
ilaprazole displayed favorable safety profile in healthy
Chinese subjects, except for a high incidence of elevated
APTT and PT. One subject withdrew the study due to
elevated PT but was recovered without any medication.
Since the abnormal APTT and PT were reported previously
when this drug was orally administered, moreover, in the
present study they were also only observed in intravenous
group, the AEs were possibly associated with EDTA salts
used in the ilaprazole intravenous infusion. It was reported
that APTT and PT would be elevated by the contamination
of high level of K2EDTA in clotting assay (Lima-Oliveira
et al., 2015). Although the elevated APTT and PT were
generally mild and transient in nature with no pattern of
dose-related, further studies are warranted to evaluate the
safety of intravenous ilaprazole, with particular concern of
the coagulation function.
Conclusions
This is the first study to investigate the pharmacokinetics,
pharmacodynamics and safety profiles of intravenous ilapra-
zole in human subjects. Ilaprazole exhibited linear pharma-
cokinetics over the intravenous dose range of 5–20 mg.
Ilaprazole was not eliminated through renal excretion and the
absolute bioavailability of ilaprazole was 55.2%. Intravenous
ilaprazole provided a faster onset of action than oral
administration. The potency of intragastric pH control and
onset of action were exhibited in a dose-dependent manner.
Intravenous ilaprazole was safe and well tolerated in healthy
Chinese subjects with no pattern of dose-related AEs.
Acknowledgements
This study was funded by the National Science and
Technology Major Project of China (2012ZX09303006-002)
and by Livzon Pharmaceutical Group Inc. (Zhuhai
Guangdong, China).
Declaration of interest
Hongyun Wang, Liwei Lang, Pei Hu and Ji Jiang are
employes of Peking Union Medical College Hospital. Ning
Ou and Ruihua Shi are employes of Jiangsu Province
Hospital. The authors report no declarations of interest.
Xenobiotica, Early Online: 1–9
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