Kyung-Sang Yu, Kyun-Seop Bae, Ji-Hong Shon et al. Pharmacokinetic and Pharmacodynamic Evaluation of a Novel Proton Pump Inhibitor, YH1885, in Healthy Volunteers // J Clin Pharmacol. 2004;44: P. 73–82.

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Авторы: Yu Kyung-Sang / Bae Kyun-Seop / Shon Ji-Hong / Cho Joo-Youn / Yi So-Young / Chung Jae-Yong / Lim Hyeong-Seok / Jang In-Jin / Shin Sang-Goo / Song Keun-Seog / Moon Byoung-Seok


Pharmacokinetic and Pharmacodynamic Evaluation of a Novel Proton Pump Inhibitor, YH1885, in Healthy Volunteers

Kyung-Sang Yu, MD, PhD, Kyun-Seop Bae, MD, PhD, Ji-Hong Shon, MD, Joo-Youn Cho, PhD, So-Young Yi, MS, Jae-Yong Chung, MD, Hyeong-Seok Lim, MD, In-Jin Jang, MD, PhD, Sang-Goo Shin, MD, PhD, Keun-Seog Song, DVM, MS, and Byoung-Seok Moon, DVM, PhD


To evaluate the pharmacokinetic and pharmacodynamic characteristics of YH1885, a novel proton pump inhibitor, a single-blind, randomized, placebo-controlled, dose-rising, parallel-group study was conducted in 46 healthy volunteers. The volunteers were randomly allocated to single dose groups of 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg (6 subjects per dose, including 2 placebos) or to multiple-dose groups of 150 mg and 300 mg (once-daily dosing for 7 days; 8 subjects per dose, including 2 placebos). The multiple-dose study was conducted separately after the single-dose study. YH1885 was administered orally after overnight fasting. Serial blood samples, urine samples, and pharmacodynamic measurements were taken. Drug concentrations in plasma and urine were determined by liquid chromatography/mass spectrometry (LC/MS). Pharmacodynamic changes were evaluated by ambulatory intragastric pH monitoring and by serial measurements of serum gastrin concentrations. Assessments of safety and tolerability also were made. Plasma concentrations of YH1885 reached peak levels 1.3 to 2.5 hours after single-dose administration and then declined monoexponentially with a terminal half-life (t½) of 2.2 to 2.4 hours in dosage groups up to 200 mg in the single-dose study. YH1885 showed linear pharmacokinetic characteristics, and little accumulation occurred after multiple administrations. The parent drug was not detected in urine. Dose-related pharmacological effects were obvious for dose groups of 150 mg and higher in the single-dose study. The mean intragastric pH and the percentage of time at pH > 4 were significantly increased. The onset of drug effect was rapid, and maximal effects were observed on the first day of administration during multiple dosing. Serum gastrin levels also showed rapid increases during dosing but with a weak dose-effect relationship. Neither serious nor dose-limiting adverse effects were observed. YH1885 was found to be safe and well tolerated and effectively inhibited acid secretion with dose-dependent increases in intragastric pH. The acid-suppressing efficacy of YH1885 needs to be further evaluated in patients with gastric acid-related diseases.

Keywords: YH1885; proton pump inhibitors; gastric acid-related diseases; pharmacokinetics


From the Department of Pharmacology, Seoul National University College of Medicine (Dr. Yu, Dr. Cho, Ms. Yi, Dr. Chung, Dr. Jang, Dr. Shin); Clinical Pharmacology Unit and Clinical Trial Center/Clinical Research Institute, Seoul National University Hospital (Dr. Lim, Dr. Jang, Dr. Shin); Asan Medical Center, Seoul (Dr. Bae); Department of Pharmacology, Inje University College of Medicine, Busan (Dr. Shon); and Yuhan Corp., Korea (Mr. Song, Dr. Moon). This study was sponsored by Yuhan Corp. Submitted for DOI: 10.1177/0091270003261321


Proton pump inhibitors (PPIs) have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease, because of their greater and longer-lasting acid-suppressive potentials than H2 receptor antagonists.1 PPIs are membrane-permeable weak bases that accumulate in the acid spaces of active gastric parietal cells, where they undergo an acid-catalyzed conversion to active sulfenamide derivatives. These derivatives covalently bind via disulfide bridges to their target, H+/K+-ATPase, and inhibit acid production by the bound cell.2 Proton pump inhibitors effectively block the acid production of 70% or more of active pumps.3

Existing PPIs, such as omeprazole,4 lansoprazole5,6, pantoprazole 7,8, rabeprazole 9,10, and esomeprazole 11,12, all share a common structure (substituted benzimi-dazoles) and mode of action, but they differ somewhat in terms of clinical pharmacology.13 YH1885, 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl) pyrimidine hydro-chloride, is a novel reversible proton pump inhibitor that is currently under clinical investigation (Figure 1).14 It has been shown to have potent acid-suppressive properties and favorable safety profiles compared to omeprazole in preclinical studies. The present study was conducted to investigate the pharmacokinetic and pharmacodynamic characteristics of YH1885 after single and multiple oral administrations to healthy volunteers.

METHODS

Subjects

Thirty healthy male volunteers, ages 20 to 36 years (mean ± SD: 25.5 ± 3.7 years) and weighing 55 to 79 kg (66.9 ± 6.2 kg), participated in the single-dose study, and 16 healthy male volunteers, ages 18 to 30 years (24.3 ± 3.0 years) and weighing 55 to 85 kg (68.4 ± 8.0 kg), were enrolled for the multiple-dose study. The subjects were assessed as being healthy by medical history, physical examination, vital signs, 12-lead electrocardi-ography (ECG), and routine clinical laboratory tests performed within 3 weeks prior to the study. Subjects were excluded for use of any drugs within 7 days prior to the study, regular heavy drinking, smoking more than 20 cigarettes per day, and a body weight beyond 85% to 115% of their ideal body weight. The study protocol was approved by the institutional review board of Seoul National University Hospital (SNUH), and the study was conducted at the SNUH Clinical Trial Center. All procedures were performed in accordance with the recommendations of the Declaration of Helsinki on biomedical research involving human subjects, as well as with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use—Good Clinical Practice (ICH-GCP) guidelines. All subjects gave written informed consent before being enrolled.

Figure 1. Chemical structure of YH1885

Figure 1. Chemical structure of YH1885

Study Design

This was a single-blind, randomized, placebo-controlled, dose-rising, parallel-group study. In the single-dose study, subjects were randomly assigned to one of five dose groups of 60, 100, 150, 200, and 300 mg; each group included 6 subjects, 2 of which received placebo. Subjects were admitted on the night before baseline evaluation and were fasted overnight beginning at 10 p.m. On the day of the baseline evaluation (day 0), all subjects were given a single dose of placebo with 240 mL of water at approximately 9 a.m. On the following day (day 1), subjects were given a single dose of YH1885 or placebo with 240 mL of water at the same time as the previous morning. Subjects were kept in the fasting state until 4 hours after drug administration on day 0 and day 1, except for 200 mL of water 2 and 4 hours after dosing on each day. The subjects were discharged on the morning of day 3 and returned for a poststudy visit on day 8.

The multiple-dose study was conducted separately after the single-dose study. Subjects were randomly assigned to one of two dose groups of 150 and 300 mg; each group included 8 subjects, 2 of which received placebo. During the first 2 days of the multiple-dose study (days 0 and 1), the subjects underwent a schedule identical to that of the single-dose study. During days 2 to 6, the subjects were given a dose of YH1885 or placebo once daily at the same time as day 1, after an overnight fasting that was continued until 2 hours after drug administration. On day 7, after overnight fasting, the subjects were given a single dose of YH1885 or placebo with 240 mL of water at the same time as day 1. Subjects were maintained in the fasting state for 4 hours after drug administration on day 7, except for 200 mL of water 2 and 4 hours after dosing. The subjects were discharged on the morning of day 9 and returned for a poststudy visit on day 14.

In both the single- and multiple-dose studies, alcohol, soft drinks, and beverages containing caffeine were prohibited beginning 2 days prior to admission for the entire study duration, which ended with the poststudy visit.

Pharmacokinetic Evaluation

Blood samples (8 mL) were taken via an indwelling cannula inserted into a forearm vein at 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours after drug administration on day 1 (and also on day 7 during the multiple-dose study). All blood samples were obtained in the semirecumbent position. The samples obtained were centrifuged at 1200 g for 10 minutes at 4°C, and plasma was immediately stored in polypropylene tubes at –20°C or less until required for analysis.

Urine was collected at intervals of 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 hours after dosing on day 1 in the single-dose study. During the multiple-dose study, urine was collected from 0 to 6, 6 to 12, and 12 to 24 hours on days 1 and 7. The volume of each collection was recorded, and aliquots were stored in polypropylene tubes at less than –20°C until required for analysis.

Plasma and urine concentrations of YH1885 were measured. Noncompartmental pharmacokinetic analysis was performed (WinNonlin Pro 4.0.1, Pharsight Corp., Mountain View, CA) using actual sampling times. Maximum drug concentrations in plasma (Cmax) and the time to reach maximum concentration (tmax) were determined from observed values. Plasma concentrations of the terminal phase were fitted to a log-linear line by the least squares method to obtain the terminal half-life (t½). Areas under the time-concentration curves (AUCs) were calculated using a combination of the trapezoidal rule and extrapolation to infinity using the elimination rate constant. Oral clearance (CL/F) was calculated as Dose/AUC.

Measurement of Drug Concentrations

Plasma and urine concentrations of YH1885 were determined by liquid chromatography/mass spectrometry (LC/MS).15 In brief, 100 µL of plasma sample was mixed with 200 µL of acetonitrile, which included an internal standard (YH439, Yuhan Co., 1.0 µg/mL). After vortexing for 30 seconds and centrifuging for 10 minutes, 20 µL of the supernatant was injected into an LC/MS system (HP 1100 series, Agilent Technologies, Palo Alto, CA), using a MeCN/acetate buffer (80/20, v/v) mobile phase at a flow rate of 1.0 mL/min and a C8 column (Cosmosil 5Cg, 250 Ч 4.6 mm i.d., Nacalai, Japan). For urine samples, the procedures used were identical, except that 300 µL of the urine sample was mixed with 600 µL of acetonitrile containing the internal standard. The lower limit of YH1885 quantification was 10 ng/mL, and calibration curves were linear over the concentration range 10 to 2500 ng/mL (r > 0.98). The accuracy of this assay was within the range 91.4% to 107.6%, and the interbatch coefficient of variation was less than 13.6% over the calibrated range.

Pharmacodynamic Evaluation

Intragastric pH values were recorded continuously for 24 hours on day 0 (baseline) and day 1 (postdose), using an ambulatory intragastric pH monitoring system. During the multiple-dose study, intragastric pH was also monitored on day 7. Before dosing, a bipolar glass pH electrode catheter (Medtronic Synectics AB, Stockholm, Sweden) was calibrated, inserted into the stomach via the nose (anaesthetized with 1% lidocaine spray), and fixed at approximately 5 cm below the lower esophageal sphincter, as determined by an abrupt pH change.16 The catheter was connected to a portable digital data recorder (MicroDigitrapper 4Mb, Medtronic Synectics AB), and the intragastric pH was sampled every 8 seconds. After finishing the recording, the electrode was removed and recalibrated. The recorded data were uploaded onto a personal computer where they were further analyzed. The mean pH during each day and the percentage of time at pH > 4 were calculated.17

During pH monitoring, the subjects were requested to maintain an identical time schedule each day, for drinking water, eating (standardized meals 4 and 9 h after dosing), smoking (less than 20 cigarettes per day), and body position. The subjects were not allowed to lie in the supine position before nighttime. Baseline plasma gastrin levels were measured 0 (predose), 6, 12, and 24 hours after placebo administration on day 0, and postdose levels were measured 6, 12, 24, 48, and 168 (poststudy visit) hours after drug administration on day 1 in the single-dose study. During the multiple-dose study, predose gastrin levels were measured on days 1, 2, 4, 7, 8, and 14 (poststudy visit).

Safety and Tolerability Assessment

Physical examinations, vital signs, 12-lead ECG, and routine clinical laboratory tests were repeated at prede-fined time points. Inquiries as to the presence of any adverse events were made at each evaluation period by asking general questions. Additional safety assessments were made at the discretion of the investigator.

Table I Pharmacokinetic Parameters following a Single Oral Administration of YH1885


60 mg

100 mg

150 mg

200 mg

300 mg

Cmax (ng/mL)

78.1 + 34.5

168.7 + 86.3

266.7 + 43.3

361.4 + 124.1

722.4 + 239.2

tmax (h)

2.3 + 0.9

1.5 + 0.4

2.5 + 0.6

2.1 + 1.3

1.3 + 0.3

t½ (h)

2.4 + 0.8

2.4 + 0.3

2.2 + 1.0

2.4 + 0.2

9.8 + 4.7

AUC∞ (ng•h/mL)

363.9 + 155.1

667.8 + 423.1

1175.4 + 286.9

1343.1 + 365.9

2817.5 + 806.0

CL/F (L/h)

200.6 + 115.8

202.0 + 116.6

133.6 + 32.8

157.6 + 43.3

116.1 + 45.1

Values are presented as mean ± standard deviation. Cmax, maximum plasma concentration; tmax, time to maximum concentration; t½, terminal half-life; AUC∞, area under the time-concentration curve extrapolated to infinity; CL/F, oral clearance.

Statistical Analysis

Linear regression and ANOVA (analysis of variance) on dose-normalized values were used to determine the dose linearity of Cmax and AUC. ANOVA was also used to evaluate any differences in the terminal half-lives and oral clearances of the dose groups. Wilcoxon signed rank tests were used to determine any differences in pharmacokinetic parameters between day 1 and day 7.

Repeated-measures ANOVA (SAS® 6.12, proc GLM) was used for within-subject analysis of pharma-codynamic parameters during the multiple-dose study. ANOVA was used to evaluate any differences in the changes of gastric pH, time at pH > 4, and serum gastrin levels between dose groups. Wilcoxon rank sum tests were used to compare pharma-codynamic parameters between placebo and other dose groups; p-values lower than 0.05 were considered statistically significant.

Figure 2. Plasma concentrations (mean + SD) of YH1885 after a single-dose oral administration. Upper: linear scale; lower: semiloga-rithmic scale

Figure 2. Plasma concentrations (mean + SD) of YH1885 after a single-dose oral administration. Upper: linear scale; lower: semiloga-rithmic scale

RESULTS

Pharmacokinetics

Plasma concentrations of YH1885 peaked 1.3 to 2.5 hours (range of dose group means) after a single-dose administration and then declined monoexponentially, with a terminal half-life (t½) of 2.2 to 2.4 hours (Figure 2) in dosage groups up to 200 mg in the single-dose study. After 300-mg dosing, the concentrations showed a biphasic decay pattern with an initial half-life similar to that of the lower dose groups but a terminal half-life of 9.8 hours (Table I). The Cmax and AUC of YH1885 increased linearly with dose (r = 0.99 and 0.98 for mean Cmax and mean AUC, respectively; p > 0.05 for ANOVA on dose-normalized values). Similarly, no significant oral clearance differences were found between the dose groups.

Table II Pharmacokinetic Parameters following Once-Daily Oral Administration of YH1885 for 7 Days


150

mg

300 n

g

Day 1

Day 7

Day 1

Day 7

Cmax (ng/mL)

215.6 + 91.3

279.3 + 108.8

821.7 + 304.4

654.1 + 291.7

tmax (h)

1.5 + 0.4

1.4 + 0.8

1.7 + 0.8

2.2 + 1.4

t½ (h)

4.1 + 3.4

14.8 + 13.1

4.5 + 2.3

26.0 + 17.0*

AUC, (ng•h/mL)

940.3 + 519.9


3237.9 + 2192.9


AUCT (ng•h/mL)

936.4 + 418.1

1391.7+711.8*

3111.9 + 1999.2

3281.8 + 1936.6

CL/F (L/h)a

206.2 + 112.5

148.4 + 105.8

131.9 + 86.7

133.8 + 102.9

Accumulation indexb


1.5 + 0.4


1.1 + 0.2

Values are presented as mean ± standard deviation. Cm , maximum plasma concentration; t , time to maximum concentration; t /2 terminal half-life; AUC , area under the time-concentration curve extrapolated to infinity; AUCT, interval AUC (0-24І1ax ; CL/F, oral clearance.

a. CL s/F (steady-state oral clearance) for day 7.

b. AUCT (day 7)/AUCT (day 1). *p < 0.05 compared to day 1.

In the multiple-dose study, concentration-time profiles were similar on days 1 and 7 for once-daily oral dosing (Figure 3). Pharmacokinetic parameters showed similar individual values for Cmax, tmax, and oral clearance for days 1 and 7. However, the terminal half-life was greater on day 7 in both dose groups, and the accumulation index was 1.5 ± 0.4 for the 150-mg dose group (Table II).

Regarding the urine samples, no parent drug was detected in any subject.

Figure 3. Plasma concentrations (mean + SD) of YH1885 during once-daily oral administration for 7 days. Upper: linear scale; lower: semilogarithmic scale

Figure 3. Plasma concentrations (mean + SD) of YH1885 during once-daily oral administration for 7 days. Upper: linear scale; lower: semilogarithmic scale

Pharmacodynamics

During the baseline study period (day 0), intragastric pH fluctuated within a range of approximately 1 to 6. Sharp increases in pH were seen after meals at 4 and 9 hours, which were followed by gradual decreases (Figure 4, dotted lines). After administering YH1885 in the single-dose study, elevations in intragastric pH were noted, especially in the higher dose groups (Figure 4, solid lines). Subjects in the placebo group showed little change. Values obtained beyond 16 hours after dosing were highly variable. In the multiple-dose study, changes in the pH-time profiles for day 1 were similar to those of the single-dose study, and the pH-time profile for day 7 was similar to that of day 1 (Figure 5). This was confirmed by the daily mean pH and the percentage of time at pH > 4 (Table III).

Differences in mean gastric pH and the percentage of time at pH > 4 increased in a dose-dependent manner, with significant values seen in dose groups of 150 mg and higher in the single-dose study (Figure 6). This pattern was more evident when only the daytime values were compared. In the multiple-dose study, increases in mean gastric pH and the percentage of time at pH > 4 were also dose dependent; values for day 7 were similar or slightly higher than those for day 1 (Figure 7).

Figure 4. Mean intragastric pH-time profiles after a single oral administration of YH1885 or placebo, in selected dosage groups in the single-dose study. Meals were given at 4 and 9 hours after dosing

Figure 4. Mean intragastric pH-time profiles after a single oral administration of YH1885 or placebo, in selected dosage groups in the single-dose study. Meals were given at 4 and 9 hours after dosing

Serum gastrin levels showed intraday variation during the baseline period (Figure 8). Taking this variation into account, serum gastrin levels increased transiently after YH1885 administration in a weakly dose-dependent fashion in the single-dose study During multiple-dose administration, daily predose gastrin levels increased until day 7, when the final dose was administered (Figure 9). Levels then returned to baseline.

Relationships between pharmacokinetic and pharmacodynamic parameters were explored using AUCs after single-dose administration and (1) changes in mean gastric pH and (2) changes in the percentage of time at pH > 4. When fitted to a simple Emax model {E = Emax • AUC/(EC50 + AUC)}, the parameter values were Emax = 1.98 and EC50 = 1265 ng•h/mL for the increase in the mean gastric pH, and Emax = 56 (%) and EC50 = 1672 ng«h/mL for the increase in the percentage of time at pH > 4. Regarding the relationship between concentration and effect, pharmacokinetic-pharmacodynamic modeling would be needed since individual time-dependent relationships and the influence of covariates are not considered in correlation analyses. This would provide another topic for investigation.

Figure 5. Mean intragastric pH-time profiles during once-daily oral administration of YH1885 for 7 days. Meals were given at 4 and 9 hours after dosing

Figure 5. Mean intragastric pH-time profiles during once-daily oral administration of YH1885 for 7 days. Meals were given at 4 and 9 hours after dosing

Safety and Tolerability

No clinically significant changes were observed by physical examination or in terms of vital signs, ECGs, or routine clinical laboratory tests in any subject. Some instances of gastrointestinal disturbances occurred as follows, but all were mild and transient. Diarrhea or loose stools was the most frequent adverse event, with 5 subjects in the single-dose study (1 each in the 60-mg, 200-mg, and 300-mg dose groups; 2 in the placebo group) and 3 subjects in the multiple-dose study (1 in the 300-mg dose group; 2 in the placebo group). Constipation was noted in 2 subjects during the multiple-dose study (1 in the 150-mg dose group; another in the placebo group). Indigestion was reported in 2 subjects (1 each in the 150-mg single-dose group and 300-mg multiple-dose group).

Figure 6. Mean (+ SD) differences in mean gastric pH (upper) and mean (+ SD) differences in the percentage of time at pH >4 (lower) between baseline (day 0) and after administration of YH1885 or placebo (day 1) in the single-dose study. *p < 0.05 compared with placebo

Figure 6. Mean (+ SD) differences in mean gastric pH (upper) and mean (+ SD) differences in the percentage of time at pH >4 (lower) between baseline (day 0) and after administration of YH1885 or placebo (day 1) in the single-dose study. *p < 0.05 compared with placebo
Figure 7. Mean (+ SD) differences in mean gastric pH (upper) and mean (+ SD) differences in the percentage of time at pH > 4 (lower) between baseline (day 0) and after YH1885 or placebo, on day 1 or day 7, during the multiple-dosing study. *p < 0.05 compared with placebo. #p < 0.05 compared with 150 mg
Figure 7. Mean (+ SD) differences in mean gastric pH (upper) and mean (+ SD) differences in the percentage of time at pH > 4 (lower) between baseline (day 0) and after YH1885 or placebo, on day 1 or day 7, during the multiple-dosing study. *p < 0.05 compared with placebo. #p < 0.05 compared with 150 mg

Other adverse events reported were headaches (2 subjects in the 300-mg single-dose group; 1 each in the single- and multiple-dose placebo groups), rhinorrhea (4 subjects in the single-dose groups), and throat discomfort due to the nasogastric probe (3 subjects in the single-dose groups; 1 in the placebo group). These events were also mild and transient.

DISCUSSION

The single-dose pharmacokinetic analysis results suggest that orally administered YH1885 was rapidly absorbed and eliminated. The terminal half-life was variable, with a second decay phase emerging in the highest dose group. This finding is thought to be related to the plasma concentration assay detection limit (i.e., the second phase was not observable in the lower dose groups due to the lower concentrations involved). However, the contribution of the second phase to the overall pharmacokinetic profile was considered minimal, and this phenomenon did not compromise dose linearity, as evidenced by the linear relationships between the AUCs and oral clearances by dose.

Figure 8. Mean changes (percent changes compared to &ndash;24 h for baseline [day 0] values or 0 h for postdose values) in serum gastrin levels after a single oral administration of YH1885 or placebo (upper). Mean (+SD) differences in the percent changes of serum gastrin levels at 6, 12, and 24 hours between baseline (day 0) and after YH1885 or placebo (lower). *p < 0.05 compared with placebo

Figure 8. Mean changes (percent changes compared to –24 h for baseline [day 0] values or 0 h for postdose values) in serum gastrin levels after a single oral administration of YH1885 or placebo (upper). Mean (+SD) differences in the percent changes of serum gastrin levels at 6, 12, and 24 hours between baseline (day 0) and after YH1885 or placebo (lower). *p < 0.05 compared with placebo

In the multiple-dose study, the terminal half-life was 4 to 6 times longer on day 7 than on day 1. This could be explained by the fact that the second decay phase started approximately 12 to 24 hours after dosing, rendering exact characterization of the elimination phase for day 1 difficult during once-daily dosing. The accumulation index was greater in the 150-mg dose group compared to the 300-mg dose group (1.5 ± 0.4 vs. 1.1 ± 0.2; p > 0.05). However, considering that the number of subjects is small, the variance is large, and the fact that the 300-mg dose group showed values near unity, overall drug accumulation was thought to be minimal. Urinary excretion of the drug was negligible.

Figure 9. Mean changes (percent changes compared to day 1 levels) in predose serum gastrin levels during once-daily oral administration of YH1885 or placebo for 7 days. *p < 0.05 compared with values for day 1

Figure 9. Mean changes (percent changes compared to day 1 levels) in predose serum gastrin levels during once-daily oral administration of YH1885 or placebo for 7 days. *p < 0.05 compared with values for day 1

Dose-related pharmacological effects were clearly demonstrated, especially in dosage groups of 150 mg and higher. Pharmacodynamic parameters, such as the mean intragastric pH and the percentage of time at pH > 4, increased in a dose-dependent fashion. During the multiple-dose study, it was shown that these effects were maximal even with the first dose, and parameter values for day 7 were similar to those of day 1. This finding differs from those of omeprazole or lanso-prazole, in which maximal effect was not reached on the first day of multiple once-daily dosing 18,19. Exact comparisons with other studies of PPIs are difficult due to differences in study design (especially the number and timing of meals and snacks, which lead to differences in baseline pH profiles), but the effects of YH1885 seem to be generally comparable to those of other PPIs. In one report involving the once-daily administration of omeprazole or lansoprazole to healthy volunteers, the percentage of time at pH > 4 was 65% after 30 mg of lansoprazole treatment for 5 days and 50% after 15 mg of lansoprazole or 20 mg of omeprazole for 5 days 19. During 300 mg of YH1885 administration, this value was 62% on the first day and 66% on day 7. In another study using rabeprazole in healthy volunteers, the mean gastric pH increased by 1.2 after a single 40-mg dose of rabeprazole 20, while a single 300-mg dose of YH1885 raised the mean pH by 1.4 (Table III).

Table III Mean pH (Upper) and Percentage of Time at pH > 4 (Lower) following Intragastric pH Monitoring during Once-Daily Administration of YH1885

Dose

Mean pH

Day 0

Day 1

Day 7

Placebo

3.2 + 1.2

3.0 + 1.0

3.2 + 1.2

150 mg

2.7 + 0.8

3.6 + 1.0*

3.6 + 0.9*

300 mg

3.2 + 0.7

4.6 + 0.8*

4.9 + 0.6*


Time at pH > 4 (%)

Day 0

Day 1

Day 7

Placebo

28.9 + 24.4

24.4 + 19.8

32.1 + 22.2

150 mg

23.2 + 16.1

39.4 + 22.7*

39.9 + 17.0*

300 mg

31.5 + 12.9

61.7 + 14.2*

65.6 + 12.0*

Values are presented as mean ± standard deviation. *p < 0.05 compared to day 0.

In this study, smokers were not prohibited from smoking. It has been reported that smoking cigarettes does not influence the median intragastric pH over 24 hours in healthy persons and ulcer patients 21.

High variability in nocturnal pH values is attributable to two factors: one is due to irregular changes in body position during sleep that affect the probe position, and the other is a phenomenon called nocturnal acid breakthrough. During PPI therapy given once daily before breakfast, it has been reported that a drop in pH begins at around 11 p.m. and that this occurs in 80% of patients and healthy controls 22.

The increased serum gastrin concentration after YH1885 administration is a response to the suppression of gastric acid secretion via a feedback mechanism 23. Although serum gastrin levels do not correspond well to gastric pH 24, early changes in serum gastrin values suggest the early onset of pharmacological actions. Moreover, the rapid normalization of gas-trin levels after the last dose suggests the early termination of the pharmacologic effects 25.

In summary, YH1885 was found safe and well tolerated and to have linear pharmacokinetic characteristics with little accumulation during multiple once-daily dosing. YH1885 effectively inhibited acid secretion, with dose-dependent increases in intragastric pH, in these healthy volunteers. Although the volunteers were not screened for Helicobacter pylori infection, the prevalence rate is assumed to be less than 60% for this age group in Korea 26-28. In the presence of H. pylori, the effect of proton pump inhibitors on intragastric pH is much increased 29. Therefore, the efficacy of YH1885 needs to be evaluated in patients with gastric acid-related diseases.

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