Dose–response relationship of lansoprazole to gastric acid antisecretory effects

Authors


Blum The Clinical Pharmacokinetics Laboratory, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209, USA.

Abstract

Background:

Proton pump inhibitors have been found to be effective in numerous studies in patients with peptic ulcer disease, particularly associated with Helicobacter pylori and gastro-oesophogeal reflux disorders. Optimal healing rates of antisecretory therapy for peptic acid disease is dependent upon the degree and duration of acid suppression and the length of treatment.

Objective:

To evaluate the extent and duration of gastric acid suppression of several lansoprazole regimens, administered for 5 consecutive days in 32 healthy adult male subjects.

Methods:

Intragastric 24-h pH monitoring was performed in 32 healthy subjects in a randomized, double-blind, four-way crossover study. Sixteen subjects (Group 1) received lansoprazole 30 mg o.d. (once daily), 15 mg b.d. (twice daily), 30 mg b.d. and 30 mg t.d.s. (three times a day) for 5 days; and 16 subjects (Group 2) received lansoprazole 30 mg o.d., 60 mg o.d., 60 mg b.d. and 60 mg t.d.s. for 5 days.

Results:

Mean 24-h intragastric pH values for lansoprazole 30 mg o.d., 15 mg b.d., 30 mg b.d. and 30 mg t.d.s. were 4.47, 4.57, 5.07 and 5.63, respectively. Multiple-dose regimens of lansoprazole 30 mg b.d. and t.d.s. produced greater acid suppression compared to lansoprazole 30 mg o.d. and 15 mg b.d. There was no significant difference in acid suppression between lansoprazole 30 mg o.d. and 15 mg b.d. Mean 24-h intragastric pH values for lansoprazole 30 mg o.d., 60 mg o.d., 60 mg b.d. and 60 mg t.d.s. were 4.13, 4.45, 5.19 and 5.13, respectively. Multiple-dose regimens of lansoprazole 60 mg b.d. and t.d.s. produced significantly greater acid suppression compared to lansoprazole 30 mg o.d. and 60 mg o.d. There was no significant difference in acid suppression between lansoprazole 30 mg o.d. and 60 mg o.d. Lansoprazole 30 mg t.d.s., 60 mg b.d. and 60 mg t.d.s. produced significantly greater percentage time above pH 3, 4, 5 and 6 than did lansoprazole 30 mg o.d. Post-regimen serum gastrin values increased by 50–130% from pre-study mean values but remained within normal range and returned to pre-study values 7–14 days post-dosing.

Conclusions:

Multiple-dose regimens of lansoprazole (≥30 mg b.d. for 5 days) produce significantly increased intragastric pH and significantly longer duration of increased intragastric pH than does lansoprazole 30 mg administered once daily.

INTRODUCTION

Effective treatment of peptic ulcer disease is correlated with gastric acid suppression. Meta-analyses of studies in patients with duodenal ulcer, gastric ulcer and gastro-oesophageal reflux disease (GERD) have demonstrated that the extent of acid suppression (i.e. higher the pH) and the duration of acid suppression, in addition to length of treatment, are useful predictors of healing rates.1[2][3]–4 Intra-oesophageal pH has been compared in patients with varying severity of GERD; the more severe the GERD, the greater the percentage of total time the pH was less than 4.5 The relationship between suppression of gastric acid and an increase in intra-oesophageal pH is known.6 Therefore, the ability to suppress gastric acid secretion adequately and over a sufficient period is particularly important in the treatment of severe GERD.

Gastric acid suppression is also important in the treatment of peptic ulcer disease associated with H. pylori infection. Although the mechanism of action is not clearly understood, it is believed that gastric acid suppression optimizes the environment for the pharmacological action of the antimicrobial agent against H. pylori. Treatment regimens consisting of two antibiotics and a proton pump inhibitor administered twice daily are effective in eradicating H. pylori.7 Eradication rates of 94% were achieved with the triple therapy regimen of lansoprazole, amoxycillin and clarithromycin.8

The objective of this study was to evaluate the effect of varying dose regimens of lansoprazole on gastric acid suppression, as measured by 24-h intragastric pH.

METHODS

This was a randomized, double-blind study with a four-way crossover design. Two groups of 16 subjects per group, for a total of 32 subjects, gave written informed consent to participate in the study according to the Declaration of Helsinki. The study protocol was approved by the Millard Fillmore Hospital Institutional Review Board (Buffalo, New York, USA). In Group 1, 16 subjects received lansoprazole 30 mg o.d. (once daily), 15 mg b.d. (twice daily), 30 mg b.d. and 30 mg t.d.s. (three times daily) in random order. In Group 2, 16 subjects received lansoprazole 30 mg o.d., 60 mg o.d., 60 mg b.d. and 60 mg t.d.s. in random order. Dosing times for the regimens were at 08.00, 13.00 and 18.00 h. Double-dummy dosing was utilized to maintain blinding. Normal ECG and laboratory analyses were required prior to entering the study. Fasting serum gastrin values were obtained prior to dosing Day 1. Each dose regimen was administered for 5 consecutive days and was followed by a washout period of at least 7 days. Subjects were confined in a Clinical Research Center for each dosing period to control for identical eating and sleeping times. All subjects were non-smokers and were not allowed food or water between meals.

Each subject had a 24-h gastric pH measurement using a Sandhill one-channel RMS-II Datalogger pH assessment system with a graphite–antimony pH and pressure sensor probe that was calibrated (Sandhill Scientific, Inc., Highlands Ranch, Colorado, USA). Placement of the pH probe in the gastric antrum was determined using a Sandhill LES Locator to locate the lower oesophageal sphincter (LES) by manometry, and then placing the probe 15–18 cm below the lower oesophageal sphincter. Electrode placement in the stomach was also confirmed by a fall in pH upon entering the stomach. The total tube placement length from nose to stomach was recorded for tube placement in Periods 2, 3 and 4. A baseline 24-h gastric pH measurement was carried out prior to dosing in Period 1 only. During each of the four crossover periods a 24-h gastric pH measurement was carried out on the fifth day of dosing.

In each group the effect of the four regimens was compared using analysis of variance with a crossover model which included regimens, period, sequence and subjects within sequence as factors. This parametric analysis was performed on mean gastric pH and the percentage time above pH 3, 4, 5 and 6 during the 24-h monitoring period, and during each of four time intervals: 08.30–13.00, 13.00–18.00, 18.00–23.00 and 23.00–08.00 h. Comparisons between each pair of treatment regimens were performed within the crossover model. A P value of ≤ 0.05 was considered statistically significant.

RESULTS

Mean intragastric pH values for Group 1 subjects are listed in Table 1. Intragastric pH values increased as the total daily lansoprazole dose increased. There was no significant difference between lansoprazole 30 mg o.d. and 15 mg b.d. Mean 24-h gastric pH values were significantly higher with lansoprazole 30 mg b.d. and t.d.s. regimens (5.07 and 5.63, respectively) compared to 30 mg o.d. (4.47). Lansoprazole 30 mg t.d.s. resulted in significantly higher mean pH values over all time intervals compared to 15 mg b.d. Mean gastric pH for lansoprazole 30 mg t.d.s. was significantly higher than lansoprazole 30 mg b.d. only during the afternoon interval of 13.30–18.30 h with mean differences of about 1.0 pH unit. Figure 1 shows the mean gastric pH values for each lansoprazole dose for Group 1 subjects.

Table 1.  . Adjusted mean pH determinations for Dosing Group 1 Thumbnail image of
Figure 1. Mean gastric pH values for each lansoprazole dose regimen for Dosing Group 1.

Figure 1. Mean gastric pH values for each lansoprazole dose regimen for Dosing Group 1.

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The duration of acid suppression expressed as the mean percentage of time above pH 3, 4, 5 and 6 over 24 h is listed in Table 2 for Group 1. As with mean 24-h gastric pH values, there was a dose-dependent pH effect for duration of acid suppression. As the total daily lansoprazole dose increased, the duration of acid suppression increased at all pH levels. With the exception of time above pH 5 for the 30 mg b.d. regimen, there was no significant difference between duration of acid suppression for lansoprazole 30 mg o.d., 15 mg b.d. and 30 mg b.d. regimens. However, lansoprazole 30 mg t.d.s. produced significantly greater acid suppression compared to lansoprazole 30 mg o.d. and 15 mg b.d. for percentage time above pH 3, 4, 5 and 6. Lansoprazole 30 mg t.d.s. also produced significantly greater acid suppression compared to lansoprazole 30 mg b.d. for percentage time above pH 5 and 6.

Table 2.  . Per cent time above pH 3,4,5 and 6 over a 24-h period for lansoprazole 30 mg o.d., 30 mg b.d. and 30 mg t.d.s. for Dosing Group 1 Thumbnail image of

Mean intragastric pH values for Group 2 subjects are listed in Table 3. Mean 24-h gastric pH values were significantly higher with lansoprazole 60 mg b.d. and t.d.s. regimens (5.19 and 5.13, respectively) compared to 30 mg o.d. and 60 mg o.d. regimens (4.13 and 4.45, respectively). The significantly higher 24-h mean gastric pH values with 60 mg b.d. and t.d.s. regimens were influenced primarily by higher pH values during the evening and night-time. The 60 mg o.d., 60 mg b.d. and 60 mg t.d.s. regimens all produced similar pH levels in the morning and afternoon intervals. Except for the morning interval, there were no significant differences between lansoprazole 30 mg o.d. and 60 mg o.d. in mean pH. There was no significant difference between the lansoprazole 60 mg b.d. and 60 mg t.d.s. regimens in mean intragastric pH. Figure 2 shows the mean intragastric pH values for Group 2 subjects.

Table 3.  . Adjusted mean pH determinations for Dosing Group 2 Thumbnail image of
Figure 2. Mean gastric pH values for each lansoprazole dose regimen for Dosing Group 2.

Figure 2. Mean gastric pH values for each lansoprazole dose regimen for Dosing Group 2.

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The duration of acid suppression expressed as the mean percentage of time above pH 3, 4, 5 and 6 over 24 h is shown in Table 4 for Group 2. There was a dose-dependent effect on acid suppression up to a total daily lansoprazole dose of 120 mg (60 mg b.d.). The lansoprazole 60 mg b.d. and 60 mg t.d.s. regimens provided a similar extent of acid suppression at all pH levels. Lansoprazole 60 mg b.d. produced significantly greater acid suppression compared to lansoprazole 30 mg o.d. and 60 mg o.d. for percentage time above pH 3, 4, 5 and 6. Lansoprazole 60 mg t.d.s. produced significantly greater acid suppression compared to lansoprazole 30 mg o.d. and 60 mg o.d. for percentage time above pH 4, 5 and 6. Per cent time above pH 3 for lansoprazole 60 mg t.d.s. was significantly greater than lansoprazole 30 mg o.d. but not lansoprazole 60 mg o.d. There was no significant difference between lansoprazole 60 mg b.d. and 60 mg t.d.s. in percentage time pH above 3, 4, 5 or 6.

Table 4.  . Per cent time above 3, 4, 5 and 6 over a 24-h period for lansoprazole 30 mg o.d., 60 mg o.d., 60 mg b.d. and 60 mg t.d.s. for Dosing Group 2 Thumbnail image of

Tables 5 and 6 56 list mean serum gastrin concentrations for Group 1 and 2 subjects, respectively. Serum gastrin values increased as the total daily dose of lansoprazole increased. Mean post-regimen serum gastrin values were within normal limits (≤100 pg/mL) and ranged from 52.5 (Group 1, 30 mg o.d.) to 84.7 pg/mL (Group 2, 60 mg t.d.s.), and represented an increase of 50–130% from pre-study mean values. However, mean gastrin values obtained 7–14 days post-dosing had returned to pre-study levels.

Table 5.  . Mean serum gastrin concentrations (pg/mL) for Dosing Group 1 Thumbnail image of
Table 6.  . Mean serum gastrin concentrations (pg/mL) for Dosing Group 2 Thumbnail image of

The most frequently reported adverse events (reported by two or more subjects) that were considered possibly or probably treatment-related were headache and nausea. No subject was prematurely discontinued from the study due to an adverse event. In addition, no clinically significant differences from baseline laboratory values were observed for any laboratory parameter.

DISCUSSION

Lansoprazole is a safe and potent inhibitor of gastric acid secretion. In this study, the degree of gastric acid suppression, as measured by mean intragastric pH, and the duration of gastric acid suppression, as measured by the percentage of time above pH 3, 4, 5 and 6, was measured in normal volunteers. Two groups, of 16 subjects each, received four treatments in crossover fashion. Group 1 received lansoprazole 30 mg o.d. (once daily), 15 mg b.d. (twice daily), 30 mg b.d. and 30 mg t.d.s. (three time daily) for 5 days. Group 2 received lansoprazole 30 mg o.d., 60 mg o.d., 60 mg b.d. and 60 mg t.d.s. for 5 days. The one regimen common to both dosing groups was the 30 mg o.d. regimen.

Lansoprazole total daily doses from 30 to 90 mg/day increased mean intragastric pH over 24 h in a dose-dependent fashion. Lansoprazole doses equal to or greater than 120 mg/day provided no greater increase in intragastric pH than did total daily doses of lansoprazole 90 mg/day. Mean 24-h intragastric pH values were significantly higher in lansoprazole 30 mg b.d. and 30 mg t.d.s. regimens by ≈0.5 and 1.0 pH units, respectively, compared with lansoprazole 30 mg o.d. and 15 mg b.d. regimens. There was no significant difference in intragastric pH values between lansoprazole 30 mg o.d. and 15 mg b.d. regimens over a 24-h period nor during any of four time intervals. High daily dose, multiple-dose, regimens of lansoprazole 30 mg b.d. and 30 mg t.d.s. provided significantly increased intragastric pH during the afternoon, evening and night-time hours compared to lansoprazole 30 mg o.d. and 15 mg b.d. Significant differences in intragastric pH between the lansoprazole 30 mg b.d. and 30 mg t.d.s. regimens were apparent only during the afternoon interval; most probably due to the additional 30 mg dose given at 13.00 h in the t.d.s. regimen.

Mean 24-h intragastric pH values were significantly higher with lansoprazole 60 mg b.d. and t.d.s. regimens by 0.8–1.0 pH units when compared to the 30 mg o.d. and 60 mg o.d. doses of lansoprazole. Significantly greater acid suppression was observed during the evening and night-time hours with lansoprazole 60 mg b.d. and t.d.s. when compared to the 30 mg o.d. and 60 mg o.d. doses. Except for the morning interval, no significant difference in the mean pH during any time interval was noted between lansoprazole 30 mg o.d. and 60 mg o.d. No significant differences in intragastric pH were noted at any time point between lansoprazole 60 mg b.d. or 60 mg t.d.s. regimens. Comparisons between mean 24-h intragastric pH for the 30 mg t.d.s. (mean 24-h pH = 5.6) and 60 mg t.d.s. (mean 24-h pH = 5.1) regimens are difficult to make because these two regimens were completed in different crossover dosing groups. In addition, there was no carryover effect is this study despite a 7-day washout period. This was not unexpected as the pharmacodynamic response of acid suppression and gastrin levels return to baseline 1–2 days after disontinuing repeated dosing of lansoprazole.9, 10

Preliminary results of a meta-analysis investigating healing rates in erosive reflux oesophagitis (GERD) showed a strong correlation between duration of time that intragastric pH was maintained above pH 4.0 and healing rate after 8 weeks of treatment.4 In this study in normal volunteers, lansoprazole administered in multiple doses (lansoprazole 30 mg t.d.s., 60 mg b.d. and 60 mg t.d.s.) produced a significantly greater percentage of time above pH 4, 5 and 6 than did lansoprazole 30 mg administered once daily. Furthermore, the lansoprazole 60 mg t.d.s. regimen confers no consistent significant advantage compared to the 60 mg b.d. regimen. Doses of lansoprazole greater than 90 mg/day (30 mg t.d.s.) did not provide a substantial incremental difference in percentage time above pH 4, 5 or 6. In a similarly designed study in normal healthy volunteers comparing the pH effect of lansoprazole 30 mg o.d., lansoprazole 30 mg b.d., lansoprazole 45 mg b.d., lansoprazole 60 mg b.d. and omeprazole 20 mg b.d., dose increments of lansoprazole 30 mg b.d. up to 60 mg b.d. did not provide a notably greater acid suppression effect.11 The percentage time above pH 3 was significantly greater with lansoprazole 30 mg b.d. (76%), lansoprazole 45 mg b.d. (78%) and lansoprazole 60 mg b.d. (81%) compared to omeprazole 20 mg b.d. (69%).11 With the exception of lansoprazole 30 mg o.d., all regimens were comparable dosage regimens with respect to the percentage time above pH 5.11

Steady-state dose–response relationships have been studied with once a day omeprazole and pantoprazole. However, there is lack of pharmacodynamic data to determine a dose-response effect with multiple daily dose administration comparing omeprazole, pantoprazole and lansoprazole. Oral administration of pantoprazole to healthy volunteers has resulted in a dose-related increase in median 24-h intragastric pH over the range 20 mg o.d. (pH 2.9) to 60 mg o.d. (pH 3.5) with minimal additional inhibition evident at 80 mg o.d. (pH 3.9) and 120 mg o.d. (pH 3.6).12, 13 Lansoprazole 30 mg o.d. and pantoprazole 40 mg o.d. have been shown to be more effective than omeprazole 20 mg o.d. in increasing intragastric pH in normal healthy volunteers with 24-h median intragastric pH values of 3.7, 3.2 and 2.75, respectively.14

Proton pump inhibitors administered concomitantly with antibiotics have demonstrated effectiveness in eradicating H. pylori. It is believed that a synergistic effect occurs with the concomitant administration of these drugs, in which the higher pH resulting from antisecretory treatment optimizes the environment for the pharmacological action of the antimicrobial agent against H. pylori15, 16 and may also increase the gastric mucosal concentrations of antibiotics.17 The influence of H. pylori serology on intragastric pH was not evaluated in this study as the subjects were not tested. Because eradication therapy against H. pylori quickly converts patients from a positive to a negative serology, the results of this study are clinically relevant.

This study provides a basis for correlating various lansoprazole dosing regimens with therapeutic effectiveness in the treatment of gastro-oesophageal reflux and peptic ulcer disease associated with H. pylori infection.

ACKNOWLEDGEMENTS

This work was supported by a grant from TAP Pharmaceuticals Inc., Deerfield, Illinois, USA.

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