Aliment Pharmacol Ther 1996 ; 10 : 359–366.
`
`Twenty-four-hour intragastric pH profiles and pharmacokinetics
`following single and repeated oral administration of the proton pump
`inhibitor pantoprazole in comparison to omeprazole
`
`M. H A R T M A N N, U. T H E I ß*, R. H U B E R, R. L U= H M A N N, H. B L I E S A T H, W. W U R S T & P. W. L U= C K E R*
`Byk Gulden Pharmaceuticals, Konstanz, Germany and * Institut fuW r Klinische Pharmakologie (IKP), Prof. Dr LuW cker GmbH,
`GruW nstadt, Germany
`
`Accepted for publication 3 January 1996
`
`S U M M A R Y
`
`Background : Pantoprazole is a proton pump inhibitor
`characterized by a low potential to interact with the
`cytochrome P450 enzyme system in man. Its effect on
`intragastric pH following single and repeated oral
`intake was investigated in comparison to omeprazole
`by continuous intragastric pH-metry at doses
`recommended for treatment of peptic ulcer disease.
`Methods : Sixteen healthy male subjects underwent two
`dosing periods. From day 1 to day 7, they were given
`once daily by mouth 40 mg pantoprazole in one period
`and 20 mg omeprazole in the other period, according
`to a double-blind randomized crossover design.
`Twenty-four-hour intragastric pH was recorded and
`frequent blood samples for pharmacokinetic analysis
`were taken on day 1 and day 7. A placebo pH profile
`was obtained prior to each treatment period.
`
`Results : Pantoprazole was significantly more effective
`than omeprazole with regard to increase in 24-h and
`daytime pH, following both single (median 24-h pH :
`1n45 vs. 1n3, P 0n05 ; median daytime pH : 1n6 vs.
`1n3, P 0n01) and repeated (median 24-h pH : 3n15
`vs. 2n05, P 0n01 ; median daytime pH : 3n8 vs. 2n65,
`P 0n05) oral intake. As compared to the first dose,
`repeated administration of both drugs markedly
`increased the effect on intragastric pH. With
`pantoprazole, steady-state serum concentrations were
`obtained after the first dose, but not with omeprazole.
`Both drugs were well tolerated without relevant
`changes in vital signs of clinical laboratory parameters.
`Conclusion : Pantoprazole 40 mg is significantly more
`effective than omeprazole 20 mg in raising intragastric
`pH.
`
`I N T R O D U C T I O N
`
`Pantoprazole is a proton pump inhibitor with a low
`potential to interact with the cytochrome P450 system
`both in animals" and in man.#, $ Its potency to inhibit
`gastric acid secretion has already been shown with the
`aspiration technique during pentagastrin stimulation.%–'
`In patients suffering from acid-related diseases 40 mg
`was shown to be the optimal therapeutic dose,( and high
`healing rates and rapid pain relief have been established
`in gastric and duodenal ulcers as well as in gastro-
`
`Correspondence to : Dr med. M. Hartmann, Byk Gulden Pharmaceuticals,
`Byk-Gulden-Strasse 2, 78467 Konstanz, Germany.
`
`reflux disease.)–"!
`In comparison to
`oesophageal
`ranitidine, pantoprazole accelerates healing and symp-
`tom relief in gastroduodenal ulcers, and in reflux oeso-
`phagitis it also improves the rate of healing.) With regard
`to gastric ulcer patients, pantoprazole 40 mg seems to be
`even more effective than omeprazole 20 mg.* Further-
`more, pantoprazole was highly effective in healing
`ranitidine-resistant peptic ulcers, and long-term main-
`tenance therapy was well tolerated.""
`It was the aim of this study to investigate the intragastric
`pH profiles following single and repeated oral adminis-
`tration of pantoprazole 40 mg in comparison to
`omeprazole 20 mg under the conditions of normal life.
`
`# 1996 Blackwell Science Ltd
`
`359
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`360 M. H A R T M A N N et al.
`
`The doses chosen reflect the recommendations for treat-
`ment of peptic ulcer disease.
`
`E T H I C S
`
`The study was approved by an ethics committee, and
`performed according to the revised Declaration of
`Helsinki and in compliance with the rules of Good Clinical
`Practice. The subjects were given comprehensive verbal
`and written information, and written informed consent
`was obtained before the start of the study.
`
`S U B J E C T S A N D M E T H O D S
`
`Subjects
`
`Protocol-correct data from 16 subjects had to be available
`for the statistical evaluation. In total, 18 male subjects
`were admitted to the study. All were assessed as healthy
`based on physical examination, medical history and
`routine clinical laboratory screening. Two were with-
`drawn for reasons not related to the treatment. Sixteen
`completed the whole study. Their age ranged from 21 to
`35 (median : 29) years, their body weight ranged from 60
`to 88 (median : 74) kg.
`
`Study design
`
`The study was performed by the contract house Institut
`fu$ r klinische Pharmakologie according to a randomized
`two-period crossover design. Each subject underwent
`two dosing periods of 9 days each in randomized order.
`On days k2 and k1 of both periods, placebo was
`administered orally. From days 1 to 7, the subjects were
`given once daily by mouth 40 mg pantoprazole in one
`period, and 20 mg omeprazole in the other period under
`double-blind conditions. During each period, the subjects
`stayed at the Institut fu$ r klinische Pharmakologie. Blood
`was taken on days 1 and 7 of both periods, before and at
`0n5, 1, 1n5, 2, 2n5, 3, 3n5, 4, 4n5, 5, 6, 7, 8, 10, 12 and
`24 h after intake of drug. Both dosing periods were
`separated by a washout period of at least 2 weeks.
`
`Medication
`Pantoprazole. 45n11 mg pantoprazole sodium sesqui-
`hydrate (two enteric-coated tablets each containing
`22n56 mg), corresponding to 40 mg pantoprazole (Byk
`Gulden Pharmaceuticals, Konstanz, Germany).
`
`Omeprazole. One capsule containing 20 mg omeprazole,
`as enteric-coated granules
`(commercially available,
`Antra, Astra Chemicals, Wedel\Hamburg, Germany).
`To obtain double-blindness, two tablets of pantoprazole
`or one capsule of omeprazole were filled in identical hard
`gelatine capsules. Identical placebo capsules were also
`provided by Byk Gulden Pharmaceuticals.
`
`Dietary
`
`Medication was administered under fasting conditions
`around 09.00 h in the morning together with 200 mL
`tap water. Breakfast, lunch and dinner were identical on
`each study day with pH-metry (days k2, 1, 7) and taken
`2, 6 and 10 h after oral administration.
`
`pH-metry
`
`Intragastric pH was recorded continuously over 24 h
`using a DL 7-recorder (Autronic GmbH, Karlsruhe,
`Germany) and glass electrodes (LOT 440-M4, Ingold,
`Urdorf, Switzerland). Before use, the electrodes were
`calibrated at pH 4 and 1. The electrodes were inserted
`through the nose up to the pH-decrease when passing the
`cardia. Then they were pushed forward for another
`5–7 cm. The length of the probe for each volunteer was
`documented in order to attain the same gastric region for
`all measurements.
`
`Pharmacokinetic analysis
`
`Pantoprazole-Na serum concentrations were determined
`by reversed-phase HPLC using a gradient technique and
`UV-detection at a wavelength of 286 nm."# Sample
`workup was performed on-line by direct injection of
`200 lL of untreated serum on a precolumn. The limit of
`quantitation was 0n03 mg\L. Serum concentrations
`were expressed as pantoprazole-Na.
`Omeprazole serum concentrations were analysed using
`the same HPLC method as for pantoprazole-Na, the only
`difference being the wavelength used for UV-detection,
`which was chosen at 301 nm for omeprazole. The
`line was : Y l
`equation
`for
`the
`calibration
`0n9938iXk0n0032. The accuracy at these concen-
`trations ranged between k22n7 % (0n015 mg\L) and
`j3 % (0n2 mg\L). The limit of quantitation was set at
`0n01 mg\L, the accuracy and precision at this con-
`centration being 21 and 6n0 %. The recoveries at concen-
`trations between 0n1 and 2 mg\L were between 101n0 %
`
`# 1996 Blackwell Science Ltd, Aliment Pharmacol Ther 10, 359–366
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`2 4-H p H W I T H P A N T O P R A Z O L E O R O M E P R A Z O L E
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`361
`
`Figure 1. Median pH profiles (n l 16, first\third quartile) after placebo and the first and seventh oral intake of pantoprazole 40 mg and
`omeprazole 20 mg. M l medication (placebo : day k2 ; drug : days 1–7), B l breakfast, L l lunch, D l dinner.
`
`(0n1 mg\L) and 106n4 % (1n0 mg\L). The precision was
`determined at 0n1, 0n5 and 2n0 mg\L and gave
`coefficients of variation of 2n47, 1n05 and 1n53 %,
`respectively.
`
`Statistical evaluation
`
`Efficacy. The median pH of the following time intervals
`was calculated for each subject and each profile :
`
`# 1996 Blackwell Science Ltd, Aliment Pharmacol Ther 10, 359–366
`
`total : 0–24 h post-administration (09.00–09.00 h) ;
`day : 0–14 h post-administration (09.00–23.00 h) ;
`night : 14–21 h post-administration (23.00–06.00 h).
`Confirmative inference statistical analysis was per-
`formed for the 24-h intervals. Separate analyses for day
`and night were only considered as supportive data.
`The comparison between the two treatments in terms of
`verum minus placebo was done non-parametrically with
`regard to the two-period crossover design using the test
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`362 M. H A R T M A N N et al.
`
`Table 1. Intragastric pH after single and repeated oral intake of pantoprazole and omeprazole
`
`Time after intake
`(clock time)
`
`0–24 h (09.00–09.00)
`
`0–14 h (09.00–23.00)
`
`14–21 h (23.00–06.00)
`
`Treatment
`
`Placebo
`First intake
`Seventh intake
`Placebo
`First intake
`Seventh intake
`Placebo
`First intake
`Seventh intake
`
`Pantoprazole 40 mg
`
`Omeprazole 20 mg
`
`Median
`N l 16
`
`1n20
`1n45
`3n15
`1n40
`1n60
`3n80
`1n00
`1n15
`1n50
`
`68 % range
`
`1n10–1n60
`1n40–1n90
`1n90–3n80
`1n10–2n00
`1n40–2n80
`2n20–4n50
`0n90–1n40
`1n10–1n90
`1n20–2n50
`
`Median
`N l 16
`
`1n20
`1n30
`2n05
`1n40
`1n30
`2n65
`1n00
`1n10
`1n40
`
`68 % range
`
`1n00–1n50
`1n10–1n50
`1n40–3n30
`1n10–1n60
`1n20–1n60
`1n50–4n20
`0n70–1n20
`0n90–1n20
`1n10–2n20
`
`Test
`
`*
`**
`
`**
`*
`
`N.S.
`N.S.
`
`Koch’s crossover test procedure based on differences drug–placebo. * P 0n05, ** P 0n01, N.S. l not significant.
`
`procedure described by Koch"$ for single dose and steady
`state separately.
`In order to compare the results of this study with
`published data on omeprazole, the per cent reduction of
`intragastric acidity was additionally calculated. This was
`done by transfering the pH values of each experiment to
`hydrogen ion activity using the formula : mmol\L l
`10−pHi1000. Then, the arithmetic mean was calculated
`for each experiment and group medians were derived
`thereof.
`
`Pharmacokinetics
`
`#
`
`The following pharmacokinetic characteristics were de-
`termined for both pantoprazole-Na and omeprazole : area
`under the concentration–time curve (AUC), maximum
`serum concentration (Cmax), the time of its occurrance
`).
`(tmax) and terminal elimination half-life (t"
`Cmax and tmax were obtained directly from the
`concentration–time profiles. The area under
`the
`concentration–time curve (AUC
`!–_ on day 1, AUC
`!–#% h
`on day 7) was determined by the trapezoidal rule as
`described previously."%
`Relative bioavailability (day 7 vs. day 1) of both
`pantoprazole and omeprazole was assessed by the in-
`dividual ratios test\reference of the corresponding AUCs
`(extent of absorption) and Cmax values (rate of absorp-
`tion). Point estimates and shortest 90 % confidence limits
`after logarithmic transformation were given for the ratios
`of the population medians of day 7 (test) and day 1
`(reference).
`
`R E S U L T S
`
`Safety and tolerability
`
`Both drugs were well tolerated. There were no clinically
`relevant changes in vital signs, ECG or clinical laboratory
`parameters nor were there relevant adverse events.
`
`Efficacy
`
`The reliability of the method used is shown by almost
`identical pH profiles and pH values following the placebo
`administration preceding each active dosing period
`(Figures 1 and 2, Table 1). Following the first dose, only
`a slight increase in median pH was observed with both
`drugs (Figure 1 and Table 1), however, pantoprazole was
`significantly more effective than omeprazole. The median
`reduction of
`intragastric acidity was 21 % with
`omeprazole and 37 % with pantoprazole.
`Repeated once daily administration led to pharmaco-
`dynamic accumulation of the effect on intragastric pH.
`On day 7, a marked increase in 24-h and daytime median
`pH was observed, which was significantly in favour of
`pantoprazole (Figure 1 and Table 1). In terms of median
`acidity, this means 80 % reduction with omeprazole,
`while with pantoprazole 98 % reduction was calculated
`for the 24-h period.
`During the night, the pH values decreased to almost
`placebo level. Only a slight increase in median pH of
`about 0n5 pH units in comparison to placebo was
`observed without statistically significant differences be-
`
`# 1996 Blackwell Science Ltd, Aliment Pharmacol Ther 10, 359–366
`
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`2 4-H p H W I T H P A N T O P R A Z O L E O R O M E P R A Z O L E
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`363
`
`the increase caused by pantoprazole was higher than
`that with omeprazole. Thus the individual data support
`the central tendency found in the statistical analysis.
`
`Pharmacokinetics
`
`The pharmacokinetic characteristics of pantoprazole
`following repeated administration (day 7) were similar to
`those after the first dose (day 1), while with omeprazole a
`41 % increase in AUC and a 32 % increase in Cmax were
`observed. The point estimates (90 % confidence inter-
`vals) for AUC and Cmax were 1n05 (0n91, 1n21) and 1n21
`(0n97, 1n50) for pantoprazole, and 1n41 (1n09, 1n84) and
`1n32 (1n04, 1n68) for omeprazole, respectively. Maxi-
`mum serum concentrations were observed after about
`3 h with pantoprazole and after about 1 h with
`omeprazole. t"
`was less than 1 h for both drugs (Table 2).
`Compared with pantoprazole,
`administration of
`omeprazole seemed to be followed by a greater variability
`of the serum concentration–time profiles (Figure 3).
`
`#
`
`Figure 2. Individual median 24-h pH values following placebo
`and the first and seventh daily oral intake of omeprazole and
`pantoprazole.
`
`tween the two drugs. In the early morning, pH increased
`again with both drugs, the increase observed with
`pantoprazole being higher than with omeprazole.
`Individual 24-h median pH values are shown in Figure
`2. The course of the median pH values was similar in
`both treatment periods within subjects, but, in general,
`
`D I S C U S S I O N
`
`The pH-elevating effect of both pantoprazole 40 mg and
`omeprazole 20 mg increased during repeated once daily
`administration. The results were significantly in favour
`of pantoprazole following both single and repeated
`administration. Increasing the dose of omeprazole from
`20 to 40 mg reveals similar pH values compared with
`pantoprazole 40 mg."& Consistently,
`treatment with
`40 mg pantoprazole appears to result in slightly higher
`healing rates in duodenal ulcer (95 vs. 91 % with
`omeprazole 20 mg at 4 weeks, N.S.) and in gastric ulcer
`
`Table 2. Pharmacokinetic characteristics of pantoprazole-Na and omeprazole
`
`Pantoprazole 40 mg
`
`Omeprazole 20 mg
`
`Day 1
`
`Day 7
`
`Day 1
`
`Day 7
`
`Geometric mean (68 % range)
`1n99 (1n14–3n47)
`2n09 (1n34–3n26)
`0n92 (0n73–1n16)
`0n78 (0n53–1n15)
`1n33 (0n69–2n58)
`1n34 (0n48–3n69)
`Median (68 % range)
`2n75 (2n50–3n50)
`
`3n00 (2n00–3n00)
`
`Geometric mean (68 % range)
`0n20 (0n13–0n32)
`0n28 (0n14–0n56)
`0n50 (0n40–0n64)
`0n58 (0n42–0n81)
`0n139 (0n08–0n25)
`0n184 (0n10–0n32)
`Median (68 % range)
`1n25 (0n50–2n00)
`
`1n00 (0n50–2n50)
`
`!–_ or AUC!–#% h (mgih\L)
`
`
`AUC
`(h)
`t"
`Cmax (mg\L)
`
`#
`
`tmax (h)
`
`# 1996 Blackwell Science Ltd, Aliment Pharmacol Ther 10, 359–366
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`364 M. H A R T M A N N et al.
`
`Figure 3. Individual serum concentration–time profiles following single (day 1) and repeated (day 7) oral intake of pantoprazole and
`omeprazole. Note the different concentration scales.
`
`patients (88 vs. 77 % with omeprazole 20 mg at 4 weeks,
`P 0n05).*
`Even after repeated administration, both drugs were
`mainly effective during the day and showed only minor
`effects on night-time pH. In particular, the efficacy during
`the day was a result of the suppression of post-prandial
`acid secretion. The decrease in intragastric pH during the
`night was followed by an increase in the early morning,
`the reason for this finding being not yet clear. Comparable
`results, obtained by use of the aspiration technique, have
`been reported for omeprazole"' and lansoprazole."( The
`results of the present study and published results on
`omeprazole and lansoprazole suggest that proton pump
`inhibitors maintain the circadian rhythm in intragastric
`pH in healthy volunteers, the pH values, however, being
`shifted to higher levels.
`The increase in intragastric pH on day 7 of once daily
`
`dosing with 20 mg omeprazole appears to be low.
`However, the median pH profile is quite similar to
`published results."' Furthermore, omeprazole reduced
`median intragastric acidity by 80 % in the present study,
`which is well within the range of mean values of 60–90 %
`reported
`for
`repeated
`administration of 20 mg
`omeprazole."', ") As to pantoprazole, the median 24-h pH
`is within the range of previous studies."*
`It has to be taken into account that the results of the
`present study were obtained in healthy volunteers. There
`is growing evidence that the antisecretory effect of proton
`pump inhibitors, in particular during the night, is higher
`in duodenal ulcer patients than in normal healthy
`subjects,"', #! a finding which is most probably explained
`by differences in the Helicobacter pylori infection rate.#"
`Hence, pH-metry studies in normal young healthy
`volunteers, usually Helicobacter pylori-negative, might
`
`# 1996 Blackwell Science Ltd, Aliment Pharmacol Ther 10, 359–366
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`2 4-H p H W I T H P A N T O P R A Z O L E O R O M E P R A Z O L E
`
`365
`
`underestimate the effect of proton pump inhibitors in
`patients. The results from an intra-individual compari-
`son, however, will not be affected by the Helicobacter
`pylori status which was not assessed in this study.
`As to pharmacokinetics, pantoprazole has shown the
`more predictable results. The pharmacokinetic charac-
`teristics following repeated administration were com-
`parable to those after the first dose, that is its full
`bioavailability is already reached after the first dose. In
`contrast, with omeprazole a 41 and 32 % increase in AUC
`and Cmax, respectively, was found, consistent with
`published results of lower bioavailability at the beginning
`of the treatment."', ##, #$ Maximum serum concentrations
`were observed about 3 h and 1 h following oral intake of
`pantoprazole and omeprazole, respectively, a difference
`which is considered to be without clinical relevance as
`there were no changes in the time course of the pH
`profiles. Despite the short elimination half-lives of less
`than 1 h for both drugs, intragastric pH increased upon
`repeated once daily dosing. This demonstrates, that the
`duration of action is far longer than the period during
`which serum concentrations are measurable. This is
`thought to be a result of covalent binding of substituted
`benzimidazoles to the gastric H+, K+-ATPase.
`In conclusion, pantoprazole was shown to be a potent
`inhibitor of intragastric acidity, and pantoprazole 40 mg
`was significantly more effective than omeprazole 20 mg
`with regard to acid inhibition.
`
`A C K N O W L E D G E M E N T S
`
`for
`to Dr S. Postius, Byk Gulden,
`We are grateful
`evaluation of the pH-metries. We are also grateful for
`skilful technical assistance to Mrs C. Eichberger, Mrs A.
`Wiedemann, Mr M. Kretschmer and Mr U. Bra$ uer.
`
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`
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