Best Practice & Research Clinical Gastroenterology
`Vol. 15, No. 3, pp. 355–370, 2001
`doi:10.1053/bega.2001.0184, available online at http://www.idealibrary.com on
`
`1
`
`Pharmacological and pharmacodynamic
`essentials of H2-receptor antagonists
`and proton pump inhibitors for the
`practising physician
`
`Jia-Qing Huang MD, MSc
`Medical Research Scientist
`
`Richard H. Hunt* MD, FRCP, FRCP(Ed), FRCPC, FACG
`Professor of Medicine
`
`Division of Gastroenterology, Department of Medicine, McMaster University Medical Center, Hamilton,
`Ontario, Canada
`
`The suppression of gastric acid secretion with anti-secretory agents has been the mainstay of
`medical treatment for patients with acid-related disorders. Although the majority of Helico-
`bacter pylori-related peptic ulcers can be healed with antibiotics, ulcer healing and symptom
`control can be significantly improved when antibiotics are given with anti-secretory agents,
`especially with a proton pump inhibitor. There is a dynamic relationship between the
`suppression of intragastric acidity and the healing of peptic ulcer and erosive oesophagitis and
`control of acid-related symptoms. The suppression of gastric acid secretion achieved with
`H2-receptor antagonists has, however, proved to be suboptimal for e€ectively controlling acid-
`related disorders, especially for healing erosive oesophagitis and for the relief of reflux
`symptoms. H2-receptor antagonists are also not e€ective in inhibiting meal-stimulated acid
`secretion, which is required for managing patients with erosive oesophagitis. Furthermore,
`the rapid development of tolerance to H2-receptor antagonists and the rebound acid
`hypersecretion after the withdrawal of an H2-receptor antagonist further limit their clinical
`use. Although low-dose H2-receptor antagonists are currently available as over-the-counter
`medications for self-controlling acid-related symptoms, their pharmacology and pharmaco-
`dynamics have not been well studied, especially in the self-medicating population. Proton
`pump inhibitors have been proved to be very e€ective for suppressing intragastric acidity to
`all known stimuli, although variations exist in the rapidity of onset of action and the potency
`of acid inhibition after oral administration at the approved therapeutic doses, which may have
`important clinical implications for the treatment of gastro-oesophageal reflux disease and
`perhaps for eradicating H. pylori infection when a proton pump inhibitor is given with
`antibiotics. Once-daily dosing in the morning is more e€ective than dosing in the evening for
`all proton pump inhibitors with respect to the suppression of intragastric acidity and daytime
`gastric acid secretion in particular, which may result from a better bio-availability being
`achieved with the morning dose. When higher doses are needed, these drugs must be given
`twice daily to achieve the optimal suppression of 24 hour intragastric acidity. Preliminary
`
`*Corresponding author.
`1521–6918/01/030355(cid:135)16 $35.00/00
`
`*c 2001 Harcourt Publishers Ltd.
`
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`356 J.-Q. Huang and R. H. Hunt
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`results have shown that esomeprazole, the optical isomer of omeprazole, given at 40 mg, is
`significantly more e€ective than omeprazole 40 mg, lansoprazole 30 mg or pantoprazole
`40 mg for suppressing gastric acid secretion. However, more studies in di€erent patient
`populations are needed to compare esomeprazole with the existing proton pump inhibitors
`with regard to their e(cid:129)cacy, cost-e€ectiveness and long-term safety for the management of
`acid-related disorders.
`
`Key words: gastric acid; pepsin; acid suppression; H2-receptor antagonists; proton pump
`inhibitors; omeprazole; lansoprazole, pantoprazole; rabeprazole; esomeprazole.
`
`Over the past three decades, there have been three important advances in the
`treatment of acid-related disorders. These include the discovery of H2-receptors and
`proton pumps for controlling gastric acid secretion, the successful synthesis of H2-
`receptor antagonists (H2RAs) in the early 1970s and proton pump inhibitors (PPIs) in
`the 1980s and, more recently, the appreciation of the importance of Helicobacter pylori
`infection in the pathogenesis of peptic ulcer disease. Although the pharmacological
`inhibition of gastric acid secretion heals peptic ulcers e€ectively, recurrence inevitably
`occurs in virtually all patients after anti-secretory treatment has ceased.
`In light of our present understanding, two major forms of peptic ulcer exist: ulcers
`related to H. pylori infection and ulcers associated with the use of non-steroidal anti-
`inflammatory drugs (NSAIDs). In both cases, anti-secretory agents play an important
`role in the management of peptic ulcer disease. Furthermore, gastro-oesophageal
`reflux disease (GORD), another increasingly common acid-related disorder, is not
`associated with either H. pylori infection or NSAID use. Therefore, reducing gastric
`acid secretion and preventing the acidic gastric contents entering the oesophagus,
`causing oesophageal mucosal damage and reflux symptoms, comprise the major
`management strategy for patients with GORD.1
`Numerous controlled clinical trials have shown that the healing of acid-related
`disorders (duodenal and gastric ulcers and erosive oesophagitis) is highly correlated
`with the degree of gastric acid suppression achieved using anti-secretory agents. A
`comprehensive analysis of 24 hour intragastric acidity data obtained from patients with
`peptic ulcer disease has confirmed the hypothesis that the healing of peptic ulcers and
`the relief of acid-related symptoms are both significantly correlated with three key
`parameters of acid suppression. These are the degree and duration of acid suppression
`over the 24 hour period and the length of anti-secretory treatment in weeks.2–5 There
`is a dynamic relationship between the suppression of gastric acid secretion and the
`healing of duodenal ulcers, gastric ulcers and erosive oesophagitis. For example, the
`healing of a duodenal ulcer or erosive oesophagitis can be predicted by the proportion
`of time (expressed as a percentage of the 24 hour period) that the intragastric pH is
`above 3 (for a duodenal ulcer) or the intra-oesophageal pH is above 4 throughout the
`24 hour period.
`Results from numerous comparative clinical trials and meta-analyses of these studies
`have shown that PPIs are significantly more e€ective than H2RAs for suppressing gastric
`acid secretion and healing duodenal and gastric ulcers and erosive oesophagitis, and for
`the relief of acid-related symptoms. PPIs are also significantly more e€ective than
`H2RAs or misoprostol for preventing and healing NSAID-associated ulcer disease.6
`This chapter reviews the pharmacological and pharmacodynamic essentials of both
`H2RAs and PPIs and their clinical relevance in the management of acid-related
`disorders.
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`Pharmacology H2-antagonists and PPIs 357
`
`H2-RECEPTOR ANTAGONISTS
`
`Four H2RAs have been used worldwide for more than two decades – cimetidine,
`ranitidine, famotidine and nizatidine – roxatidine also having been marketed in a
`number of regions. These agents are specific antagonists that inhibit acid secretion by
`competitively and reversibly blocking the H2-receptors on the basolateral membrane
`of the parietal cell. The drugs di€er slightly in structure but have many similarities in
`their pharmacological properties. H2RAs only partially inhibit the acid secretion
`stimulated by gastrin and are more e€ective for inhibiting intragastric acidity during
`periods of basal acid secretion.7,8 As the longest period of basal acid secretion occurs
`nocturnally, dosing after an evening meal or at bedtime is optimal for these agents.9,10
`In an early study comparing di€erent dosing regimens of cimetidine (400 mg twice a
`day or 300 mg at night) and ranitidine (150 mg twice daily or 300 mg at night), Gledhill
`et al showed no significant di€erence between these two dosing regimens for both
`cimetidine and ranitidine in the reduction of 24 hour intragastric acidity. Nocturnal acid
`secretion was, however, controlled significantly better with ranitidine at night.9
`Furthermore, recent studies suggest that bedtime ranitidine 150 or 300 mg is more
`e€ective than bedtime omeprazole 20 mg for controlling the nocturnal acid break-
`through observed in subjects treated with omeprazole 20 mg twice daily.11,12 Acid
`breakthrough, defined as a decrease in intragastric pH to less than 4 for 1 hour or
`more, occurs nocturnally in more than 90% of subjects receiving omeprazole 20 mg
`twice daily.12 This phenomenon is considered to be driven largely by histamine.11,12
`The clinical significance of the nocturnal acid breakthrough is, however, not clear.
`Although evening dosing regimens provide prolonged nocturnal acid suppression,
`they are ine€ective for su(cid:129)ciently increasing daytime intragastric pH and cannot
`overcome food-stimulated acid secretion.13,14 Many patients do not respond to H2RAs
`despite increased dosages.15 Furthermore, H2RAs are not e€ective for suppressing
`peptic activity and pepsin secretion during the daytime, as shown in many 24 hour pH-
`monitoring studies.16–18 The suppression of nocturnal acid secretion achieved with an
`evening dose of H2RAs may therefore be more relevant for managing patients with
`duodenal ulcer than with GORD, since healing GORD requires the e€ective control
`of both daytime and night-time gastric acid secretion.
`Numerous controlled clinical trials have been published regarding the e€ects of H2RAs
`on gastric acid suppression and the relationship between the inhibition of acid secretion
`and the healing of peptic ulcers and GORD, and these have been systematically analysed
`by our group.2–5,19 Nevertheless, several interesting and important issues deserve
`further discussion, for example the development of tolerance to H2RAs, rebound acid
`hypersecretion and the pharmacodynamics and clinical uses of low-dose H2RAs.
`
`Tolerance
`
`‘Tolerance’ is a term frequently used in clinical pharmacology but often misunderstood
`and poorly explained in studies examining the e€ect of H2RAs in the treatment of acid-
`related disorders. By definition, ‘tolerance’ has developed when it becomes necessary
`to increase the dose of a drug to obtain an e€ect previously seen with a lower dose.
`This strict definition does not apply to H2RAs for several reasons:
`1.
`Increasing the dose of ranitidine does not achieve the same anti-secretory e€ect in
`the clinical situation or experimentally when given by a pH feedback pump after
`chronic oral dosing.20
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`358 J.-Q. Huang and R. H. Hunt
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`2. Clinical experience with H2RAs during chronic treatment, for example in the
`maintenance treatment of duodenal ulcer, does not support progressive pharmaco-
`logical tolerance since there is no need to increase the dose of H2RAs in order to
`keep patients in remission.21
`
`Therefore, the change of response to H2RAs may be better explained by an
`exaggerated ‘first-dose’ e€ect, as has been shown with many types of anti-hypertensive
`drugs.20
`Theoretically, the development of tolerance to H2RAs is particularly likely to occur
`when a high dose is used. This has been confirmed by several recent studies examining
`the anti-secretory e€ect of high-dose ranitidine given orally over varying periods of
`continuous treatment.22–26 Lachman and Howden examined the development of
`pharmacological tolerance to 5 day continuous treatment with ranitidine 150 mg four
`times a day, a recommended dose for treating patients with GORD.22 The mean 24 hour
`intragastric pH increased from 2.62 at pre-dosing to 4.22 on day 1 of ranitidine
`administration and 3.28 on day 5. There was a significant fall in the mean 24 hour
`intragastric pH between day 1 and day 5 of ranitidine treatment (P (cid:136) 0.001). Similar
`di€erences were also observed in the mean percentage of time that the intragastric pH
`was above 3, 4 and 5 between day 1 and day 5. However, neither the variation in
`pharmacokinetic parameters of ranitidine over the 5 days of treatment nor the subjects’
`H. pylori status could explain the decrease in the anti-secretory e€ect of ranitidine.22
`It seems that pharmacological tolerance develops even more quickly when H2RAs
`are administered intravenously rather than orally. In a study comparing the e€ects of
`intravenous ranitidine and omeprazole for treating patients with bleeding peptic ulcer,
`Labenz et al found a significant loss of anti-secretory e€ect for ranitidine (0.25 mg/kg
`per hour after a bolus of 50 mg) during the second half of a 24 hour treatment when
`the intragastric pH was below 6 for 20–46% of the time compared with 0.1–0.15% with
`omeprazole (8 mg per hour after a bolus of 80 mg).25 Furthermore, an individual dose
`titration of ranitidine has proved to be ine€ective in overcoming the loss of anti-
`secretory e€ect once tolerance has been established.24 The results of these studies may
`provide some explanation for the disappointing e€ect of H2RAs for adequately
`controlling gastric acid secretion, especially in conditions in which extended anti-
`secretory treatment is needed.
`
`Rebound acid hypersecretion
`
`A temporary increase in gastric acid secretion to above pre-treatment values after the
`abrupt withdrawal of H2RAs has been reported in many studies in both healthy
`volunteers27–29 and patients with a history of duodenal ulcer.30,31 This rebound acid
`hypersecretion may contribute to a rapid return of ulcer symptoms and ulcer
`recurrence.
`Interestingly, rebound is seen more often in subjects treated with
`cimetidine, ranitidine and nizatidine than in those receiving famotidine, although no
`direct comparison has been made between H2RAs.28,30 There is no di€erence between
`H. pylori-positive and negative subjects with respect to the degree of rebound acid
`hypersecretion.29
`The underlying mechanism of rebound acid hypersecretion is not clearly under-
`stood and cannot be associated with hypergastrinaemia.28,31 Recent animal studies have
`shown that upregulation of the H2-receptor and adenylate cyclase of the parietal cell
`may be the cause of acid hypersecretion after the withdrawal of prolonged treatment
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`with H2RAs.32 Although the rebound acid hypersecretion is a transient phenomenon,
`the clinical implications should not be ignored.
`
`Pharmacology H2-antagonists and PPIs 359
`
`Low-dose H2RAs
`Low-dose H2RAs such as ranitidine 75 mg or famotidine 10 mg have been available as
`over-the-counter medications for a few years and have proved to be e€ective and safe
`for self-controlling acid-related symptoms.33,34 Results from pharmacodynamic studies
`have shown that low-dose H2RAs are significantly more e€ective for suppressing acid
`secretion than antacids and placebo even though the onset of action with the low-dose
`H2RAs is slower than that seen with antacids.35–39
`In a three-way cross-over study comparing the anti-secretory e€ects of single-dose
`ranitidine 75 mg with cimetidine 200 mg or placebo in 24 healthy volunteers, Grimley
`et al found that ranitidine was significantly more e€ective than cimetidine or placebo
`for inhibiting intragastric acidity during both the daytime and the night-time periods.35
`The mean weighted intragastric acidity (mmol/l) in the daytime (0–10 hours post-
`dosing) was 31.03 with placebo, decreasing to 10.37 (P 5 0.001 versus placebo) with
`ranitidine and 16.23 (P 5 0.001 versus placebo) with cimetidine. Ranitidine was
`significantly more e€ective than cimetidine for controlling intragastric acidity during
`this period (P 5 0.001). During the night (10–20 hours post-dosing), similar di€er-
`ences were observed, except for the comparison between cimetidine and placebo. The
`results suggest that the acid inhibitory e€ect achieved with ranitidine 75 mg lasts
`longer than that with cimetidine 100 mg. The anti-secretory e€ect of low-dose H2RAs
`can, however, be a€ected when the drugs are taken with food.40
`It is worth pointing out that most pharmacodynamic data published in the literature
`have been obtained from healthy volunteers. It is not clear, therefore, whether these
`data can be translated easily to patients who self-medicate to control acid-related
`symptoms. More studies are needed to assess the anti-secretory e€ect of low-dose
`H2RAs in the self-medicating population with acid-related symptoms.
`
`PROTON PUMP INHIBITORS
`
`The PPIs, omeprazole, lansoprazole, pantoprazole and rabeprazole are potent acid-
`suppressing agents that inhibit the final common pathway for acid secretion by the
`parietal cell. They all contain a pyridylmethylsulphinyl benzimidazole moiety but di€er
`from each other as a result of substitutions on the pyridine or benzimidazole rings.
`The PPIs are all weak bases with a pKa of about 4, and they share a generally similar
`mechanism of action at the parietal cell. As such, they concentrate in the acidic
`compartment of the secretory canaliculus of the parietal cells and then undergo an
`acid-catalysed transformation to a tetracyclic cationic sulphenamide. The sulphenamide
`reacts with specific cysteines, which results in the inhibition of the H(cid:135), K(cid:135)-ATPase
`proton pumps.41,42 The binding is covalent with omeprazole,
`lansoprazole and
`pantoprazole, the inhibition of the activity of the acid pump being essentially
`irreversible, so the suppression of acid secretion is more complete than with other
`classes of anti-secretory drug. The substituted benzimidazoles, however, bind only to
`those pumps which are inserted into the secretory canalicular membrane and actively
`secreting acid, sparing those inactive pumps which are resting in the cytosol.43
`The inhibition of the secreting pumps results in an initially profound but time-
`dependent elevation of intragastric pH. The recovery of acid secretion depends largely
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`360 J.-Q. Huang and R. H. Hunt
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`on the rate of de novo synthesis of acid pumps and the breakdown of the covalent
`complex. When the drug concentration, after the first dose, has decreased to below
`threshold, any pumps that become inserted into the secretory canaliculus are able to
`secrete acid until the second dose. Newly active pumps are inhibited by the second
`dose, which also has a cumulative e€ect on the pre-existing pumps, although this
`cumulative inhibition of acid secretion will eventually be balanced out by newly
`synthesized pumps. Therefore, intragastric acidity is rapidly restored after a single oral
`dose of PPI.
`Twenty-four hour gastric anacidity does not occur with the once or even twice-daily
`oral administration of PPIs. In order to achieve anacidity, the continuous intravenous
`administration of a PPI may be needed. The full restoration of acid secretion, as
`measured by 24 hour intragastric pH, generally occurs 72 hours after the last dose of a
`PPI.43 Therefore, acid inhibition achieved by the PPIs targeting the proton pump is
`more e€ective than that achieved by agents targeting the parietal cell receptors.
`PPIs have been shown in numerous clinical trials to be significantly better than any
`H2RA for suppressing intragastric acidity.2–5,19 PPIs result in a prolonged and highly
`e€ective inhibition of both basal and stimulated gastric acid secretion to all known
`stimuli, including meals. The e€ect of PPIs on intragastric acidity is highly dose
`dependent, the rapidity of onset of action depending on the bio-availability of the
`individual PPI.44–46
`The PPIs also have e€ect on peptic activity, decreasing pepsin output and reducing
`secretory volume, which directly inhibits peptic activity47,48, whereas increasing the
`intragastric pH to a level greater than 4 indirectly eliminates peptic activity because
`the activation of pepsin is highly pH dependent.17 This mechanism may partly explain
`the di€erence between PPIs and H2RAs in healing peptic ulcer and especially erosive
`oesophagitis, because the intragastric pH achieved with H2RAs over a 24 hour period
`mostly still allows pepsin to show some proteolytic activity, leading to the retardation
`of mucosal healing.17
`
`Omeprazole
`
`Omeprazole was the first of the PPIs shown to be superior to H2RAs in suppressing
`gastric acid secretion, relieving symptoms and healing gastric and duodenal ulcers and
`GORD.2–5,49 Meta-analyses of clinical trials have shown a clear advantage for
`omeprazole over various dose regimens of H2RAs for the inhibition of 24 hour intra-
`gastric acidity and the healing of peptic ulcers and GORD.2–5,19 Omeprazole 20 mg in
`the morning suppresses 90% of 24 hour intragastric acidity, 88% of nocturnal acidity
`and 92% of daytime acidity, whereas the best acid suppression profile achieved with
`H2RAs occurs with ranitidine 300 mg at bedtime, which inhibits 24 hour intragastric
`acidity by 68%, nocturnal acidity by 90% and daytime acidity by 50%.2
`Although the reduction of nocturnal intragastric acidity is an important deter-
`minant of ulcer healing, the suppression of 24 hour intragastric acidity has proved to
`be more critical, especially for the management of patients with GORD. If, for
`example, the suppression of nocturnal acidity is increased from 24 to 95% by an H2RA,
`a therapeutic gain of 21% in duodenal ulcer healing can be expected at 4 weeks.
`However, when the suppression of overall 24 hour acidity is increased from 40 to 100%
`by the inclusion of the PPI e€ect, the therapeutic gain is almost doubled, to 40%.2
`Omeprazole inhibits basal and maximum acid secretion stimulated by all known
`stimuli and in a dose-dependent manner, although there are marked variations in
`individual responses to omeprazole at lower doses of 5–10 mg.50,51 In an early report,
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`Pharmacology H2-antagonists and PPIs 361
`
`Howden et al studied the e€ects of single and repeated doses of omeprazole 10 mg on
`gastric acid secretion in six healthy volunteers.50 Analyses of gastric acid secretion
`were performed on the first and seventh days of treatment, the results being
`compared with those obtained from a previous placebo study. After single doses of
`omeprazole, no significant changes in basal acid output (BAO) or pentagastrin-
`stimulated peak acid output (PAO) were seen compared with the results achieved with
`placebo. After 7 days treatment, however, there was a significant reduction in both
`BAO (93.1%) and PAO (66.5%). Pharmacokinetic studies confirmed a significant
`increase in the bio-availability of omeprazole after repeated dosing since the Cmax
`increased significantly in all subjects from 92 mg/l per hour on the first day to 193 mg/l
`per hour on the seventh day and so did the area under the plasma omeprazole
`concentration time curve from 218 mg/l per hour to 339 mg/l per hour.50
`Higher doses of omeprazole (20–80 mg daily) provide a much more predictable
`inhibition of 24 hour intragastric acidity. Omeprazole 40 mg given in the morning and
`in the evening increased the median 24 hour intragastric pH to 5.0 and 4.5, compared
`with 1.9 with placebo, after 5 days of treatment in eight healthy volunteers in a cross-
`over study. This is equivalent to an inhibition of hydrogen ion activity of over 99% for
`both omeprazole regimens.52
`The increase in the anti-secretory e€ect of omeprazole was caused by the increased
`absorption of the drug as measured by the Cmax and area under the curve (AUC).52
`This enhanced drug absorption may,
`in part, result from the pharmacological
`characteristics of omeprazole as an acid-labile compound such that its absorption
`increases as intragastric acidity decreases. Indeed, as reported in many other studies,
`the bio-availability of omeprazole increases with the duration of treatment. In healthy
`volunteers, the bio-availability of enteric-coated omeprazole 20 mg was 40% on the
`first day, increasing to 65% on the seventh day of dosing.53
`Unlike the situation with H2RAs, the morning administration of omeprazole is
`better than evening dosing for suppressing 24 hour intragastric acidity. Chiverton et al
`found that, in patients with a healed duodenal ulcer, omeprazole 20 mg given in the
`morning was significantly better than dosing in the evening for inhibiting gastric acid
`secretion.54 The mean 24 hour intragastric pH was 3.9 + 1.8 for dosing in the
`morning, 2.9 + 1.1 for the evening dose and 1.7 + 0.1 for placebo (P 5 0.01
`between the morning dose and placebo).54
`The profound suppression of 24 hour intragastric acidity also has an important
`impact on peptic activity. By plotting the frequency distribution of 24 hour intragastric
`pH against the peptic activity curve, Hirschowitz et al demonstrated that the majority
`of pH values achieved during treatment with cimetidine 1 g and ranitidine 300 mg
`daily were below 3 and within the range of maximum peptic activity, whereas
`omeprazole 30 mg daily consistently increased the intragastric pH to above 4, a level at
`which peptic activity is essentially abolished.17 This additional advantage of omeprazole
`over H2RAs may be particularly relevant to healing both peptic ulcers and especially
`erosive oesophagitis.
`
`Lansoprazole
`
`Lansoprazole was the second PPI approved for treating patients with acid-related
`disorders. In approved therapeutic doses, lansoprazole, given orally, has a higher bio-
`availability and faster onset of anti-secretory e€ect than omeprazole, although both
`agents have many similarities in structure and mechanism of action.53,55 Results from
`pharmacokinetic studies have shown that, after a single dose of lansoprazole, the
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`absolute bio-availability is 81% for the 15 mg and 85–91% for the 30 mg doses
`respectively56,57 and remains steady after repeated dosing.56 The fast onset of action with
`lansoprazole has been confirmed in a recent study in nine healthy volunteers, in whom
`once-daily lansoprazole 30 mg was given for 4 days, the maximum anti-secretory e€ect
`being obtained 6 hours after the first dose and remaining consistent with subsequent
`dosing.58
`Pharmacodynamic studies have shown that lansoprazole inhibits basal and stimulated
`gastric acid secretion dose-dependently.59,60 In an early study of the e€ect of di€erent
`doses of lansoprazole (15, 30 and 60 mg given for 1 week) on BAO and gastrin-
`stimulated maximum acid output (MAO), Mu¨ ller et al found a significant and dose-
`dependent decrease in BAO and MAO in all subjects.61 On days 2 and 8, a significant
`decrease in MAO was seen with all three doses of lansoprazole, the reduction in MAO
`observed on day 8 being more pronounced compared with the pre-treatment MAO (a
`fall of 94% for the 60 mg, 90% for the 30 mg and 69% for the 15 mg dose of lansoprazole
`respectively). Together with the decrease in MAO, the volume of gastric secretion was
`also significantly reduced. All these changes returned to normal 1 week after stopping
`the treatment, suggesting the end of inhibition of acid secretion by lansoprazole.61
`In patients with healed duodenal ulcer and acid hypersecretion, lansoprazole also
`inhibited dose-dependently and significantly the BAO and pentagastrin-stimulated
`PAO.62 All three doses of lansoprazole (10, 20 and 30 mg administered as a single dose
`in the evening) significantly inhibited the PAO after the first dose on day 1 and
`repeated doses on day 7. It seems, however, that lansoprazole at a dose of 10 mg did
`not su(cid:129)ciently inhibit the BAO even after repeated dosing for 7 days, whereas the
`BAO was e€ectively suppressed by doses of 20 and 30 mg but only on day 7.62 The less
`e€ective anti-secretory e€ect reported in this study might have resulted from the
`di€erent dosing schedule used in this study because the rate of absorption and bio-
`availability of
`lansoprazole have been shown to be lower when the dose is
`administered in the evening than with dosing in the morning.56
`Lansoprazole 30 mg given twice daily has proved to be the maximum dose
`frequency to achieve the optimal anti-secretory e€ect compared with other dose
`frequencies.60,63 Doses greater than 30 mg twice daily generally do not show any
`significant advantages over lansoprazole 30 mg twice daily in suppressing intragastric
`acidity.63 In a comparative study of multiple doses of lansoprazole (30 mg once daily,
`30 mg twice daily, 45 mg twice daily and 60 mg twice a day) and omeprazole 20 mg
`twice a day, Timmer et al have shown that lansoprazole 30 mg twice daily has the best
`anti-secretory profile in terms of the holding time that the intragastric pH was above
`564, which has been suggested as an optimal intragastric pH for combination with
`antibiotics in the eradication of H. pylori infection.43
`Several comparative studies have indicated that a single dose of lansoprazole 30 mg
`has a better e€ect than omeprazole 20 mg in suppressing intragastric acidity65–69
`because of the pharmacokinetic di€erences between the two PPIs. After the first dose,
`the bio-availability of lansoprazole is over 85% and remains constant after repeated
`dosing58,66, whereas the bio-availability of omeprazole is only 35% after the first dose and
`rises to about 60% after repeated dosing.50 The plasma half-life of lansoprazole is also
`longer and the tmax significantly shorter, hence lansoprazole 30 mg has a faster onset of
`action than omeprazole 20 mg, providing a maximum anti-secretory e€ect on day
`1.58,66,70
`Results from a comparative study have shown that, when compared with placebo,
`lansoprazole 30 mg per day decreased meal-stimulated acid secretion over a 24-hour
`period on the first day by 45.1%, followed by omeprazole 40 mg per day by 41.7%,
`
`Page 8 of 16
`
`Patent Owner Ex. 2053
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Pharmacology H2-antagonists and PPIs 363
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`lansoprazole 15 mg per day by 34.6%,and omeprazole 20 mg per day by 15.6%.66 When
`compared with the new tablet formulation of omeprazole 20 mg, lansoprazole 30 mg
`has also been shown to be more e€ective for suppressing intragastric acidity, with a
`lower individual variability.69
`Therefore, according to pharmacodynamic studies, there is a dose-dependent e€ect
`for lansoprazole and omeprazole on the suppression of intragastric acidity with a
`potency order of lansoprazole 60 mg 4 lansoprazole 30 mg (cid:129) omeprazole 40 mg 4
`omeprazole 20 mg (cid:129) lansoprazole 15 mg.66,67,69,70 The di€erence in acid suppression
`between PPIs may be of clinical importance since the relief of acid-related symptoms as
`well as the healing of gastric and duodenal ulcers and erosive oesophagitis correlates
`with the degree of suppression of intragastric acidity.2–5
`
`Pantoprazole
`Like omeprazole and lansoprazole, pantoprazole binds covalently to the H(cid:135), K(cid:135)-
`ATPase and irreversibly inhibits acid secretion by the proton pump. Although it shares
`many similarities in terms of structure and mechanism of action with the former two
`PPIs, pantoprazole is chemically more stable than omeprazole or lansoprazole under
`near-neutral conditions.46 This greater acid stability may improve the tissue selectivity
`of the drug for the parietal cell since it reduces the likelihood of the compound
`reacting with proteins containing thiol groups that lie outside the parietal cell. After a
`single oral dose, pantoprazole 40 mg is absorbed rapidly, with an average tmax of about
`2.5 hours, this being slightly longer than the tmax achieved with omeprazole (1–3
`hours) and lansoprazole (2 hours).71 The absolute bio-availability of pantoprazole has
`been reported to be 75–80%71,72, this increasing with repeated dosing. Pantoprazole
`also shows dose linearity and thus a predictable anti-secretory e€ect.73
`Pantoprazole 20–60 mg once daily given orally produces a dose-dependent inhibition
`of 24-hour intragastric acidity in both healthy volunteers and patients with peptic ulcer
`disease46,74,75, with minimal additional anti-secretory e€ects at doses above 60 mg.74,76
`Hannan et al77 studied the anti-secretory e€ects of pantoprazole 40 mg and 60 mg given
`for 5 days and found that, on day 5, the median 24 hour intragastric pH values di€ered
`significantly between placebo (pH 1.4), pantoprazole 40 mg (pH 2.3) and pantoprazole
`60 mg (pH 3.5). The holding time for the intragastric pH above 3 was also significantly
`longer with pantoprazole 40 mg (33%) and 60 mg (58%) compared with placebo (14.9%).
`This was equivalent to a decrease in 24 hour intragastric acidity of 87% with 40 mg and
`99% with 60 mg pantoprazole respectively.77
`However, in a more recent study reported by Koop et al, pantoprazole 40, 80 and
`120 mg was found to be equally e€ective for inhibiting gastric acid secretion.76 In a
`review of the pantoprazole literature, Fitton and Wiseman foun