Aliment Pharmacol Ther 2000; 14: 963–978.
`
`Review article: comparison of the pharmacokinetics,
`acid suppression and efficacy of proton pump inhibitors
`
`C. A. M. STEDMAN* & M. L. BARCLAY* ,(cid:160)
`*Departments of Gastroenterology and (cid:160)Clinical Pharmacology, Christchurch Hospital, Christchurch, New Zealand
`
`Accepted for publication 16 March 2000
`
`SUMMARY
`
`Proton pump inhibitors have dramatically influenced
`the management of acid-peptic disorders in recent years.
`They all have a broadly similar mechanism of action and
`are extensively metabolized in the liver via cytochromes
`P450 2C19 and 3A4. There is some variation in their
`potential
`for drug interactions due to differences in
`enzyme inhibition. Relatively few serious adverse effects
`have been reported for the proton pump inhibitors.
`Comparative studies of acid suppression suggest that
`lansoprazole and pantoprazole have a potency similar to
`that of omeprazole on a mg for mg basis; however,
`rabeprazole may have a greater potency than
`
`omeprazole. Lansoprazole and rabeprazole display a
`more rapid onset of maximal acid suppression than the
`other proton pump inhibitors.
`Comparative studies using proton pump inhibitors for
`the treatment of reflux oesophagitis, duodenal ulcer
`healing and Helicobacter pylori eradication show little
`overall difference in outcome between the proton pump
`inhibitors when used
`in their
`standard
`doses.
`Lansoprazole and rabeprazole provide earlier and
`better symptom relief than the other proton pump
`inhibitors in some studies of peptic ulcer treatment. The
`few studies of gastric ulcer treatment suggest that there
`is an advantage in using the proton pump inhibitors
`that have a higher standard daily dose.
`
`INTRODUCTION
`
`Proton pump inhibitors have influenced the manage-
`ment of acid-peptic disorders dramatically over the last
`10 years. Three of
`these agents are now widely
`available; omeprazole (available since 1989),
`lansop-
`razole (1995), and pantoprazole (1997). Rabeprazole is
`now also becoming available in some countries.
`These agents selectively and irreversibly inhibit the
`gastric hydrogen/potassium adenosine triphosphatase
`(H+/K+-exchanging ATPase), part of the ‘proton pump’
`that performs the final step in the acid secretory
`process.1 They thereby inhibit both basal and stimulated
`secretion of gastric acid, independently of the nature of
`parietal cell stimulation.1–2 Clinical uses include the
`treatment of peptic ulcer disease, gastro-oesophageal
`
`1
`
`Dr M. L. Barclay, Department of Clinical Pharmacology,
`Correspondence to:
`Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand.
`
`reflux disease, Barrett’s oesophagus, Zollinger–Ellison
`Syndrome, and the eradication of Helicobacter pylori as
`part of combination regimens.
`In this review, all
`four agents are compared with
`regard to pharmacokinetics, potency, acid suppression,
`clinical efficacy and toxicity, and potential
`for drug
`interactions. There are fewer comparative data avail-
`able for rabeprazole, but this is included where such
`data are available. In general, only studies directly
`comparing two or more of these agents have been
`included, although other data have been used in some
`cases when no direct comparison studies were available.
`
`STRUCTURE AND MECHANISM OF ACTION
`
`Proton pump inhibitors are all substituted benzimida-
`zole derivatives (Figure 1). They function as pro-drugs,
`accumulating within the parietal cell canaliculus where
`acid-catalysed conversion of the pro-drug to a tetracy-
`
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`
`Figure 1. Structural formulae of the proton pump inhibitors omeprazole, lansoprazole, pantoprazole and rabeprazole and the
`tetracyclic sulphenamide to which they are converted in the parietal cell canaliculus after protonation.
`
`clic planar sulphenamide occurs (Figure 1).3 The sul-
`phenamide then binds covalently to key cysteine groups
`on the proton pump to cause prolonged inhibition of
`gastric acid secretion.1–2 Acid production by the proton
`pump can generally only be restored through endoge-
`nous synthesis of the H+K+-exchanging ATPase, which
`has a half-life of production of approximately 50 h.1
`However, rabeprazole differs because it converts more
`rapidly to the activated sulphenamide form than the
`other proton pump inhibitors and also dissociates more
`
`readily from the H+K+-ATPase, resulting in both a faster
`rate of inhibition and also a shorter duration of action.4–5
`The drugs are weak bases and accumulation within
`the acidic parietal cell canaliculus is dependent on the
`pH gradient and pK of each agent. The pH of the parietal
`cell canaliculus is 0.8, whereas that of other acidic
`compartments such as lysosomes is 4.5–5.1–3 The
`important site of protonation for accumulation of these
`drugs is the pyridine N (Figure 1). All four of the proton
`pump inhibitors have a pyridine N pK of less than 4.5,
`
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`REVIEW: COMPARISON OF THE PROTON PUMP INHIBITORS
`
`965
`
`which should favour selectivity of the drugs for the
`parietal cell. The pK of the pantoprazole pyridine N
`(3.96) is slightly lower than that of omeprazole (4.13)
`or lansoprazole (4.01), although this difference has not
`been shown to be of direct clinical significance.2 The pK
`for the N of the benzimidazole rings are all much lower.1
`The drugs all have similar high levels of activation at a
`very low pH, whereas in the near neutral pH range of
`4–6, pantoprazole is more chemically stable and less
`activated, and rabeprazole is less stable than the other
`two drugs.5–6 The conversion rate from the pro-drug to
`the active sulphenamide is slower for pantoprazole.1, 2
`Acid inhibition is not necessarily maximal after the
`first dose. Acid catalysed activation of the drug is
`necessary, so only activated parietal cells will be
`inhibited, whereas resting parietal cells (approximately
`25% of the cell mass) will escape initial inhibition.1 Both
`pantoprazole and omeprazole display an increase in acid
`inhibitory effect over several days of repeated adminis-
`tration, whereas acid inhibition with lansoprazole is
`maximal after the first dose.7–8
`The mechanism of action is similar for all of the proton
`pump inhibitors, and they all bind to one common
`distinct site on the alpha subunit of the proton pump
`(probably cysteine 813 on the luminal loop between
`transmembrane domains 5 and 6). Pantoprazole may
`also bind to the adjacent cysteine 822, and omeprazole
`to cysteine 892. Lansoprazole and rabeprazole both bind
`to additional sites at cysteine 892 and cysteine 321.9
`Pantoprazole has greater selectivity for the cysteine
`813/822 sites, but the clinical significance of these
`differences is unclear.1–2
`
`The drugs are all acid-labile, so when administered
`orally they must be formulated in an enteric coating to
`protect them from rapid degradation in the stomach.
`They are rapidly absorbed in the duodenum.
`
`PHARMACOKINETICS
`
`The values for the main pharmacokinetic parameters
`for the proton pump inhibitors are shown in Table 1 for
`comparison.
`There is a poor correlation between maximal plasma
`drug concentration (Cmax) and the degree of acid
`suppression in studies of omeprazole. The maximal
`plasma drug concentration varies widely depending on
`the rate of passage in the gastrointestinal tract, release
`of drug and intraduodenal pH.8 However, the area
`under the plasma concentration–time curve (AUC) does
`correlate well with acid suppression, and the area under
`the same curves for omeprazole 20 mg (0.2–1.2 lg Æ h/
`mL) and rabeprazole 20 mg (0.8 lg Æ h/mL) or 40 mg
`(1.0 lg Æ h/mL) are significantly lower than for panto-
`prazole 20 mg (2 lg Æ h/mL) or 40 mg (4.6–4.9 lg Æ h/
`mL), or lansoprazole 30 mg (1.7–5 lg Æ h/mL).8, 11–12
`The proton pump inhibitors all have similar short
`plasma half-lives of elimination at approximately 1 h
`and are therefore unlikely to accumulate even when
`clearance is significantly reduced.8–11, 13 However, the
`duration of acid inhibition is relatively long (48–72 h)
`because of the irreversible binding of the sulphenamide
`to the H+K+-ATPase. Rabeprazole has a shorter dur-
`ation of action as it can dissociate to a greater extent
`than the other drugs.
`
`Table 1. Comparison of the pharmacokinetics of the proton pump inhibitors (results expressed as reported range)
`
`Pharmacokinetic parameters
`
`Omeprazolea 20 mg
`
`Pantoprazoleb 40 mg
`
`Lansoprazolec 30 mg
`
`Rabeprazoled 20 mg
`
`AUC (lg Æ h/mL)
`Cmax (lg/mL)
`Tmax (h)
`t1/2 (h)
`Cl (L Æ h/kg)
`Vd (L/kg)
`Bioavailability (%)
`
`Protein binding (%)
`Dose linearity
`
`0.2–1.2
`0.08–8
`1–3
`0.6–1
`0.45
`0.31–0.34
`Variable 35 fi 65
`(with repeated doses)
`95
`non-linear
`
`2–5
`1.1–3.3
`2–4
`0.9–1.9
`0.08–0.13
`0.13–0.17
`Constant
`57–100
`98
`linear
`
`1.7–5
`0.6–1.2
`1.3–2.2*
`0.9–1.6
`0.2–0.28
`0.39–0.46
`Constant
`80–91
`97–99
`linear(cid:224)
`
`0.8
`0.41
`3.1(cid:160)
`1
`0.50
`
`95–98
`linear
`
`Data from References: a 2, 7, 10, 15, 16, 18, 27, 62; b 2, 6, 11, 15, 101; c 2, 8, 10, 12, 13, 16, 92; d 4.
`AUC, area under the concentration curve; Cmax, maximum serum concentration; Tmax, time to maximum serum concentration; t1/2,
`elimination half-life; Cl, drug clearance; Vd, apparent volume of distribution.
`* Delayed to 3.5–3.7 with food; (cid:160)delayed by 1.7 h with food; (cid:224)non-linear in some studies for doses < 20 mg and intravenous administration.
`
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`966
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`C. A. M. STEDMAN & M. L. BARCLAY
`
`the proton pump
`The oral bioavailabilities (F) of
`inhibitors differ significantly. The oral availability of
`omeprazole is initially low at approximately 35–40%
`but increases to about 65% on repeated dosing.7, 10 This
`may reflect improved drug absorption associated with
`increases in gastric pH and reduced breakdown of the
`acid-labile drug in the stomach. In contrast, pantopra-
`zole has a constant bioavailability of approximately
`77%, independent of dose.11 Lansoprazole also has a
`constant high bioavailability of 80–91% at therapeutic
`doses, although studies have shown that bioavailability
`is reduced at doses lower than 20 mg/day.8, 13
`For pantoprazole and rabeprazole, there is a linear
`relationship between dose and plasma concentra-
`tions after the administration of single and multiple
`doses.5, 11, 14, 15 For omeprazole the kinetics are
`dose-dependent, with non-linear increases in maximal
`plasma drug concentration occurring with increasing
`doses.7 For lansoprazole, there is a linear increase in
`maximal plasma drug concentration and the area under
`the plasma concentration–time curve in relation to the
`dose administered at standard therapeutic doses.8
`All of the proton pump inhibitors are highly protein
`bound (> 95%), rapidly metabolized in the liver and
`have negligible renal clearance.
`
`Pharmacokinetics in special populations
`
`A summary of the pharmacokinetics of the proton pump
`inhibitors in special situations is given in Table 2. Food
`has been shown to result in delayed absorption of
`lansoprazole, with a reduction in maximal plasma drug
`concentration and F in some studies but not
`in
`others.8, 12, 16, 17 Similar effects have been seen with
`omeprazole and pantoprazole, but these have been of
`
`borderline significance.15 Concurrent administration of
`antacids has been reported to result in a slight reduction
`in bioavailability of lansoprazole but this has not been
`shown for omeprazole or pantoprazole.8, 18, 19
`Renal impairment would not be expected to signifi-
`cantly alter the pharmacokinetics of these drugs as they
`are highly metabolized. Whilst there are studies con-
`firming this for the three older drugs, there are some
`studies with conflicting results for both lansoprazole and
`pantoprazole.11, 20–22 However, these small effects are
`unlikely to be clinically significant.
`significant
`In contrast,
`studies have shown that
`hepatic impairment results in a seven to ninefold
`increase in the area under the plasma concentration–
`time curve and a prolongation of the half-life to 4–8 h
`for all proton pump inhibitors.20–24 This could poten-
`tially result in an increase in dose-related side-effects
`although this has not been confirmed clinically. It is
`unlikely to result in significant drug accumulation, as
`these drugs are generally administered once daily.
`However, it would seem reasonable to use lower doses
`in this population, as the desired therapeutic effect
`should be obtainable at a lower dose. Consistent with
`the expected effects of ageing on physiological function,
`the area under the plasma concentration–time curve of
`these drugs also increases by up to 50–100% in the
`elderly.11, 25 Drug clearance is reduced with increasing
`age and the half-life of elimination increases to approxi-
`mately 1.5 h in the elderly.11, 26
`Three per cent of the population are poor metabolizers
`of proton pump inhibitors, with a reduction in clearance
`that is associated with an increase in half-life and a five
`to tenfold increase in the area under the plasma
`concentration–time curve. Studies show that there is
`co-segregation of S-mephenytoin polymorphism with
`
`Table 2. The effects of different conditions on the pharmacokinetics of the proton pump inhibitors
`
`Omeprazolea
`
`Pantoprazoleb
`
`Lansoprazolec
`
`Rabeprazoled
`
`Food-effect on absorption
`
`Minimal
`
`Minimal
`
`Concurrent antacid use
`Renal impairment
`Hepatic impairment
`
`Elderly
`
`No change
`No change
`›AUC +++
`›t1/2 +++
`flCl
`›AUC, ›t1/2
`
`No change
`Conflicting results
`›AUC +++
`›t1/2 +++
`flCl
`›AUC
`
`Delayed absorption, flCmax,
`flF (some studies)
`Conflicting results
`Conflicting results
`›AUC +++
`›t1/2 +++
`flCl
`›AUC, ›t1/2
`
`Minimal
`
`—
`—
`›AUC +
`›t1/2 +
`—
`
`Data from References: a 6, 16, 18, 23; b 6, 11, 15, 18, 19, 22, 23, 26, 62, 92, 101; c 6, 8, 12, 16, 17, 20, 23, 25, 92; d 24, 111.
`AUC, area under the concentration curve; Cmax, maximum serum concentration; Tmax, time to maximum serum concentration; t1/2,
`elimination half-life; Cl, drug clearance; Vd, apparent volume of distribution; ()), not tested; (+), small change; (+++), large change.
`
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`REVIEW: COMPARISON OF THE PROTON PUMP INHIBITORS
`
`967
`
`proton pump inhibitor normal and poor metabolizers,
`suggesting that metabolism is via CYP 2C19.4, 27–29
`
`Cytochrome P450 enzyme metabolism
`
`Proton pump inhibitors are metabolized in the liver by
`P450 cytochromes and this subject has been reviewed
`previously.18, 29–31 All four proton pump inhibitors are
`metabolized by CYPs 2C19 and 3A4 to varying degrees.
`Omeprazole is metabolized predominantly by CYP 2C19
`(responsible for 80% of clearance) with dose-dependent
`enzyme saturation, and has a lower affinity for CYP 3A4,
`which may function as a high capacity enzyme that
`prevents very high omeprazole concentrations.31–33
`Lansoprazole is also metabolized by CYPs 2C19 and
`3A4, although the relative importance of each enzyme is
`less clear.28, 31, 33 Although pantoprazole is metabolized
`by both CYPs 2C19 and 3A4, it differs in that it has a
`lower affinity for P450, and is also subsequently metab-
`
`olized by a sulphotransferase, which is non-saturable and
`not part of the CYP system.2, 34–36
`Table 3 shows the results of studies that have inves-
`tigated possible interactions between the proton pump
`inhibitors and other drugs that may result via effects on
`the CYP450 enzymes. There is some evidence that
`omeprazole and lansoprazole may be weak inducers of
`CYPs 1A1 and 1A2. Concurrent administration of
`lansoprazole results in increased theophylline metabo-
`lism (area under the plasma concentration–time curve
`decreases by 13%).37–38 In addition, caffeine metabo-
`lism is increased in people on high doses of omeprazole,
`although other studies have shown little or no effect on
`caffeine metabolism when using low doses of omepra-
`zole in extensive metabolisers.39–42 At present these
`interactions appear unlikely to be of clinical signifi-
`cance. CYP 3A4 is induced by omeprazole and lansop-
`razole in human hepatocyte cultures but no clinically
`significant interactions with drugs metabolized by CYP
`
`Table 3. Proton pump inhibitor interactions with other drugs via CYP 450 metabolism
`
`CYP 450 enzyme/drug tested
`
`Omeprazolea
`
`Lansoprazoleb
`
`Pantoprazolec
`
`Rabeprazoled
`
`CYP 1A2
`Theophylline
`Caffeine
`
`CYP 2C9
`Phenytoin
`S Warfarin
`Carbamazepine
`Diclofenac
`Tolbutamide
`
`CYP 2C19
`Diazepam
`Mephenytoin
`R warfarin
`
`CYP 2D6
`Debrisoquine
`Propranolol
`Metoprolol
`
`CYP 3A4
`Nifedipine
`Cyclosporin
`Quinidine
`Lignocaine
`Contraceptives
`Erythromycin
`
`No interaction
`›Cl*
`
`?›Cl
`—
`
`No interaction
`No interaction
`
`No interaction
`—
`
`flCl (by 15–20%)
`?flCl (3%)
`flCl
`—
`›AUC (by10%)
`
`No interaction
`No interaction
`—
`—
`—
`
`flCl (by 26–54%)
`flCl
`›concentration ·2
`
`No interaction
`—
`No interaction
`
`No interaction
`No interaction
`No interaction
`
`?flCl
`No interaction
`No interaction
`No interaction
`No interaction
`No interaction
`
`—
`No interaction
`—
`
`—
`—
`—
`—
`?effect on ovulation
`—
`
`No interaction
`No interaction
`No interaction
`No interaction
`—
`
`No interaction
`No interaction
`No interaction
`
`No interaction
`—
`No interaction
`
`No interaction
`—
`—
`—
`No interaction
`—
`
`No interaction
`No interaction
`—
`—
`
`No interaction
`—
`No interaction
`
`—
`—
`—
`
`—
`—
`—
`—
`—
`—
`
`Data from References: a 30, 31, 39–42, 44, 45, 112; b 18, 30, 31, 37, 38, 40, 46; c 18, 19, 30, 31, 47, 48; d 4, 43, 49, 51, 52.
`CYP, Cytochrome P450; Cl, drug clearance; AUC, area under the concentration curve; ()), not tested; (?), result not clear; *, in high doses
`or in CYP 2C19 poor metabolisers.
`
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`
`3A4 have been documented.31 Pantoprazole has little or
`no potential for enzyme induction and rabeprazole does
`not affect theophylline metabolism.19, 43
`Omeprazole inhibits CYPs 2C9 and 2C19 and in those
`with the extensive metaboliser phenotype there is
`evidence that omeprazole administration results in
`significant decreases in the clearance of diazepam,
`phenytoin, and possibly carbamazepine and S-warfa-
`rin.44–45 Lansoprazole may reduce the efficacy of the
`oral contraceptive, but otherwise there have been no
`clinically significant interactions reported for lansopra-
`zole, pantoprazole or rabeprazole.19, 43, 46–49
`Proton pump inhibitors may alter the absorption of
`some other drugs by increasing the gastric pH. Omep-
`razole and rabeprazole use results in small increases in
`the absorption of digoxin, and similar effects would be
`expected with the other proton pump inhibitors.31, 50–51
`However, the difference did not reach statistical signifi-
`cance in studies of digoxin with pantoprazole.19 Proton
`pump inhibitors may increase the absorption of acid-
`labile antibiotics, such as penicillin V and erythromycin,
`by increasing gastric pH. Rabeprazole reduces the
`absorption of ketoconazole, resulting in reductions in
`the maximal plasma drug concentration and the area
`under the plasma concentration–time curve of ketoco-
`nazole.52
`In summary, the proton pump inhibitors, as a group,
`are extensively metabolized via the cytochrome P450
`system, and some drug interactions of probable clinical
`significance have been reported for omeprazole. Lan-
`soprazole and rabeprazole have less potential for drug
`interactions and no interactions of clinical relevance
`have been reported for pantoprazole.
`
`EFFICACY
`
`Acid suppression/pH studies
`
`The primary effect of the proton pump inhibitors is
`gastric acid suppression, the degree of which has been
`shown to correlate with healing rates
`for
`reflux
`oesophagitis (good healing when the gastric pH is
`greater than 4 for 16 h/day) and peptic ulcer (healing
`when pH > 3).53 The degree of acid suppression is
`probably the best in vivo parameter with which to
`compare the potency of the proton pump inhibitors.
`Omeprazole, lansoprazole and pantoprazole have been
`marketed in different standard doses, and few studies
`compare their potency on a mg for mg basis.
`
`Table 4 summarizes the results of studies comparing
`the acid suppressing effects of
`the proton pump
`inhibitors. A number of studies have examined the
`effect on gastric pH of
`lansoprazole compared with
`omeprazole. Three studies have shown that lansopra-
`zole 30 mg taken orally on a daily basis maintained the
`pH at greater than 3 for a significantly greater time
`than omeprazole 20 mg, and two studies have shown a
`higher median 24-h pH for lansoprazole.10, 54, 55 Three
`other studies found no significant difference overall in
`any pH parameters when comparing omeprazole and
`lansoprazole and their results conflicted with respect to
`the effects of these proton pump inhibitors on daytime
`and night-time pH.56–58
`One study has shown that gastric pH was greater than
`3 for 76% of the time with lansoprazole 60 mg/day and
`69% with omeprazole 40 mg/day (P (cid:136) 0.002).59
`Omeprazole 40 mg was significantly superior to lan-
`soprazole 30 mg at maintaining the pH above 5, but
`not above 3. These results suggest that on a mg for mg
`basis, the potency of lansoprazole and omeprazole is
`similar.
`Two studies compare equal doses (40 mg) of panto-
`prazole and omeprazole. In one study, no significant
`difference was found in any measured parameters for
`pH.60 In the other, the mean nocturnal pH was higher
`for pantoprazole (3.4) than for omeprazole (1.7), but
`there was no difference in other measurements of pH.61
`Pantoprazole 40 mg has also been compared with
`omeprazole 20 mg and the results showed a signifi-
`cantly higher daytime and 24 h pH on both days 1 and
`7 with pantoprazole, although there was no difference
`in mean night-time pH. There was a markedly increased
`rise in intragastric pH with repeated administration of
`both drugs.62
`Overall these results suggest that pantoprazole and
`omeprazole have a similar potency on a mg for mg
`basis.
`In one study, daytime pH, median 24-h pH and
`percentage time that pH was greater than 4 were
`significantly higher with lansoprazole 30 mg than
`pantoprazole 40 mg. Night-time pH was significantly
`higher with lansoprazole 30 mg at day 1 only. It was
`also noted that the antisecretory effect appears to be
`maximal after the first dose of lansoprazole, whereas for
`pantoprazole, antisecretory activity increased signifi-
`cantly from the first to the 7th day.63
`Rabeprazole 20 mg results in a significantly faster
`onset of antisecretory action than omeprazole 20 mg,
`
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`REVIEW: COMPARISON OF THE PROTON PUMP INHIBITORS
`
`969
`
`Table 4. Studies comparing the PPIs with respect to gastric acid suppression
`
`Reference
`
`Number of
`patients
`
`Drug & dosage
`(mg/day)
`
`Duration
`(days)
`
`Median
`24 h pH
`
`Median percentage of time (%)
`
`pH > 3
`
`pH > 4
`
`pH > 5
`
`Omeprazole vs. lansoprazole
`Timmer et al.59
`(20)
`
`Verdu et al.56
`(HP +ve)
`Tolman et al.10
`
`(18)
`
`(17)
`
`Blum et al.55
`
`(29)
`
`Bruley Des
`Varannes et al.54
`Geus et al.57
`
`(12)
`
`(16)
`
`Seensalu et al.58
`
`(16)
`
`Dammann et al.113
`
`(10)
`
`Omeprazole vs. pantoprazole
`Brunner et al.60
`(12)
`
`Hartmann et al.62
`
`(16)
`
`Koop et al.61
`
`(7)
`
`Omeprazole vs. rabeprazole
`Williams et al.5
`(24)
`
`Lansoprazole vs. pantoprazole
`Florent et al.63
`(12)
`
`L30 mg
`L30 mg b.d.
`L45 mg b.d.
`L60 mg b.d.
`O20 mg b.d.
`L30 mg
`O20 mg
`L15 mg
`L30 mg
`O20 mg
`L15 mg
`L30 mg
`O20 mg
`L30 mg
`O20 mg
`L30 mg
`L30 mg b.d.
`O20 mg
`O20 mg b.d.
`L15 mg
`L30 mg
`L60 mg
`O20 mg
`O40 mg
`L15 mg
`L30 mg
`O20 mg
`O40 mg
`
`P40 mg
`O40 mg
`P40 mg
`O20 mg
`P40 mg
`O40 mg
`
`R20 mg
`
`O20 mg
`
`L30 mg
`
`P40 mg
`
`Lansoprazole vs. pantoprazole/omeprazole
`Scholtz et al.64
`(18)
`P40 mg
`L30 mg
`O20 mg
`
`9
`
`7
`
`7
`7
`5
`
`5
`
`7
`
`7
`
`5
`
`7
`
`7
`
`7
`
`1
`8
`1
`8
`
`1
`7
`1
`7
`
`5
`
`4.1m
`4.6
`4.7
`4.8
`4.4
`5.4
`5.5
`4.0m
`4.9*
`4.2
`4.0m
`4.5*
`4.0
`NS
`
`3.7
`5.1
`4.2
`5.4
`2.9
`3.0
`3.8
`3.0
`4.2
`
`6.4
`6.4
`3.2
`2.1
`4.2
`4.0
`
`3.2
`4.7
`2.0
`4.2
`
`3.8*
`3.8
`2.5
`3.4
`
`3.2
`3.7
`2.8
`
`Overall efficacy
`(significance)
`
`L60 ‡ O40
`O40 ‡ L30
`
`L30 = O20
`
`L30 > L15,O20
`
`L30 > L15,O20
`
`L30 ‡ O20
`
`L30 = O20
`O40 > L60
`(night pH)
`
`O20 = L15,L30
`O40 = L60
`
`L30 > O20#
`L30 = O40
`
`O40 = P40
`
`P40 > O20**
`
`P40 = O20
`(except night pH)
`
`R20 ‡ 020***
`
`65m
`76
`78
`81
`69
`85–87
`84–86
`L30 > 020, O15**
`
`64m
`75*
`63
`L > O*
`
`60
`88
`68
`94
`
`48m
`63*
`51
`NS
`
`46
`70
`53
`78
`
`37m
`48
`49
`52
`46
`
`32
`51
`29
`61
`
`91
`88 NS
`
`87
`83 NS
`
`55
`69
`37
`60
`
`65
`61
`35
`49
`
`54
`50
`
`44
`60
`25
`51
`
`51
`49
`23
`34
`
`41
`46
`35
`
`22
`23
`8
`12
`
`L30 > P40
`
`L > O
`L = P
`
`Abbreviations: * = P < 0.05, ** = P < 0.01, *** = P < 0.001, > = significantly superior to comparator agent on all efficacy parameters,
`‡ = significantly superior to comparator agent in some efficacy parameters, = = comparable efficacy to comparator agent, NS = no significant
`difference, m = mean values, L = lansoprazole, O = omeprazole, P = pantoprazole, # = meal stimulated acid secretion measured rather than pH.
`
`(cid:211) 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 963–978
`
`Page 7 of 16
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`Patent Owner Ex. 2008
`CFAD v. Pozen
`IPR2015-01680
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`

`
`970
`
`C. A. M. STEDMAN & M. L. BARCLAY
`
`with a greater percentage of time for which the pH is
`above 3 and 4 at days 1 and 8, but no significant
`difference in median 24-h pH at 8 days.5
`There is one published abstract comparing three
`proton pump inhibitors with respect to the effects on
`gastric pH.64 In order of decreasing potency, this study
`ranked lansoprazole 30 mg > omeprazole 20 mg, and
`lansoprazole 30 mg was ranked equal to pantoprazole
`40 mg, although the pH values were slightly higher for
`lansoprazole 30 mg. However, the study population
`was small and there was no comment regarding the
`statistical significance of the results.
`Overall, these studies support equivalent potency for
`omeprazole vs. lansoprazole, and also omeprazole vs.
`pantoprazole. However, one study has shown that
`30 mg of
`lansoprazole gave better acid suppression
`than 40 mg of pantoprazole, suggesting that lansopra-
`zole has a greater potency. In some studies, omeprazole
`20 mg has a lesser effect on pH than the other two
`drugs in standard doses, which would be consistent
`with its lower dose. One study suggests that rabeprazole
`has a greater potency than omeprazole when compared
`on a mg for mg basis. The significance of
`these
`differences can only be fully assessed in trials examining
`clinical outcomes as endpoints.
`
`Gastro-oesophageal reflux disease
`
`Treatment. Table 5 summarizes the results of studies
`comparing the clinical efficacy of the proton pump
`inhibitors for the treatment of reflux oesophagitis. There
`are at least nine reported studies comparing lansopraz-
`ole with omeprazole for
`the treatment of
`reflux
`oesophagitis. Of those comparing lansoprazole 30 mg
`with omeprazole 20 mg, six studies out of seven show
`no significant difference in endoscopic healing rates at 4
`and 8 weeks.65–70 One study showed lansoprazole
`30 mg to be superior in endoscopic healing at 4 weeks,
`although the published details of
`this
`study are
`limited.71 There are trends in three studies for lanso-
`prazole 30 mg to provide earlier symptom relief than
`omeprazole 20 mg.66, 68, 69 Lansoprazole 30 mg has
`been compared with omeprazole 40 mg, and no
`significant differences were found in healing rates or
`symptom relief.72
`Both lansoprazole 30 mg and omeprazole 20 mg have
`been shown to be superior to lansoprazole 15 mg for the
`healing of oesophagitis.66 No studies have shown any
`difference between pantoprazole 40 mg and omeprazole
`
`20 mg for healing rates or symptom relief in patients
`with reflux oesophagitis.73–75
`In one study of 202 patients with GERD, rabeprazole
`20 mg and omeprazole 20 mg had equivalent healing
`rates and symptom relief at 4 and 8 weeks.76
`
`Maintenance of remission. When maintenance of remis-
`sion was assessed in patients with treated oesophagitis,
`there was no significant difference between omeprazole
`20 mg and lansoprazole 30 mg.77
`One small study of remission maintenance compared
`omeprazole 40 mg, lansoprazole 60 mg and pantopra-
`zole 80 mg and showed a dramatic difference in
`remission rates in favour of omeprazole 40 mg.78
`However,
`the number of patients was very small
`compared with other
`larger
`studies
`that
`showed
`no significant difference between omeprazole and
`lansoprazole in standard doses for remission mainte-
`nance.77
`
`Peptic ulcer disease
`
`Gastric ulcer. The studies comparing the efficacy of
`proton pump inhibitors for the treatment of peptic
`ulcer disease are summarized in Table 6. There have
`been at least three studies comparing different proton
`pump inhibitors for gastric ulcer healing.79–81 Rates
`of ulcer healing were
`significantly greater with
`lansoprazole 30 mg than omeprazole 20 mg, on an
`intention-to-treat analysis at 8 weeks (P (cid:136) 0.04), and
`a trend favoured lansoprazole treatment at 4 weeks
`(P (cid:136) 0.06).79 The time to relief of symptoms was
`shorter with lansoprazole (mean 6.6 days compared
`with 11 days) and the trend for the overall percent-
`age of patients with symptom relief favoured lansop-
`razole.
`Gastric ulcer healing rates were greater at 4 weeks
`with pantoprazole 40 mg than with omeprazole 20 mg
`when analysed on a per protocol basis (87.7% com-
`pared with 76.7%, P < 0.05), but the difference was not
`significant on an intention-to-treat analysis.80 There
`was no significant difference
`in symptom relief,
`although the trend favoured pantoprazole.
`In a 6-week study of 227 patients with active gastric
`ulcer treated with omeprazole 20 mg or rabeprazole
`20 mg, there was no significant difference in healing
`rates at 3 or 6 weeks, but
`the results
`favoured
`rabeprazole with regard to ulcer pain frequency, and
`severity of daytime and night-time pain.81
`
`(cid:211) 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 963–978
`
`Page 8 of 16
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`Patent Owner Ex. 2008
`CFAD v. Pozen
`IPR2015-01680
`
`

`
`Table 5. Studies comparing the clinical efficacy of PPIs: gastro-oesophageal reflux disease
`
`REVIEW: COMPARISON OF THE PROTON PUMP INHIBITORS
`
`971
`
`Number of
`patients
`
`Drug & dosage Duration
`(mg/day)
`(weeks)
`
`Outcome
`
`Healing
`
`Symptoms
`
`Other
`
`Reference
`
`Omeprazole vs. lansoprazole
`Vcev et al.65
`
`Castell et al.66
`
`Corallo et al.67a
`
`Hatlebakk et al.68
`
`Mee et al.69
`
`Cordova-Villabos et al.70a
`
`Sekiguchi et al.71
`
`Mulder et al.72
`
`Carling et al.77
`(remission maintenance)
`Omeprazole vs. pantoprazole
`Corinaldesi et al.73
`
`Hotz et al.74a
`
`Mossner et al.75
`
`Omeprazole vs. rabeprazole
`Dekkers et al.76
`
`60
`
`1284
`
`145
`
`229
`
`604
`
`20
`
`68
`
`211
`
`248
`
`241
`
`521
`
`286
`
`202
`
`Omeprazole vs. lansoprazole vs. pantoprazole
`Jasperson et al.78
`36
`(remission maintenance)
`
`8
`
`8
`
`8
`
`4,8
`
`8
`
`4
`
`4
`
`8
`
`48
`
`8
`
`8
`
`4,8
`
`NS
`
`NS
`
`L30 = O20 >
`L15**
`L,O > placebo
`
`L30 ‡ O20*
`L,O > placebo*
`
`Nausea
`L15 > O20,L30
`AE:L30,O20 > L15
`
`NS
`
`NS
`
`NS
`
`NS
`
`L > O
`
`NS
`
`NS
`(relapse rates)
`
`NS
`
`NS
`
`NS
`
`Headache O > L*
`
`NS
`
`L ‡ O
`@ 4 weeks*
`L ‡ O
`@ 3,7 days*
`NS
`
`—
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`›ALT/SGPT O > R*
`Flatulence O > R*
`
`4,8
`
`NS
`
`4
`
`O > P,L**
`
`O > P,L**
`
`L 30
`O 20
`L 15
`L 30
`O 20
`Placebo
`L 30
`O 20
`L 30
`O 20
`L 30
`O 20
`L 30
`O 20
`L 30
`O 20
`L 30
`O 40
`L 30
`O 20
`
`P 40
`O 20
`P 40
`O 20
`P 40
`O 20
`
`R 20
`O 20
`
`O 40
`L 60
`P 80
`
`Abbreviations: * = P < 0.05, ** = P < 0.01, > = significantly superior to comparator agent; ‡ = significantly superior to comparator agent
`in some efficacy parameters; ‘=’ = comparable efficacy to comparator agent; NS = no significant difference; L = lansoprazole; O = omeprazole;
`P = pantoprazole; R = rabeprazole; a = abstract only; AE = proportion of patients experiencing any adverse event.
`
`There are few trials comparing proton pump inhibitors
`on a mg for mg basis for the treatment of gastric ulcer,
`and therefore it is difficult to make firm conclusions
`about differences in potency and effectiveness in this
`context. However, any differences seen in the available
`studies would be consistent with the differences in the
`standard dose administered.
`
`Duodenal ulcer. Several studies have compared lanso-
`prazole with omeprazole in the treatment of acute
`
`(cid:211) 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 963–978
`
`duodenal ulcer.82–86 None of these studies have shown
`a statistically significant difference in healing rates at
`4 weeks, although in two studies lansoprazole 30 mg
`was associated with an increased healing rate at
`2 weeks compared with omeprazole 20 mg.85–86 One
`study showed a trend in favour of lansoprazole for the
`relief of pain at 4 weeks.84
`Lansoprazole 30 mg has been compared with ome-
`prazole 40 mg for the initial healing of duodenal ulcer,
`and no significant difference was found between the
`
`Page 9 of 16
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`Patent Owner Ex. 2008
`CFAD v. Pozen
`IPR2015-01680
`
`

`
`972
`
`C. A. M. STEDMAN & M. L. BARCLAY
`
`Table 6. Studies comparing the clinical efficacy of the PPIs: Peptic ulcer disease
`
`Number of
`patient