Aliment Pharmacol Ther 2005; 22 (Suppl. 3): 25–30.
`
`Review article: immediate-release proton-pump inhibitor therapy –
`potential advantages
`
`C. W. HOWDEN
`Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
`
`Accepted for publication 15 September 2005
`
`SUMMARY
`
`The absorption of most oral proton-pump inhibitors is
`delayed by the enteric coating required to protect the
`acid-labile proton-pump inhibitor from degradation in
`the stomach and, as a result, antisecretory effect is also
`delayed.
`This article provides an overview of the pharmacoki-
`netics and pharmacodynamics of a new immediate-
`release omeprazole [(IR-OME) Zegerid power for oral
`suspension; Santarus Inc., San Diego, CA, USA] and its
`potential advantages over delayed-release proton-pump
`inhibitors.
`Immediate-release omeprazole has a higher mean peak
`plasma omeprazole concentration (Cmax) and a signifi-
`cantly shorter mean time to reach Cmax (tmax) than
`delayed-release omeprazole. Immediate-release omep-
`razole 40 mg has a prolonged antisecretory effect with
`median intragastric pH above 4.0 for 18.6 h/day at
`
`steady-state, after 7 days of once daily dosing. The
`sodium bicarbonate in immediate-release omeprazole
`protects the uncoated omeprazole from degradation by
`gastric acid. The accelerated antisecretory action of
`immediate-release omeprazole compared with delayed-
`release omeprazole may be due to the activation of
`proton pumps by the rapid neutralization of intragastric
`acid by the sodium bicarbonate. The faster onset of
`action seen with immediate-release omeprazole is not
`achieved by using an antacid with a delayed-release
`proton-pump inhibitor, because administering antacids
`with conventional delayed-release proton-pump inhib-
`itors does not significantly enhance absorption of the
`proton-pump inhibitor.
`In conclusion, immediate-release omeprazole is asso-
`ciated with rapid absorption of omeprazole and rapid
`onset of antisecretory effect, without compromising the
`duration of acid suppression.
`
`DELAYED-RELEASE ENTERIC-COATED PPIs
`
`Currently available delayed-release proton-pump inhib-
`itors (PPIs) are orally administered as enteric-coated
`preparations. Different formulations have been devel-
`oped: omeprazole (OME), lansoprazole and esomeprazole
`are generally administered as gelatine capsules con-
`taining enteric-coated granules, whereas pantoprazole
`and rabeprazole are given as enteric-coated tablets. The
`different enteric coatings, which are necessary to
`
`Correspondence to: Dr C. W. Howden, Division of Gastroenterology, 676 N.
`St Clair Street, Suite 1400, Chicago, IL 60611, USA.
`E-mail: c-howden@northwestern.edu
`
`protect the acid-labile PPI from acid degradation within
`the stomach, have the potential disadvantage of delay-
`ing PPI absorption. An alternative oral formulation of
`lansoprazole – the lansoprazole orally disintegrating
`tablet (LODT) – also depends on an enteric coating; the
`oral pharmacokinetics of lansoprazole after dosing with
`LODT are essentially identical to those obtained after
`dosing with capsules of enteric-coated granules of
`lansoprazole.1
`The PPIs employing any form of enteric coating for
`oral administration can be considered to be delayed-
`release (DR) preparations, as the enteric coating reduces
`the rate of absorption of the PPI into the systemic
`circulation. In its standard DR formulation, the proto-
`
`Ó 2005 Blackwell Publishing Ltd
`
`25
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 1
`
`

`

`capsules.5 A subsequent study of comparative pharma-
`cokinetics, found that the absorption of OME from SOS
`was less efficient than from intact DR-OME capsules.6
`The bioavailability of OME from SOS relative to standard
`capsules of DR-OME was 81.2% [95% confidence
`interval (CI): 59.1–103.3] after a single-dose but fell
`to 58.4% (95% CI: 30.5–86.3) after 5 days of once daily
`dosing.6 Other investigators have confirmed impairment
`of OME absorption from SOS.7 Thus, the lower than
`expected antisecretory effect of SOS was likely due to
`impaired absorption of OME when given in that form.
`
`PHARMACOKINETICS OF OMEPRAZOLE WHEN
`ADMINISTERED AS IR-OME
`
`There is rapid absorption of OME when IR-OME is
`administered orally. In a comparative study with DR-
`OME,
`IR-OME (prototype formulation) displayed a
`significantly shorter tmax and a higher Cmax (Figure 1).8
`Mean tmax was 25 min with IR-OME and 127 min with
`DR-OME (P < 0.01); mean Cmax was 1019 ng/mL with
`IR-OME and 544 ng/mL with DR-OME. The AUC for
`OME was not significantly different between the IR and
`DR formulations; mean values were 1120 and
`1170 ngÆh/mL, respectively.
`Both Cmax and AUC increased between 1 and 7 days of
`once daily dosing with IR-OME (commercial formula-
`tion). For the 20 mg dose, mean Cmax increased from
`672 to 902 ng/mL between days 1 and 7, while mean
`AUC increased from 825 to 1446 ngÆh/mL.9 For the
`40 mg dose, mean Cmaxincreased from 1412 ng/mL on
`day 1 to 1954 ng/mL on day 7, while mean AUC
`increased from 2228 to 4640 ngÆh/mL. There was no
`
`IR-OME (n = 7)
`DR-OME (n = 10)
`
`0
`
`1
`
`2
`
`4
`3
`Time post-dose (h)
`
`5
`
`6
`
`900
`800
`700
`600
`500
`400
`300
`200
`100
`0
`
`Omeprazole concentration (ng/mL)
`
`Figure 1. Mean plasma concentration from fasting subjects with
`immediate-release omeprazole (IR-OME) 40 mg prototype formu-
`lation (n ¼ 7) and delayed-release (DR)-OME 40 mg (n ¼ 10;
`adapted from Hepburn and Goldlust8).
`
`26
`
`C. W. HOWDEN
`
`typical PPI OME has poor absorption after a single dose,
`and displays marked interindividual variability in the
`parameters of maximum plasma concentration (Cmax),
`time to achieve Cmax (tmax) and area under the plasma
`concentration/time curve (AUC).2, 3 For single oral
`doses of 10, 30 and 60 mg of OME, mean tmax was,
`respectively, 3.3, 2.3 and 2.5 h with marked interindi-
`vidual variability.2, 3
`Although the DR-PPIs have had an enormous impact
`on the management of gastro-oesophageal reflux dis-
`ease (GERD) and other acid-related disorders, they do
`not achieve maximum effectiveness after a single dose.
`This may be due in part to their poor absorption with
`initial dosing. A recent
`systematic review of
`the
`effectiveness of PPIs in relieving symptoms of GERD,
`found that most patients did not obtain complete relief
`of daytime or night-time symptoms with the first dose.4
`Lack of a prompt response of GERD to PPI therapy may
`contribute to patient dissatisfaction with treatment and
`may lead to unnecessary increases in dose or inappro-
`priate switching to alternate members of the class.
`There would, therefore, be some clinical utility of a
`formulation that ensured rapid absorption of the PPI
`and a more rapid onset of antisecretory activity.
`
`IMMEDIATE-RELEASE OMEPRAZOLE
`
`The recent introduction in the US of immediate-release
`omeprazole [(IR-OME) Zegerid powder for oral suspen-
`sion; Santarus Inc., San Diego, CA, USA] may go some
`way to answering the unmet needs associated with the
`DR-PPIs. The currently available formulation consists of
`pure, non-enteric-coated OME powder 40 mg or 20 mg
`per unit dose along with 1680 mg of sodium bicarbon-
`ate (containing 460 mg of sodium). This is designed to
`be constituted with water to be drunk. It is flavoured
`with peach and peppermint.
`It is important to distinguish IR-OME from another
`formulation containing OME and sodium bicarbonate
`called ‘simplified omeprazole suspension’ (SOS). While
`IR-OME has no form of enteric coating, SOS is prepared
`by opening standard capsules of DR-OME, dropping the
`granular contents into 8.4% sodium bicarbonate solu-
`tion and agitating the mixture until the enteric coating
`of
`the granules disintegrates and a suspension is
`formed.5 When administered via gastrostomy once
`daily for 7 days, this formulation produced an antise-
`cretory effect that was lower than would have been
`predicted had the patients been given standard DR-OME
`
`Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 22 (Suppl. 3), 25–30
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 2
`
`

`

`REVIEW: IMMEDIATE-RELEASE PPI THERAPY
`
`27
`
`seen from 4 to 6 h after dosing likely reflects enhanced
`and accelerated absorption of OME from the IR formu-
`lation.
`The more rapid onset of antisecretory action with IR-
`OME is not achieved at the expense of any shortening of
`effect. Healthy volunteers received 7 days of once daily
`dosing with IR-OME (commercial formulation) 20 mg
`(n ¼ 28) or 40 mg (n ¼ 24); 24 h intragastric acidity
`was monitored on day 7 (at pharmacodynamic steady-
`state). The primary end point was the time during
`which the intragastric pH was maintained above 4. IR-
`OME 20 mg maintained intragastric pH above 4 for
`51% (12.2 h), while IR-OME 40 mg kept intragastric
`pH above 4 for 77% (18.6 h) of the 24-h recording
`period (Figure 2).9, 10
`Morning administration of IR-OME is associated with
`profound control of postprandial acidity throughout the
`day, which is seen as early as day 1 and is maintained
`
`(a) 20 mg
`Dose Meal
`
`Baseline
`
`Day 7
`
`0
`
`3
`
`6
`
`15
`9
`12
`Time (hours)
`
`18
`
`21
`
`24
`
`8 7 6 5 4 3 2 1 0
`
`Gastric pH
`
`(b) 40 mg
`Dose Meal
`
`Baseline
`
`Day 7
`
`0
`
`3
`
`6
`
`9
`15
`12
`Time (hours)
`
`18
`
`21
`
`24
`
`8 7 6 5 4 3 2 1 0
`
`Gastric pH
`
`Figure 2. Effect of 7 days of once daily dosing with immediate-
`release omeprazole (IR-OME) 20 mg (a) and 40 mg (b) on 24 h
`intragastric pH (Zegerid Package Insert and data on file;
`Santarus9, 10).
`
`significant change in mean tmax between days 1 and 7
`for either the 20 mg or the 40 mg dose. For the 20 mg
`dose, mean tmax was 29.8 min on day 1 and 28.3 min
`on day 7. Corresponding values for the 40 mg dose
`were 26.6 and 34.7 min.9 Similarly, mean plasma
`elimination half-life (t1/2) was dose-independent and did
`not change significantly with repeated dosing. For the
`20 mg dose, t1/2 was 0.86 h on day 1 and 1.08 h on
`day 7. Corresponding values for the 40 mg dose were
`1.00 and 1.38 h.9
`The sodium bicarbonate is critical to the effective
`absorption of OME from IR-OME because it protects the
`uncoated OME from acid degradation within the
`stomach. When uncoated OME 40 mg was adminis-
`tered without
`sodium bicarbonate to 10 healthy
`volunteers 1 h before ingestion of a standardized meal,
`the median Cmax was 186.4 ng/mL and the median
`AUC was 225 ngÆh/mL.10 However, when the same
`dose of uncoated OME was given with 30 mmol of
`sodium bicarbonate, median Cmax was 911.5 ng/mL
`and median AUC was 965.7 ngÆh/mL.
`
`PHARMACODYNAMIC STUDIES WITH IR-OME
`
`Just as with the pharmacokinetics, the sodium bicar-
`bonate content is critical to understanding the phar-
`macodynamics of IR-OME. When pure, uncoated OME
`powder was administered to 10 healthy volunteers 1 h
`before a meal, median integrated intragastric acidity
`from 0 to 210 min was 35 mmolÆh/L. When the same
`dose was given with 30 mmol of sodium bicarbonate,
`median integrated intragastric acidity over the same
`time period was only 0.5 mmolÆh/L.10
`In a crossover trial, 10 healthy volunteers received a
`single 40 mg dose of DR-OME; after a washout period of
`at least 1 week, seven of the subjects received 40 mg of
`uncoated IR-OME (prototype formulation).8 Intragastric
`acidity was monitored from 0 to 30 min and from 4 to
`6 h after ingestion. Within the first 30 min, DR-OME
`had no measurable effect on intragastric acidity, while
`IR-OME reduced the mean gastric acid concentration by
`78% from baseline. From 4 until 6 h after ingestion,
`there was a mean gastric acid concentration reduction
`from baseline of 27% for DR-OME and 65% for IR-OME.
`Thus, the antisecretory effect of IR-OME was detectable
`earlier than that of DR-OME and lasted at least as long.
`While the effect seen within the first 30 min may have
`been due largely to the neutralizing capacity of the
`sodium bicarbonate, the more profound suppression
`
`Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 22 (Suppl. 3), 25–30
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 3
`
`

`

`of circulating OME by activated parietal cells leading to
`irreversible inhibition of a large proportion of available
`molecules of H+,K+-ATPase. This may help to explain
`both the rapidity of onset of the antisecretory effect and
`its prolonged duration. This hypothesis assumes that
`OME is principally absorbed from the proximal small
`intestine when ingested as IR-OME, just as with the
`conventional DR formulation.
`
`EFFECTS OF CONCOMITANT ANTACID ON
`ABSORPTION OF DR-PPIs
`
`Because DR-PPIs do not produce maximal symptom
`in GERD patients with the first dose,4 patients
`relief
`may combine a DR-PPI with antacid during the first
`few days of treatment. Therefore,
`it is important to
`know whether antacids alter the absorption of DR-PPIs
`and, in view of the advantages conferred by the sodium
`bicarbonate in IR-OME, whether co-administration
`of antacids augments absorption of PPIs from DR
`formulations.
`A study in 12 healthy male volunteers, found that
`median tmax, median Cmax and AUC were not statisti-
`cally different when a single-dose of OME 20 mg was
`administered with or without a liquid antacid.13 When
`six healthy male volunteers were given single doses of
`OME 30 mg with or without a liquid antacid, tmax, Cmax
`and AUC were not significantly changed by adminis-
`tration of the antacid.14 Median tmaxwith OME was
`3.25 h when given alone and 1.0 h when given with
`antacid; however, this was not statistically significant
`due to the small sample size and the marked interindi-
`vidual variability seen in the rate of absorption.
`Similarly, the effects of antacids on the pharmacokinet-
`ics of rabeprazole were studied in 12 healthy male
`volunteers, and no significant differences in mean tmax,
`Cmax, AUC, or t1/2 were seen when rabeprazole was
`given alone, with antacid, or after antacid.15
`Results with lansoprazole 30 mg, when administered
`with or without an antacid to 12 healthy subjects,
`showed no significant differences in mean tmax or
`AUC.16 However, mean Cmax was significantly reduced
`when lansoprazole was administered with or after the
`antacid compared with when given alone.
`Therefore, current evidence indicates that antacids do
`not have a major effect on the absorption or disposition
`of the DR-PPIs. There is no evidence to suggest that
`antacid co-administration enhances the absorption of
`DR-PPIs, and it is unlikely that administration of DR-
`
`28
`
`C. W. HOWDEN
`
`at day 7. IR-OME 40 mg dosed once daily controlled
`intragastric acidity following breakfast and lunch (98%
`and 100% reductions on days 1 and 7, respectively for
`both meals), as well as dinner (92% and 100%
`reductions on days 1 and 7, respectively).10
`According to Goldlust et al., 17 healthy subjects
`received IR-OME 20 mg (commercial formulation) each
`morning for 7 days; on day 8, they received two doses of
`20 mg in the morning and at bedtime. The addition of
`the bedtime dose maintained intragastric pH above 4 for
`significantly longer than the morning dose alone, over
`both the nocturnal and entire 24-h period (Figure 3).11
`
`POSSIBLE MECHANISM OF ACTION OF IR-OME
`
`As noted above, both the absorption of OME and the
`onset of its antisecretory effect are more rapid when
`administered as IR-OME than as DR-OME. The putative
`mechanism of action to explain these observations is as
`follows. Following ingestion of
`IR-OME as an oral
`suspension, the sodium bicarbonate causes a prompt
`rise in intragastric pH. While this serves the primary
`function of protecting the uncoated OME from acid
`degradation within the stomach, it may also provide a
`temporary stimulus to gastrin release from antral G
`cells. Sodium bicarbonate solution has previously been
`shown to raise circulating gastrin levels within 30 min
`of oral ingestion.12 The rise in circulating gastrin may
`stimulate the parietal cell mass and promote the
`functioning molecules of H+,K+-ATPase
`insertion of
`into the secretory canaliculi. Since the peak plasma
`concentration of OME occurs around 30 min after
`ingestion of IR-OME, this allows for the rapid uptake
`
`IR-OME 20 mg qam × 7 days
`IR-OME 20 mg qam × 7 days + 20 mg b.d. on day 8
`*
`
`*
`
`24 h
`
`Nocturnal
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`% time gastric pH > 4
`
`Figure 3. Effect of additional evening dose of immediate-release
`omeprazole (IR-OME) 20 mg on 24 h and nocturnal intragas-
`tric acidity (n ¼ 17; *P < 0.001; adapted from Goldlust et al.11).
`
`Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 22 (Suppl. 3), 25–30
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 4
`
`

`

`OME with an antacid would result in the favourable
`pharmacokinetic and pharmacodynamic profile seen
`with IR-OME.
`
`SUMMARY AND CONCLUSIONS
`
`IR-OME is unique among PPI formulations in that it has
`no enteric coating. It is associated with rapid absorption
`of OME and rapid onset of antisecretory effect. Single
`daily doses of IR-OME produce prolonged acid suppres-
`sion, including postprandial periods. IR-OME is different
`from the earlier OME/sodium bicarbonate combination
`called SOS. The SOS formulation contains residual
`enteric coating from the OME granules, and has inferior
`pharmacokinetic and pharmacodynamic properties
`when compared with conventional DR-OME. The
`favourable pharmacokinetic and pharmacodynamic
`profiles seen with IR-OME do not appear to be achiev-
`able by using an antacid with a DR-PPI, because this is
`not associated with improvement or acceleration of PPI
`absorption.
`
`DISCUSSION
`
`How does IR-OME differ from a traditional DR-PPI given
`with antacid?
`
`Currently available studies do not indicate that con-
`comitant antacid improves the absorption of DR-PPIs
`including OME, lansoprazole and rabeprazole.13–16 IR-
`OME is uniquely formulated with no enteric coating and
`the antacid sodium bicarbonate. It is not anticipated
`that giving a conventional DR-PPI with an antacid
`could reproduce the favourable pharmacokinetic and
`pharmacodynamic profile seen with IR-OME.
`
`Do traditional antacids elevate serum gastrin?
`
`There is limited experimental evidence that serum
`gastrin concentrations increase following the ingestion
`of antacids. Feurle12 found a prompt rise in serum
`gastrin, which approximately doubled within 1 h, fol-
`lowing infusion of sodium bicarbonate into the stomach
`of healthy volunteers and duodenal ulcer patients.
`Intragastric instillation of sodium chloride did not
`produce any measurable effect on serum gastrin levels.12
`Another study in healthy volunteers and patients with
`a history of duodenal ulcer showed that the adminis-
`tration of sodium bicarbonate by intragastric infusion
`
`REVIEW: IMMEDIATE-RELEASE PPI THERAPY
`
`29
`
`raised serum gastrin levels to a greater degree than the
`same dose administered intravenously.17 However,
`serum gastrin concentrations were not significantly
`elevated above baseline until after 5 h of continuous
`intragastric infusion of sodium bicarbonate. The rise in
`serum gastrin was 23–30% of that achieved with the
`intragastric instillation of a homogenized steak meal.
`
`What is the site of omeprazole absorption when administered
`as IR-OME?
`
`It is thought that the OME in IR-OME is absorbed from
`the proximal small intestine, just as it is when given as
`in a DR formulation. However, because IR-OME is
`ingested as a liquid, there is rapid transfer to the
`duodenum where subsequent absorption is more rapid
`than with DR-OME. However, the site of absorption of
`IR-OME has not been studied.
`
`Are there any other specific advantages to IR-OME in the
`management of GERD?
`
`The more rapid absorption of OME and the more rapid
`onset of acid suppression may offer a clinical benefit.
`Multiple randomized-controlled trials attest
`to the
`efficacy of different DR-PPIs when taken on-demand
`by patients with endoscopy-negative GERD.18 The rapid
`onset of action may make IR-OME the PPI formulation
`of choice for on-demand treatment of GERD although
`this has not been investigated clinically.
`Theoretically, the liquid formulation of IR-OME would
`be a more attractive option than a tablet or capsule of a
`DR-PPI for patients with gastroparesis or delayed gastric
`emptying. Furthermore, patients with gastroparesis
`have constant stimulation of gastric acid secretion
`because of the prolonged dwell-time of
`food in the
`stomach. The prolonged antisecretory effect seen with
`IR-OME may help to counteract this situation.
`Other groups of GERD patients who might benefit
`specifically from IR-OME would be those with swallow-
`ing difficulties,
`those who do not
`take breakfast
`regularly or who have difficulty always taking their
`DR-PPI before food (because there is evidence that IR-
`OME dosed independently of food still exerts its maximal
`antisecretory effect), patients who work shifts or who
`have a demanding travel schedule (because of problems
`timing their dose of a DR-PPI) and, as already
`mentioned, patients who wish to take their PPI on-
`demand for control of GERD symptoms.
`
`Ó 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 22 (Suppl. 3), 25–30
`
`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 5
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`

`

`30
`
`C. W. HOWDEN
`
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`MYLAN PHARMS. INC. EXHIBIT 1006 PAGE 6
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