Table 1: Different administration options for delayed-release PPIs

Formulations	Lansoprazole	Esomeprazole	Rabeprazole	Pantoprazole	Omeprazole
Capsule or tablets	X	X	X	X	X
Capsule granules sprinkled on selected soft foods	X	X			X
Capsule granules mixed into selected beverages	X
Capsule granules ﬂushed through a nasogastric tube with apple juice or water, depending on product	X	X
IV formulation	X	X		X	X**
Packet for oral suspension	X
Orally disintegrating tablet	X
Available as OTC preparation					X*

Includes only US FDA approved options.

OTC, over-the-counter; IV, intravenous; PPI, proton-pump inhibitor; FDA, Food and Drug Administration.

*Omeprazole OTC available only as 20 mg formulation.

**IV omeprazole is available in some countries.

In addition to such specialized formulations, some of the encapsulated DR-PPIs can be administered as non- encapsulated intact enteric-coated granules with certain ﬂuids or mixed with some soft foods. Such administration may make these agents more suitable for some patients with swallowing disorders and for some elderly patients and children, but this is not associated with any acceleration of PPI absorption or onset of antisecretory effect. Some of these reconstituted formulations are suitable for administration through a nasogastric tube. Table 1 contains a list of the various alternative dosing formulations for DR-PPIs.

PER-GASTROSTOMY ADMINISTRATION:

Studies have been conducted on examining the antisecretory effects of OME^2,3and lansoprazole^4,5when given via gastrostomy tubes. In these experiments, patients with indwelling gastrostomy tubes had 24 h intragastric pH monitoring at baseline and after 7 days of once daily administration of either intact non-encapsulated OME granules in orange juice,²‘simpliﬁed omeprazole suspension’ (SOS),³intact non-encapsulated lansoprazole granules in orange juice⁴and ‘simpliﬁed lansoprazole suspension’ (SLS).⁵SOS and SLS are produced by opening a capsule of OME 20 mg or lansoprazole 30 mg, respectively, and dropping the granular contents into 10 mL of 8.4% sodium bicarbonate. The mixtures have to be gently agitated for a few minutes to obtain milky-white suspensions for subsequent tube administration. Each of the above formulations was found to suppress 24 h intragastric acidity. The degree of acid suppression obtained with intact OME or lansoprazole granules in orange juice and with SLS was similar to what would be expected had the patients ingested capsules of the respective DR-PPIs. However, the level of acid suppression found with SOS was less than would have been expected had the patients been given intact OME capsules.³For administration of a DR-PPI via a gastrostomy tube, SLS or predisintegrated LODT would be appropriate choices. Administration of intact OME or lansoprazole granules in orange juice (or, potentially, other liquids) is not recommended because of the theoretical risk of tube blockage, although this was not encountered in the studies described above. SOS is not recommended because of poor OME absorption and consequently disappointing antisecretory effects. Omeprazole absorption from ‘simpliﬁed omeprazole suspension’ The relative bioavailability of OME from SOS has been found to be less than that of intact capsules.^{6, 7}This likely explains the poorer than expected antisecretory effect seen with per-gastrostomy administration of SOS.²After 5 days of once daily oral dosing with intact OME 20 mg capsules, mean maximum plasma concentration (Cmax) increased from 222 to 430 ng/mL (P < 0.05) whereas mean Cmax only increased from 172 to 198 ng/mL with 5 days of SOS 20 mg (N.S.).⁶Mean area under the plasma OME concentration/time curve (AUC) increased from197 to 454 ngÆh/mLwith 5 days of once daily dosing with intact OME capsules 20 mg (P < 0.05), but only increased from 198 to 265 ngÆh/mL with repeated doses of SOS 20 mg (N.S.).⁶Similarly, Song et al. found that the OME AUC was higher after intact OME capsules than after SOS and noted the expected increase in AUC after 7 days of dosing with the capsules but not with SOS.⁷It should be clearly understood that SOS is a different preparation than sodium bicarbonate-containing immediate-release (IR) OME (Zegerid powder for oral suspension; Santarus, Inc., San Diego, CA, USA) powder for oral suspension, which is discussed in detail elsewhere in this supplement.

PHARMACOKINETICS OF DR-PPIs:

Table 2 compares the pharmacokinetic properties of currently available DR-PPIs. Rates of absorption after oral ingestion are highly variable for the DR-PPIs; time to achieve maximum plasma concentration (tmax) can be up to 3 h for individual DR-PPIs. Absolute bioavailability is also highly variable within the class of DR-PPIs. For OME and esomeprazole, bioavailability is not maximal after a single oral dose. All PPIs are extensively protein-bound, and all undergo hepatic metabolism. All of the currently available DR-PPIs have a short elimination half-life (t_1/2) of between 1 and 2 h. Aside from bioavailability in the ﬁrst few days of oral dosing, there are no substantive differences among currently available DR-PPIs with respect to pharmacokinetics.

PHARMACODYNAMICS OF DR-PPIs:

There have been numerous studies comparing the antisecretory effects of DR-PPIs. Typically, these have been reported as mean or median 24 h pH or suppression of 24 h intra-gastric acidity expressed as time above a predetermined pH threshold.

Gastric pH has been determined either through frequent aspiration of small quantities of gastric juice with ex-vivo measurement of pH and subsequent titration, or by continuous intra-gastric pH monitoring using an indwelling pH electrode. The proportion of time during which intra-gastric pH can be maintained above 3 has been correlated with the ability of antisecretory drugs to heal duodenal ulcer.⁸Maintenance of intra-gastric pH above 4 has been correlated with the ability to heal gastric ulcer^{9, 10}and erosive oesophagitis.¹¹Using single oral doses of DR-PPIs, Pantoﬂickova et al. reported that 24 h intra-gastric pH was maintained above 4 for 8.0 h with rabeprazole 20 mg, 7.4 h with lansoprazole 30 mg, 4.9 h with pantoprazole 40 mg, 2.9 h with OME 20 mg and 3.0 h with OME 20 mg multiunit pellet suspension (MUPS).¹²However, different investigators have reported different rank orders for the effects of DR-PPIs on intra-gastric pH. In ﬁve-way crossover study of the effects of 5 days of different DR-PPIs on 24 h intra-gastric acidity, Miner et al. found that esomeprazole 40 mg produced the greatest effect on intragastric pH, maintaining pH >4 for 14.0 h of the 24-h period.¹³Corresponding results for rabeprazole 20 mg, OME 20 mg, lansoprazole 30 mg and pantoprazole 40 mg were, 12.1, 11.8, 11.5 and 10.1 h, respectively (P < 0.05, esomeprazole vs. all other DR- PPIs; Figure 1). Therefore, with the possible exception of esomeprazole, there are only small differences among existing DR-PPIs for antisecretory effect when chronically administered as standard doses.

SUMMARY AND CONCLUSIONS:

Figure 1: Effects of standard doses of currently available delayed-release proton-pump inhibitors (PPIs) on intragastric acidity. Data from a ﬁve-way crossover study in 35 patients with gastro-oesophageal reﬂux disease (GERD), during which each PPI was administered once daily for 5 days. *P < 0.001 vs. all others (adapted from Miner et al.¹³).

The DR-PPIs effectively suppress gastric acid secretion and successfully treat acid-related disorders as mentioned above. There are only minor differences among existing members of the class, and these have not been translated into consistent, clinically meaningful advantages for any individual DR-PPI. The drugs’ enteric coatings impair their systemic absorption, and may delay the onset of maximal antisecretory effect. Alternative dosing formulations may be more convenient for some speciﬁc groups of patients but still rely on some form of enteric coating.

DISCUSSION:

What are the pros and cons of different delayed-release PPI formulations?

Differences among existing DR-PPIs formulations are of small absolute magnitude and are not associated with any consistently demonstrable differences in clinical outcomes. Currently, lansoprazole has the greatest number of alternative dosing formulations approved by the US Food and Drug Administration (FDA; Table 1). Omeprazole has the lowest absolute bioavailability after the ﬁrst dose. Bioavailability increases progressively with repeated once daily doses of OME due to auto-inhibition of its metabolism. Lansoprazole has the highest absolute bioavailability after the ﬁrst dose (Table 2). In standard marketed doses, esomeprazole may have the greatest antisecretory effect at pharmacodynamic steady-state (Figure 1). Omeprazole, lansoprazole and esomeprazole are easier to administer in liquids or soft foods than rabeprazole or pantoprazole because the ﬁrst three are given as capsules of enteric-coated granules while the latter two are enteric-coated tablets.

Are there meaningful advantages for any one DR-PPI over the others?

Absolute differences among the DR-PPIs are of small magnitude and have not been demonstrated to be of clinical relevance. When clinical end points such as the healing of ulcers or oesophagitis are compared, there are small and inconsistent differences seen between DR-PPIs. Esomeprazole has demonstrated slightly better healing rates compared with OME, lansoprazole or pantoprazole in erosive oesophagitis.^14–16However, the differences are small in magnitude and appear to offer only limited clinical beneﬁt. Furthermore, there is no clinically signiﬁcant difference between esomeprazole and lansoprazole in improving symptoms of gastro- oesophageal reﬂux disease (GERD).^{15, 17–19}

To what extent does the formulation of a PPI inﬂuence its use?

In the US, the two DR-PPIs that are currently most often prescribed are esomeprazole and lansoprazole. As both are usually given as capsules of enteric-coated granules, it could be argued that formulation has little inﬂuence. However, alternative dosing formulations are important for particular groups of patients. For example, elderly patients may have difficulty swallowing intact capsules or tablets; if a PPI is clinically indicated, IR-OME or the LODT may be more appropriate choices. For administration of a PPI through a nasogastric or gastrostomy tube, preparations consisting of intact granules in a liquid carry the potential concern of tube blockage as does lansoprazole DR oral suspension. IR-OME or predisintegrated LODT may be preferable for enteral tube administration.

How do simpliﬁed omeprazole suspension and the lansoprazole orally disintegrating tablet compare with immediate-release omeprazole?

The IR-OME is unique among the PPIs in that it has no form of enteric coating; it is protected from acid degradation by an excipient, sodium bicarbonate (see other article in this supplement for a full discussion of IR-OME). IR-OME is fundamentally different from SOS, which is formed by allowing enteric-coated granules of OME to disintegrate in a solution of 8.4% sodium bicarbonate. SOS requires compounding and takes longer to prepare than IR-OME. IR-OME is packaged in single-dose packets (both 40 and 20 mg) that can be constituted with water. IR-OME is associated with a more rapid absorption of OME than conventional DR-OME capsules and has a faster onset of antisecretory activity.²⁰Absorption of OME from SOS is actually less than from DR capsules and its antisecretory effect is relatively disappointing. ^{6, 7}The LODT contains enteric-coated granules of lansoprazole. Although the granules of lansoprazole in LODT are much smaller than those in the capsules, they still have some residual enteric coating that affects lansoprazole absorption. The pharmacokinetic proﬁle of lansoprazole from LODT is virtually identical to that from standard DR capsules.¹Therefore; LODT offers no advantage over lansoprazole capsules for rate of drug absorption and – by extension – rate of onset of antisecretory activity.

REFERENCES:

1. Freston JW, Chiu YL, Mulford DJ, Ballard ED. Comparative pharmacokinetics and safety of lansoprazole oral capsules and orally disintegrating tablets in healthy subjects. Aliment Pharmacol Ther 2003; 17: 361–7.

2. Sharma VK, Heinzelmann EJ, Steinberg EN, Vasudeva R, Howden CW. Nonencapsulated, intact omeprazole granules effectively suppress intragastric acidity when administered via a gastrostomy. Am J Gastroenterol 1997; 92: 848–51.

3. Sharma VK, Vasudeva R, Howden CW. The effects on intragastric acidity of per-gastrostomy administration of an alkaline suspension of omeprazole. Aliment Pharmacol Ther 1999; 13: 1091–5.

4. Sharma VK, Ugheoke EA, Vasudeva R, Howden CW. The pharmacodynamics of lansoprazole administered via gastrostomy as intact, non-encapsulated granules. Aliment Pharmacol Ther 1998; 12: 1171–4.

5. Sharma VK, Vasudeva R, Howden CW. Simpliﬁed lansoprazole suspension – a liquid formulation of lansoprazole – effectively suppresses intragastric acidity when administered through a gastrostomy. Am J Gastroenterol 1999; 94: 1813–7.

6. Sharma VK, Peyton B, Spears T, Raufman JP, Howden CW. Oral pharmacokinetics of omeprazole and lansoprazole after single and repeated doses as intact capsules or as suspensions in sodium bicarbonate. Aliment Pharmacol Ther 2000; 14: 887–92.

7. Song JC, Quercia RA, Fan C, Tsikouris J, White CM. Pharmacokinetic comparison of omeprazole capsules and a simpliﬁed omeprazole suspension. Am J Health Syst Pharm 2001; 58: 689–94.

8. Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to deﬁne optimal dosing with antisecretory drugs. Gut 1987; 28: 1120–7.

9. Howden CW, Jones DB, Peace KE, Burget DW, Hunt RH. The treatment of gastric ulcer with antisecretory drugs. Relationship of pharmacological effect to healing rates. Dig Dis Sci 1988; 33: 619–24.

10. Howden CW, Hunt RH. The relationship between suppression of acidity and gastric ulcer healing rates. Aliment Pharmacol Ther 1990; 4: 25–33.

11. Bell NJ, Burget D, Howden CW, Wilkinson J, Hunt RH. Appropriate acid suppression for the management of gastro-oesophageal reﬂux disease. Digestion 1992; 51 (Suppl. 1):59–67.

12. Pantoﬂickova D, Dorta G, Ravic M, Jornod P, Blum AL. Acid inhibition on the ﬁrst day of dosing: comparison of four proton pump inhibitors. Aliment Pharmacol Ther 2003; 17: 1507–14.

13. Miner P Jr, Katz PO, Chen Y, Sostek M. Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a ﬁve-way crossover study. Am J Gastroenterol 2003; 98: 2616–20.

14. Richter JE, Kahrilas PJ, Johanson J, et al. Efﬁcacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001; 96: 656–65.

15. Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002; 97: 575–83.

16. Labenz J, Armstrong D, Lauritsen K, et al. A randomized comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive oesophagitis: the EXPO Study. Aliment Pharmacol Ther 2005; 21: 739–46.

17. Howden C, Ballard E, Robieson W. Evidence for therapeutic equivalence of lansoprazole 30 mg and esomeprazole 40 mg in the treatment of erosive oesophagitis. Clin Drug Investig 2002; 22: 99–109.

18. Chey W, Huang B, Jackson R. Lansoprazole and esomeprazole in symptomatic GERD. A double-blind, randomised, multicentre trial in 3000 patients conﬁrms comparable symptom relief. Clin Drug Investig 2003; 23: 69–84.

19. McQuaid KR, Laine L. Early heartburn relief with proton pump inhibitors: a systematic review and meta-analysis of clinical trials. Clin Gastroenterol Hepatol 2005; 3: 553–63.

20. Hepburn B, Goldlust B. Comparative effects of an omeprazole antacid complex-immediate release (OACIR) and omeprazole delayed-release (OME-DR) on omeprazole pharmacokinetics and gastric pH in healthy subjects. Gastroenterology 2003; 124: A228.

Received on 01.03.2012 Modified on 20.03.2012

Research J. Pharm. and Tech. 5(4): April 2012; Page 462-465

	Esomeprazole	Lansoprazole	Omeprazole	Pantoprazole	Rabeprazole
Absolute bioavailability (%)	60-90	>80	40	77	52
Time to peak plasma level (h)	1.5	1.7	0.5-3.5	2-4	2-5
Plasma half-life (h)	1.0-1.5	1.5	0.5-1.0	1.0	1-2
Plasma protein binding (%)	97	97	95	98	95
Hepatic metabolism	Yes	Yes	Yes	Yes	Yes