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Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Ilaprazole for the Treatment of Gastro-EsophagealReflux

Edoardo Savarino, Andrea Ottonello, Irene Martinucci, Pietro Dulbecco &Vincenzo Savarino

To cite this article: Edoardo Savarino, Andrea Ottonello, Irene Martinucci, Pietro Dulbecco &Vincenzo Savarino (2016): Ilaprazole for the Treatment of Gastro-Esophageal Reflux, ExpertOpinion on Pharmacotherapy

To link to this article: http://dx.doi.org/10.1080/14656566.2016.1232389

Accepted author version posted online: 06Sep 2016.Published online: 06 Sep 2016.

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1

Publisher: Taylor & Francis

Journal: Expert Opinion on Pharmacotherapy

DOI: 10.1080/14656566.2016.1232389

Drug Evaluation

Ilaprazole for the Treatment of Gastro-Esophageal Reflux

Edoardo Savarino MD, PhD 1, Andrea Ottonello MD2, Irene Martinucci MD3, Pietro Dulbecco

MD2, Vincenzo Savarino MD2

1 Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy 2 Division of Gastroenterology, Department of Internal Medicine, University of Genoa, Genoa, Italy 3 Division of Gastroenterology, Department of Internal Medicine, University of Pisa, Pisa, Italy

Running Title: Ilaprazole and Gastro-Esophageal Reflux Treatment

Corresponding author:

Vincenzo Savarino, MD, PhD

Department of Internal Medicine and Medical Specialties

University of Genoa

Viale Benedetto XV, n. 6

16132 Genoa, Italy

Email: vsavarin@unige.it

Funding

This paper was not funded

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity

with a financial interest in or financial conflict with the subject matter or materials discussed in the

manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert

testimony, grants or patents received or pending, or royalties.

2

Authors contribution:

E Savarino, MD, PhD, A Ottonello, MD, I Martinucci, MD, P Dulbecco, MD, and V Savarino, MD,

each contributed to the writing of the manuscript and have approved the final version.

3

ABSTRACT (Word Count: 200)

Introduction: Despite the undoubted benefit of proton pump inhibitors (PPIs), they have several

shortcomings, such as a slow onset of action and a remarkable inter-individual variability, that limit

the complete success of these drugs. Recently, a new PPI, ilaprazole, has been developed and used

in GERD patients.

Areas covered: The present review provides an update on the following points: current knowledge

of GERD mechanisms; limitations of actual therapies; pharmacokinetic profile and metabolism of

ilaprazole; initial studies on the therapeutic efficacy of ilaprazole in GERD.

Expert opinion: Compared with all other approved PPIs, ilaprazole has shown an extended plasma

half-life, a metabolism not significantly influenced by CYP2C19 genetic polymorphism and similar

safety. This characteristics account for a low inter-individual variability, particularly in Asian

populations, a higher suppression of gastric acid secretion, a more rapid acid control and

consequent quicker symptom relief and a better effect on nocturnal acidity. However, clinical

investigations assessing the efficacy of ilaprazole in the management of GERD are lacking and

therefore the potential improvements achievable with ilaprazole in the current standard of care for

acid-suppressing treatment must be confirmed in large and randomly controlled clinical trials

enrolling patients with both erosive and non-erosive reflux disease.

Key Words: Ilaprazole, Gastro-Esophageal Reflux Disease, PPI

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1. Introduction

Gastroesophageal reflux disease (GERD) develops when the reflux of gastric contents into

the esophagus leads to troublesome symptoms with or without mucosal damage and/or

complications (1). When defined as at least weekly heartburn and/or regurgitation, its prevalence in

Western countries generally ranges from 10% to 20%, according to various studies (2). There is

evidence that the prevalence of GERD has increased over the past two decades, representing also a

major problem for costs to healthcare systems in many countries (3). The reasons for the rise of

GERD and its complications have not been clearly identified, but many investigations have put

forward an evident link with the increasing parallel prevalence of obesity (4,5). Indeed, the last few

decades have witnessed a global increase in obesity of epidemic proportions and this condition has

been shown to induce the occurrence of all the various mechanisms sustaining GERD (6).

2. Phenotypic manifestations of GERD

For many years, erosive reflux disease (ERD) has been considered the only clinical

presentation of GERD and accordingly, all studies aimed at evaluating the efficacy of powerful

antisecretory drugs, such H2 antagonists and proton pump inhibitors (PPIs), were carried out in

patients with esophageal mucosal erosions. However, in the past 15 years we have realized that

ERD represents the minority of patients with GERD (≈ 30%), whereas the majority of them (≈

70%) are included in the non-erosive reflux disease (NERD) phenotype, in that they have typical

reflux symptoms, particularly heartburn, without any esophageal mucosal lesion visible at

endoscopy (7).

However, it is now clear that patients with NERD cannot be anymore considered as a unique

population on the simple basis of the absence of esophageal mucosal erosions at upper GI

endoscopy, because they are markedly heterogeneous from a pathophysiological point of view

(8,9). Indeed, the recent use of 24-hour impedance pH monitoring has allowed us to subdivide

NERD population into several well-defined subgroups of patients with specific functional patterns

(Figure 1): 1) true NERD with abnormal esophageal acid exposure 2) hypersensitive esophagus,

with normal esophageal acid exposure and positive symptom association with acid or non-acid

reflux or both and 3) functional heartburn, with normal esophageal acid exposure and negative

symptom association analysis with any type of chemical reflux. This last subgroup does not pertain

to the realm of GERD and, given the lack of reflux episodes underlying the symptoms, does not

respond usually to PPI therapy (10).

3. Principles of GERD therapy

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The aims of GERD treatment are the following:

- Relief of reflux symptoms and improvement of quality of life

- Healing of esophageal mucosal lesions, if present

- Prevention of recurrence and complications

It is worth mentioning that only in recent years with the continuous improvement in our

knowledge of the higher prevalence of the above-mentioned NERD phenotype, the primary

endpoint of GERD therapy in clinical trials and in daily medical practice has moved from the

regression of mucosal damage to the achievement of symptom relief. So, the standard approach to

GERD patients is today represented by the empiric therapy with once daily PPIs, which have

become the first choice drugs to treat reflux and have almost completely replaced H2 antagonists

(11). Accordingly, symptom relief and improvement of quality of life are best viewed as the mirror

of PPI effectiveness.

4. Overview of PPI market

In the past 50 years, the identification of the cellular regulators of acid secretion culminated

in the development of novel pharmacokinetic agents, namely, H2RAs and PPIs, which allowed the

effective and safe treatment not only of pepetic ulcer in the pre-H. pylori era but also of GERD and

other acid-related disorders. Antisecretory therapy has advanced dramatically since the introduction

of cimetidine in the mid-1970s and subsequently other molecules have been added to the market,

such as ranitidine, famotidine, etc. However, H2RAs have a relatively short duration of action and

suppress acid secretion for approximately 4-8 hours (12). Consequently, multiple doses of these

drugs are likely to be required. A further shortcoming of H2RAs is that tolerance generally

develops within 2 weeks of repeated administration. Conversely from H2RAs, PPIs control both

basal and food-stimulated acid secretion and produce more complete and longer-lasting acid

suppression than the former ones and their pharmacological effect is maintained for about 16-18

hours, thus permitting the use of a single daily dose (12). So, they have become the first-choice

therapy in patients with GERD and other acid-related diseases, replacing almost completely

H2RAs. The market of these drugs has progressively increased to the point that it is estimated that

over 113 million PPI prescriptions are filled globally each year in the United States and this,

together with over-the-counter use, accounted for over $13.6 billion sales worldwide in 2009

(13,14).

5. Shortcomings and limitations of current PPIs

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Currently available PPIs, which are the standard of care for acid-related disease, have a

well-established efficacy and safety profile, but they are still far from the ideal antisecretory

compound. An ideal drug should allow full acid control around the clock as well as dose-dependent

and predictable pharmacokinetic and pharmacodynamic properties. Moreover, an ideal agent should

display high oral bioavailability, a rapid onset of action and few, if any, clinically relevant

interactions with food or concomitantly administered drugs (12).

At variance with the above considerations, the so-called first-generation PPIs (omeprazole,

pantoprazole and lansoprazole) have remarkable limitations, because their half-life is relatively

short (0.5 to 2.1 hours) and consequently, the onset of their pharmacological action is rather slow.

Furthermore, they are not able to achieve 24-hour suppression of gastric acid secretion and

nocturnal acid breakthrough may occur even in patients receiving PPIs twice daily (15). Also, the

efficacy may vary among individuals due to cytochrome P450 polymorphism (16). All the above

shortcomings limit their usefulness as on-demand GERD therapy and their benefit in the control of

symptoms occurring during the night.

The so-called second-generation PPIs (rabeprazole and esomeprazole) offer several key

advantages over the previously mentioned molecules of the same class in terms of a quicker acid

inhibition, higher potency and longer duration of action. However, despite these improvements,

they do not permit to obtain clinical results which are significantly better than those achievable with

the first-generation PPIs (17).

Taking all the above considerations into account, it is clear that there is room for

improvement and therefore several researchers focused their attention to the development of new

PPIs able to overcome the above limitations in the current standard of care for acid suppressing

treatment.

6. Refractoriness to PPIs.

Despite the high efficacy of PPIs in GERD, about 30%-40% of patients remain symptomatic

on once daily PPI therapy and this is particularly true for those with NERD (18). A universally

accepted definition of PPI failure is lacking, but an incomplete or unsatisfactory response to a full

course (12 weeks) of these drugs can be reasonably considered as “refractory GERD”. The reasons

for clinical non response to PPIs can be subdivided into two main categories: patient- and therapy-

related (Table 1).

The patient-related reasons include poor adherence to treatment, presence and size of a

possible hiatal hernia (19) and biliary reflux into the esophagus (20). The therapy-related reasons

7

include hepatic cytochrome P450 polymorphism, particularly common in Asian people, nocturnal

acid breakthrough episodes and PPI-induced delay in gastric emptying with consequent dyspepsia

(21).

The fact that about 30%-40% of GERD patients display an inadequate response to PPIs

underscores the urgent need for further new therapeutic options (Table 2), particularly considering

that GERD is one of the most common chronic gastrointestinal disorder in Western countries (2).

7. Ilaprazole chemistry

Recently, a new benzimidazole compound, ilaprazole {2-[[(4-methoxy-3-methyl)-2-

pyridinylmethylsulfinyl-5-(1H-pyrrol-1-yl)-1H-benzimidazole, CAS 172152-36-2)}, designated

also as IY81149, was synthesized at Il-Yang Pharmacy Co. (Seoul, Korea) and is presently

developed by Livzon Pharmaceutical Group Inc. (Zhuhai, China). Its chemical structure is reported

in the summary box and clearly shows that this molecule belongs, like first-generation (omeprazole,

lansoprazole and pantoprazole) and second-generation (rabeprazole and esomeprazole) PPIs, to

benzimidazole compounds. After intestinal absorption, they accumulate specifically and selectively

in the secretory canaliculus of the parietal cell and block the H+K+ ATP-ase, which is the final step

of acid secretion.

8. Ilaprazole: pharmacokinetic and pharmacodynamics properties of a novel PPI

Preliminary data from in vivo preclinical studies and clinical investigations have shown that

ilaprazole can elicit a marked and dose-dependent suppression of gastric acid secretion, together

with more prolonged plasma half-life and similar safety as compared to omeprazole and therefore it

can be of help in improving and overtaking the above described limitations of traditional PPIs (22).

Ilaprazole is a colorless crystalline powder prepared as enteric-coated capsules or tablets; it

is administered by oral route and absorbed at intestinal level. The main plasma pharmacokinetic

parameters of ilaprazole, after daily oral administration of 10 mg for 7 days, can be summarized as

follows : the area under the curve of plasma concentration over time from 0 to 24 h (AUC0-24 h)

ranges between 1766.6 and 2243.t ng h/ml; the peak concentration at steady state (Css,max) ranges

between 236 and 292 (ng/ml); the time to reach Css,max (tmax), that can be estimated by direct

inspection read of the plasma concentration-time curves, ranges between 3.4 and 3.7 h; the

elimination half-life (t1/2) ranges between 8.1 and 10.1 h (23). The impact of the hepatic cytochrome

P450 (CYP) polymorphism on the pharmakinetics of ilaprazole deserves careful consideration. In

fact, two major CYP3A5 polymorphic alleles (CYP3A5*1 and *3) have been identified in the

Chinese population (24) and, of note, in Chinese healthy subjects, Li et al (25) observed no

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significant correlation between CYP3A5 genetic variations and disposition after administration of

10 mg ilaprazole as a single oral dose. In particular, there were no significant variations in the

plasma AUC and peak plasma concentration (Cmax) of ilaprazole in individuals with CYP3A5*1 or

CYP3A5*3 genotypes. Moreover, in the same study, there was no correlation between ilaprazole

metabolism and CYP2C19 genotypes. Overall, based on current knowledge, genotype variations of

CYP3A5 or CYP2C19 do not appear to affect ilaprazole metabolism.

As the extension of plasma half-life is a critical factor in accelerating the onset of action,

compounds with a half-life longer than that of current PPIs may be expected to display first-day

efficacy. Indeed, a mean half-life of 3.6 h has been reported for ilaprazole in healthy volunteers (26)

and this is far longer than that estimated for both first- and second-generation PPIs (0.5-2 hours)

(27), thus contributing to a more rapid control of acid-related symptoms.

Moreover, by examining the metabolites of ilaprazole, it has been found that it is

predominantly metabolized by CYP3A and only partially by CYP2C19 (28). So, the impact of

CYP450 polymorphism on the pharmakinetics of ilaprazole is lower than that of previous PPIs and

this property combined with the prolonged elimination half-life is expected to impact positively, in

terms of both lower inter-individual variability and longer-lasting acid inhibition, on the control of

gastric acid secretion by this new PPI.

Several in vivo investigations evaluated the antisecretory activity of this compound, which

proved to be 2-3 times stronger than that of omeprazole (29). The high antisecretory activity of

ilaprazole was confirmed in GERD patients where the drug, given at 10 and 20 mg daily, provided a

greater and prolonged suppression of acid secretion compared with omeprazole 20 mg (30). In

another study (31), significant differences were found between ilaprazole and omeprazole in terms

of intragastric mean pH values. In fact, given at the dose of 20 mg daily, ilaprazole allowed to

obtain significantly higher mean pH values than omeprazole 20 mg on day 1 (7.78 vs 6.67, p <

0.05) and 5, 10 and 20 mg of ilaprazole were all superior to omeprazole 20 mg on day 5 (7.51, 8.14

and 7.95 vs 7.44, respectively, p < 0.05). The Authors concluded that ilaprazole was comparable to

omeprazole at relatively low dosage on day 5 of administration, but, using equivalent dosages as

high as 20 mg of the two PPIs, ilaprazole had quicker onset of action on day 1 compared to

omeprazole. So, the improved pharmacodynamic activity of ilaprazole may reflect its improved

pharmacokinetic properties in comparison to other PPIs.

9. Vonoprazan : a new antisecretory agent

Recently, a new antisecretory agent pertaining to the class of potassium-competitive acid

blockers (pCABs), vonoprazan, has been synthesized and has been shown to provide higher

9

suppression of gastric acid secretion as compared to lansoprazole in GERD patients (32). At

variance from all available PPIs, vonoprazan acts directly on H+K+ ATPase irrespectively of its

activity, thus providing a fast onset of action without requiring acid activation and specific

administration timing. Clinical and pharmacological investigations have confirmed a more rapid,

potent and prolonged inhibition of acid secretion, including a better nighttime acid control, and a

less antisecretory variability, as compared with PPIs. Preliminary data in patients with erosive

esophagitis have shown the non-inferiority of vonoprazan to lansoprazole in terms of both symptom

relief and healing rate. Moreover, thanks to its above-mentioned pharmacokinetic advantages,

vonoprazan combined to antibiotics has been shown to be more effective than triple therapy

containing lansoprazole in obtaining the eradication of H. pylori infection as part of first-line and

second-line triple therapy in patients with a history of gastric or duodenal ulcer (33). However, the

clinical use of vonoprazan in GERD patients raises some concerns about its efficacy and safety in

the long-term that deserve verification and careful investigation. So far, there are no comparative

studies between vonoprazan and ilaprazole from both pharmacological and clinical point of view.

10. Ilaprazole and GERD

The greatest part of the available literature on ilaprazole therapeutic outcome pertains to

patients with peptic ulcer disease, who had also reflux symptoms associated to the ulcer ones in

several clinical trials. So, data about the efficacy of ilaprazole for the acute treatment of GERD with

and without erosive esophagitis as well as for the long-term maintenance of healed ERD and

symptom relief in both ERD and NERD patients are very scant. However, the better ability of

ilaprazole, even at low dosage, in suppressing acid secretion compared to omeprazole 20 mg in the

above-mentioned pharmacodynamic study in GERD patients (30), permits to anticipate that its

efficacy will be greater than that of omeprazole in ERD patients. Indeed, a randomized, double-

blind, controlled clinical study, comparing the ulcer-healing effects of ilaprazole 5 and 10 mg daily

with omeprazole 20 mg daily for 4 weeks, evaluated also, as secondary aim, the post-treatment

outcome of associated reflux symptoms, such as heartburn and acid regurgitation (34). In this

setting, the two PPIs were comparable, but even ilaprazole 5 mg was as successful as omeprazole

20 mg daily. In a further study, Wang et al (35), investigating patients with duodenal ulcer, found a

complete relief of associated heartburn (38.7% of patients at baseline) in 95.2%, 100%, 90% and

92.3% of cases treated with 5-, 10-, 20-mg ilaprazole and 20-mg omeprazole, respectively. With

regard for the second typical symptom of GERD, that is acid regurgitation, which was present in

46.8% of ulcer patients at baseline, all cases treated with different dosages of ilaprazole had

complete relief, as compared with only 11.5% of patients receiving 20 mg omeprazole. Finally, a

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larger phase III trial carried out to compare ilaprazole 10 mg/day with omeprazole 20 mg/day in the

healing of duodenal ulcer, showed that both treatments were equally effective in controlling all

symptoms after 4 weeks of therapy, including regurgitation and heartburn appearing during the

night (36). Also Gao et al (37) explored the effects of 7-day ilaprazole-based bismuth-containing

quadruple therapy for the first-line treatment of H. pylori infection versus an esoprazole-based

regimen in a large group of infected patients and found that there was no difference between the

two PPIs in terms of both eradication rates and symptom relief, including heartburn.

Overall, the above studies were not performed exclusively in GERD patients, but their

results seemed to be highly predictive of a good success of ilaprazole, even at low dosages, in

patients with both ERD and NERD and therefore further clinical trials are urgently needed to

confirm this expectation.

11. Safety of ilaprazole

Information on the safety profile of ilaprazole is not consistent, owing to the limited

availability of published data on GERD patients. However, two 4-week studies on the treatment of

peptic ulcer, showed that ilaprazole, given at both 5 and 10 mg daily, was as tolerable and safe as

omeprazole 20 mg daily (30,31).

Obviously, further studies are warranted in order to better assess ilaprazole safety,

particularly on the long-term.

12. Regulatory aspects

Ilaprazole is a new PPI that was developed by IL-YANG Pharmaceutical Company Ltd.

(Seoul, South Korea), and presently owned by Lizvon Pharmaceutical Group Inc. (China). It has

been approved by the State Food and Drug Administration of China (license ID: CN 1121714A) for

the treatment of gastric and duodenal ulcer in 2007 and in South Korea for the treatment of the

same ulcers in 2009 and erosive esophagitis in 2012 with a recommended dose of 10 mg/daily.

13. Conclusions

GERD is one of the most widespread chronic gastrointestinal disorders in Western

countries, affecting up to 20% of the general population. Acid suppression represents the mainstay

of GERD medical treatment and, to date, the currently available first- and second-generation PPIs

(omeprazole, pantoprazole, lansoprazole, rabeprazole, esomeprazole) represent the best therapeutic

option for this disease, since they are able to provide a satisfactory symptomatic relief and an

almost complete healing of esophageal mucosal injuries. However, despite their well-established

11

success, recent studies have documented that about 30%-40% of GERD patients display a poor or

absent response to PPIs, thus underlying the need for new therapeutic options for these patients.

However, the possible mechanisms of refractoriness to PPIs often require esophageal

pathophysiological examinations in order to understand the reasons for which these drugs do not

work as expected (38-41).

In this context, ilaprazole was developed by Il Yang Pharmacy Co. (Seoul, Korea) to

overcome the shortcomings of currently available PPIs. Up to date, this drug has been shown to

induce an irreversible inhibition of gastric H+-K+-ATPase in a dose-dependent manner with greater

acid suppression as compared with omeprazole. These improved pharmacodynamic features are the

mirror of the peculiar pharmacokinetic properties of ilaprazole, which are characterized by an

extended plasma elimination half-life, as compared to current PPIs. This longer half-life may

contribute in speeding the relief of symptoms, particularly in patients with NERD. Furthermore, at

variance with the majority of available PPIs, the hepatic metabolism of ilaprazole is not

significantly influenced by CYP2C19 genetic polymorphism. This aspect reduces the inter-

individual variability in the antisecretory action of ilaprazole, with potential advantages in clinical

applications (e.g. a better control of nocturnal acid breakthrough).

Overall, the improved pharmacokinetics and pharmacodynamics of ilaprazole might

translate into significant clinical benefits, which need to be substantiated by randomized and

controlled trials in GERD patients.

14. Expert opinion

Nowadays, GERD is the most frequent acid-related disorder we can face in our daily clinical

practice. PPIs represent the first choice therapy to treat patients with this disease and they have

almost completely replaced H2 antagonists because of their better effectiveness. In fact, PPIs are

able to control adequately typical reflux symptoms and to induce the healing of erosive esophagitis,

when present. Moreover, they have been shown to reduce the formation of esophageal strictures

(42) and the rate of development of dysplasia from Barrett intestinal metaplasia (43).

However, despite the good efficacy of both first- and second-generation PPIs, these drugs

have several limitations that make difficult to overcome some relevant unmet needs of GERD

medical therapy. For instance, they have generally a slow onset of action, are affected by hepatic

cytochrome P450 polymorphism and do not cover completely gastric acid secretion during the

whole 24-hour period, particularly overnight. Taking into consideration the above shortcomings, the

clinical consequences are the poor symptom control during the first day of administration, the inter-

12

individual variability of gastric acid suppression and the scant effect on nocturnal symptoms, which

can appear in about 50% of GERD patients (44).

Therefore, there is need for the availability of novel PPIs with better pharmacokinetic and

pharmacodynamic properties and ilaprazole is a molecule representing a real progress in this field.

In fact, it has a prolonged bioavailability compared with the traditional PPIs (3.6 h vs 0.5-2.1 h), a

greater and longer inhibition of acid secretion assessed against omeprazole and is not affected by

CY2C19 polymorphism. Accordingly, it has the potential to achieve a fast symptom relief also in

the first day of therapy and this is very important in relation to the fact that the majority of GERD

patients have the NERD phenotype (≈ 70%) and they do need only a quickest as possible control of

their symptoms, because there are not mucosal lesions to heal. Moreover, the antisecretory effect of

ilaprazole is more reproducible among various individuals, because it is not influenced by the

hepatic metabolism of the drug, which depends only partially by CYP2C19, in contrast with almost

all other PPIs. Finally, the long-lasting duration of action permits to obtain a more uniform acid

inhibition over the entire 24-hour period with a more adequate effect on nocturnal symptoms and

using a lower and safer dosage than the other PPIs.

The clinical results on the use of ilaprazole in GERD patients are scant, but its efficacy on

the control of heartburn and regurgitation has been shown to be excellent in several trials carried

out to assess the healing of peptic ulcer. In these investigations ilaprazole, at low dosage (5 and 10

mg), has been shown to be comparable or even better than omeprazole 20 mg daily. Unfortunately,

so far there are no sufficient studies comparing the pharmacokinetic and pharmacodynamic

properties of ilaprazole with those of second-generation PPIs. Obviously, the potential

improvements in the current standard of care for acid-suppressing treatment must be confirmed in

large and randomly controlled clinical trials evaluating exclusively patients with both ERD and

NERD.

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REFERENCES

1. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006; 101:1900-20. **This is the Consensus paper that has first classified the variuos clinical manifestations of GERD on the basis of their symptoms and this classification continues to be valid after 10 years 2. Dent J, El-Serag HB, Wallander MA, et al. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2005; 54:710-7. 3. El Serag H. Role of obesity in GORD-related disorders. Gut 2008; 57:281-4. 4. Pandolfino JE. The relationship between obesity and GERD: "big or overblown". Am J Gastroenterol 103:1355-7. 5. Savarino E, Zentilin P, Marabotto E, et al. Overweight is a risk factor for both erosive and non-erosive reflux disease. Dig Liver Dis. 2011; 43:940-5. 6. Pandolfino JE, El Serag HB, Zhang Q, et al. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology 2006; 130:639-49. 7. Savarino E, Zentilin P, Savarino V. NERD : an umbrella term including heterogeneous subpopulations. Nat Rev Gastroenterol Hepatol 2013; 10:371-80. ** This review has definitively stated that the term NERD can be considered an umbrella underlying various subpopulations which differ from a pathophysiological point of view 8. Savarino E, Tutuian R, Zentilin P, et al. Characteristics of reflux episodes and symptom association in patients with erosive esophagitis and nonerosive reflux disease: study using combined impedance-pH off therapy. Am J Gastroenterol. 2010;105:1053-61. 9. Savarino E, Pohl D, Zentilin P, et al. Functional heartburn has more in common with functional dyspepsia than with non-erosive reflux disease. Gut. 2009; 58:1185-91. 10. Savarino E, Zentilin P, Tutuian R, et al. Impedance-pH reflux patterns can differentiate non-erosive reflux disease from functional heartburn patients. J Gastroenterol 2012; 47:159-68. 11. Vigneri S, Termini R, Leandro G, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med. 1995; 26;333:1106-10. 12. Scarpignato C, Pelosini I, Di Mario F. Acid suppression therapy: where do we go from here? Dig Dis. 2006; 24:11-46. * This review has emphasized the strengths and limitations of currently available PPIs in the treatment of acid-related disorders 13. Katz MH. Failing the acid test : benefits of proton pump inhbitors may not justify the risks for many users. Arch Intern med 2010; 170:747-8. 14. Madanick RD. Proton pump inhibitors side effects and drug interactions: much ado about nothing. Cleve Clin J Med 2011; 78:39-49. 15. Tytgat GN. Shortcomings of the first-generation proton pump inhibitors. Eur J Gastroenterol Hepatol. 2001; 13 Suppl 1:S29-33. 16. Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol. 2004; 95:2-8. 17 Savarino V, Di Mario F, Scarpignato C. Proton pump inhibitors in GORD. An overview of their pharmacology, efficacy and safety. Pharmacol Res. 2009; 59:135-53. 18. Sifrim D, Zerbib F. Diagnosis and management of patients with reflux symptoms refractory to proton pump inhibitors. Gut. 2012; 61:1340-54. 19. Frazzoni M, De Micheli E, Grisendi A, et al. Hiatal hernia is the key factor determining the lansoprazole dosage required for effective intra-oesophageal acid suppression. Aliment Pharmacol Ther 2002; 16:881-6. 20. Tack J. Review article: the role of bile and pepsin in the pathophysiology and treatment of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2006; 24(suppl 2):10-6.

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21. Scarpignato C, Franzè A. Esophageal exposure to acid in GERD patients with and without delayed gastric emptying. Effect of cisapride. hepatogastroenterology 1992; 39:91-2. 22. Kim EJ, Lee RK, Lee SM, et al. General pharmacology of IY-81149, a new proton pump inhibitor. Arzneimittelforschung. 2001; 51:51-9. * This study evaluates the pharmacological effects of ilaprazole. 23. De Bortoli N, Martinucci I, Giacchino M, et al. The pharmacokinetics of ilaprazole for gastro-esophageal reflux treatment. Exp Opin Drug Metab Toxicol 2013; 9: 1361-9. * This review summarizes all the pharmacokinetic properties of ilaprazole and part of them represent the basis for its better performance in comparison with omeprazole and the other PPIs 24. Liu CH, Peck K, Huang JD, et al. Screening CYP3A single nucleotide polymorphisms in a Han Chinese population with a genotyping chip. Pharmacogenomics. 2005; 6:731-47. 25. Li Y, Zhang W, Guo D, et al. Pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes. Clin Chim Acta. 2008; 391:60-7. 26. Goldwater R, Lee SM, Chung GJ, et al. A phase I, randomized, parallel placebo-controlled safety, tolerance and pharmacokinetic study of multiple doses of IY-8119 in fasting male volunteers. Clin Pharmacol Ther; 1999; 65:126 (abstr PI-35). 27. Sachs G, Shin JM, Howden CW. Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther. 2006; 23 Suppl 2:2-8. 28. Cho H, Choi MK, Cho DY, et al. Effect of CYP2C19 genetic polymorphism on pharmacokinetics and pharmacodynamics of a new proton pump inhibitor, ilaprazole. J Clin Pharmacol. 2012; 52:976-84. * This study suggests that the pharmacokinetics and pharmacodynamics of ilaprazole are not significantly influenced by the CYP2C19 genetic polymorphisms. 29. Kil BJ, Kim IW, Shin CY, et al. Comparison of IY81149 with omeprazole in rat reflux oesophagitis. J Auton Pharmacol. 2000; 20:291-6. 30. Periclou AP, Goldwater R, Lee SM, et al. A comparative pharmacodynamic study of IY-81149 versus omeprazole in patients with gastroesophageal reflux disease. Clin Pharmacol Ther. 2000; 68:304-11. 31. Du YQ, Guo WY, Zou DW, et al. Acid inhibition effect of ilaprazole on Helicobacter pylori-negative healthy volunteers: an open randomized cross-over study. J Dig Dis. 2012; 13:113-9. ** This is the only study comparing the acid inhibition effect of ilaprazole vs omeprazole in healthy volunteers. 32. Savarino E, Martinucci I, Furnari M, et al. Vonoprazan for treatment of gastroesophageal reflux: pharmacodynamic and pharmacokinetic considerations. Expert Opin Drug Metab Toxicol 2016; 8:1-9. 33. Murakami K, Sakurai Y, Shiino M, et al. Vonoprazan, a novel potassium-competitive acid blocker, as a component of first-line and second-line triple therapy for Helicobacter pylori eradication: a phase III, randomised, double-blind study. Gut 2016; 65:1439-46. 34. Ho KY, Kuan A, Zano F, et al. Randomized, parallel, double-blind comparison of the ulcer-healing effects of ilaprazole and omeprazole in the treatment of gastric and duodenal ulcers. J Gastroenterol. 2009; 44:697-707. 35. Wang L, Zhou L, Lin S, et al. A new PPI, ilaprazole compared with omeprazole in the treatment of duodenal ulcer: a randomized double-blind multicenter trial. J Clin Gastroenterol. 2011 ; 45:322-9. 36. Wang L, Zhou L, Hu H, et al. Ilaprazole for the treatment of duodenal ulcer: a randomized, double-blind and controlled phase III trial. Curr Med Res Opin 2012; 28:101-9. 37. Gao W, Cheng H, Hu FL, et al. Ilaprazole-based bismuth-containing quadruple regimen for the first-line treatment of Helicobacter pylori infesction: a multicenter, randomized, controlled clinical study. Zhonghua Yi Xue Za Zhi 2012; 92:2108-12.

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38. Zentilin P, Dulbecco P, Savarino E, et al. Combined multichannel intraluminal impedance and pH-metry: a novel technique to improve detection of gastro-oesophageal reflux. Literature review. Dig Liver Dis 2004; 36:565-9. 39. Savarino V, Savarino E, Parodi A, et al. Functional heartburn and non-erosive reflux disease. Dig Dis. 2007; 25:172-4. 40. Savarino E, Marabotto E, Zentilin P, et al. The added value of impedance-pH monitoring to Rome III criteria in distinguishing functional heartburn from non-erosive reflux disease. Dig Liver Dis. 2011; 43:542-7. 41. de Bortoli N, Nacci A, Savarino E, et al. How many cases of laryngopharyngeal reflux suspected by laryngoscopy are gastroesophageal reflux disease-related? World J Gastroenterol. 2012; 18:4363-70. 42. Ruigomez A, Garcia Rodriguez LA, Wallander MA, et al. Esophageal stricture: incidence, treatment patterns, and recurrence rate. Am J Gastroenterol 2006; 101:2685-92. 43. Kastelein F, Spaander MC, Steyerberg EW, et al. Proton pump inhibitors reduce the risk of neoplastic progression in patients with Barrett's esophagus. Clin Gastroenterol hepatol 2013; 11:382-8. 44. Bruley des Varannes S, Ducrottè P, et al. Gastroesophageal reflux disease: impact on work productivity and daily life activities of daytime workers. A French cross-sectional study. Dig Liver Dis 2013; 45.200-6.

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Box 1. Drug summary.

Drug name (generic) Ilaprazole Phase (for indication under discussion)

III

Indication (specific to discussion)

Gastroesophageal reflux disease, both erosive and non-erosive

Pharmacology description/mechanism of action

H+K+-transporting ATPase inhibitor

Route of administration Oral Chemical structure

Pivotal trial(s) Ref. 32-34

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Figure 1. Stratification of endoscopy-negative patients based on 24-hour impedance-pH monitoring and reported response to proton pump inhibitors (PPI) therapy

True NERD

(abnormal esophageal acid exposure)

Hypersensitive Esophagus

(normal esophageal acid exposure and positive

symptoms association analysis)

Functio

(normal eexposur

symptoms as

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Table 1. Putative Mechanisms for no response to medical therapy in GERD

Mechanisms for Refractory GERD Refractoriness patient-related Poor Compliance and improper timing of PPI administration Large hiatal hernia Weakly acidic reflux Duodeno-gastroesophageal/bile reflux Visceral hypersensitivity Delayed gastric emptying Psychological comorbidity Functional Heartburn Concomitant functional gastric and/or bowel disorders Refractoriness therapy-related Slow onset of action Reduced PPI bioavailability , rapid metabolism Residual acid reflux Nocturnal Acid Breaktrough PPI-induced delay in gastric emptying with consequent dyspepsia

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Table 2. Alternative therapeutic options in case of PPI refractoriness

Therapeutic Interventions: Improving Compliance and Time of Administration Lifestyle Modifications Histamine 2 Receptor Antagonists (H2RAs) New Proton Pump Inhibitors (Ilaprazole, Dexlansoprazole) TLESR Reducers Promotility Drugs Alginates, Sucralfate Visceral Pain Modulators Endoscopic Treatment (Stretta, Endoplicator) Antireflux Surgery Alternative Medicine (Hypnotherapy) Psychological Treatment Functional Gastrointestinal Disorders Treatment

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