PROTON

PUMP
INHIBITOR
S
Dr. Ghulam Mustafa
Sr. Medical Manager & Compliance Officer
Proton Pump Inhibitors 26

• Proton-pump inhibitors (PPIs) represent a class of drugs most prominently

known for their use in acid-related disorders.
• They are indicated for:

1. Esophagitis
2. Non-erosive reflux disease
3. Peptic ulcer disease
4. Prevention of nonsteroidal anti-inflammatory drug-induced ulcers
5. Zollinger-Ellison Syndrome
6. Part of the triple therapy regimen for Helicobacter pylori infections

26. Fass, R., & Frazier, R. (2017). The role of dexlansoprazole modified-release in the management of gastroesophageal reflux
disease. Therapeutic advances in gastroenterology, 10(2), 243–251. [Link]
Mechanism of Action of PPIs 26

• PPIs function to decrease acid

secretion in the stomach

• PPIs block the H+/K+ ATPase

enzyme proton pump in the
parietal cells of stomach.

• The H+/K+ ATPase enzyme serves

as the final step of acid secretion
in the stomach.

• Hepatic P450 enzymes degrade

PPIs through the CYP2C19.

26. Fass, R., & Frazier, R. (2017). The role of dexlansoprazole modified-release in the management of gastroesophageal reflux
disease. Therapeutic advances in gastroenterology, 10(2), 243–251. [Link]
Some Facts

•It is known that some GERD patients (17–35%) treated with omeprazole or other proton pump inhibitors
continue experiencing symptoms of the disease

•Studies show that up to 35.4% of patients and 34.8% of physicians are not fully satisfied with the outcome
of treatment based on traditional PPIs

•The resistance to hyposecretory treatment can arise from a variety of factors.

Some Facts

•Some of them are physician-related (incorrect diagnosis, inappropriate drug dose, insufficiently long treatment), others

•Patient-related (lack of compliance, genotypic differences determining drug metabolism)

•Drug-related (duration of maintaining gastric pH above 4).

•One of the causes underlying the inefficacy of PPIs in the treatment of GERD can also be non-acidic reflux or nocturnal
acid breakthrough in the stomach accompanied by sleep disorders
What is Dexlansoprazole?

• Dexlansoprazole is a Proton Pump Inhibitor.

• It is indicated for
1. Healing of all grades of erosive esophagitis (EE).

2. Maintaining healing of EE and relief of heartburn.

3. Treating heartburn associated with symptomatic non-erosive

gastroesophageal reflux disease (GERD).
For Erosive Esophagitis 27

• There are two pivotal randomized controlled trials

that assessed the efficacy and safety of
dexlansoprazole MR in healing erosive esophagitis.

• A total of 4092 patients with erosive esophagitis

were randomized to receive dexlansoprazole MR 60
mg, dexlansoprazole MR 90 mg, or lansoprazole 30
mg once daily and week 8 healing was assessed.

• Secondary clinical endpoints included week 4

healing and week 8 healing in patients with
moderate-to-severe erosive esophagitis.

27. Metz DC, Howden CW, Perez MC, et al. Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-release technology, effectively controls
symptoms and prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther 2009;
For Erosive Esophagitis 28

• Dexlansoprazole MR (30 mg and 60 mg) was non-inferior to lansoprazole 30

mg once daily.

• However, dexlansoprazole MR 60 mg was superior to lansoprazole 30 mg

in one trial (85% versus 79% healing rates).

• Integrated data from these two trials demonstrated that dexlansoprazole MR

90 mg was significantly better than lansoprazole 30 mg in patients with
moderate-to-severe erosive esophagitis, which resulted in a therapeutic gain
of 8%.

28. Sharma P, Shaheen NJ, Perez MC, et [Link] trials: healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-
release formulation-results from two randomized controlled studies. Aliment Pharmacol Ther 2009
 Percent of patients with healed Los Angeles
grade C or D erosive esophagitis at 8 weeks

(life table analysis)

Lansoprazole is the only PPI to which dexlansoprazole MR

has been directly compared.

Lesions had been healed in 92.3–93.1% of the patients compared to 86.1–91.5%

Ref: Mermelstein J, Mermelstein AC, Chait MM. Proton pump inhibitors for the treatment of patients with erosive esophagitis and gastroesophageal reflux disease: current evidence and
safety of dexlansoprazole. Clin Exp Gastroenterol. 2016;9:163-172. Published 2016 Jul 13. doi:10.2147/CEG.S91602
For Maintenance of Erosive Esophagitis
Healing 29,30

• According to a study, approximately 90% of the patients with healed erosive

esophagitis, who are not maintained on anti-reflux medication will relapse
within 6 months after discontinuation of treatment.

• In two randomized, placebo-controlled trails, Dexlansoprazole MR 30 mg and

60 mg were superior to placebo for maintaining healed erosive esophagitis (p
< 0.0025).

• Using life table analysis, maintenance rates were 75%, 83%, and 27% for
dexlansoprazole 30 mg, 60 mg and placebo, respectively.

29. Dickman R, Maradey-Romero C, Gingold-Belfer R, et al. Unmet needs in the treatment of gastroesophageal reflux disease. J Neurogastroenterol Motil 2015
30. Metz DC, Howden CW, Perez MC, et al. Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-release technology, effectively controls
symptoms and prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther 2009
For Maintenance of Erosive Esophagitis
Healing 31

• Both dexlansoprazole 60 mg and 90 mg were superior to placebo for

maintaining healing of erosive esophagitis. Maintenance rates were 87%, 82%
and 26%, respectively, using life table analysis.

• Both doses were superior to placebo for the percentage of 24-h heartburn-free
days and nights.

• Both doses of dexlansoprazole MR, were well tolerated with diarrhea,

flatulence, gastritis, abdominal pain and upper respiratory tract infection more
common in dexlansoprazole MR than placebo but were not dose related.

31. Howden CW, Larsen LM, Perez MC, et al. Clinical trial: efficacy and safety of dexlansoprazole MR 60 and 90 mg in healed erosive oesophagitis-maintenance of
healing and symptom relief. Aliment Pharmacol Ther 2009
Dexlansoprazole for NERD 32

• One study evaluated the efficacy and safety of dexlansoprazole MR in

controlling symptoms in patients with NERD. This was a 4-week, double-blind,
placebo-controlled trial.

• A total of 947 NERD patients were randomized to receive dexlansoprazole MR

30 mg, 60 mg or placebo once daily.

• All enrolled patients had to have heartburn for at least 6 months and normal
esophageal mucosa on upper endoscopy.

• During the 7-day run-in period patients had to have at least 4 days with
heartburn symptoms.
32. Fass R, Chey WD, Zakko SF, et al. (2009) Clinical trial: the effects of the proton pump inhibitor dexlansoprazole MR on daytime and nighttime heartburn in patients
with non-erosive reflux disease. Aliment Pharmacol Ther 29
 Dexlansoprazole for NERD 32

• Dexlansoprazole MR 30 mg and 60 mg
provided a significantly better median 24 H Heartburn Free Days
percentages of 24-hour heartburn-free 60.00%

days compared with placebo (54.9% and 50.00%

50.0% versus 17%, respectively). 40.00%

30.00%
55%
50%
• The percentage of nights without 20.00%

heartburn was also significantly greater in 10.00% 18%

patients receiving dexlansoprazole MR 60
0.00%
mg and 30 mg than placebo (80.8% and Dexlansoprazole
30 mg
Dexlansoprazole
60 mg
Placebo

76.9% versus 51.7%).

32. Fass R, Chey WD, Zakko SF, et al. (2009) Clinical trial: the effects of the proton pump inhibitor dexlansoprazole MR on daytime and nighttime heartburn in patients
with non-erosive reflux disease. Aliment Pharmacol Ther 29
Nighttime Heartburn
and Sleep Distrubances 33

• Nocturnal symptoms and sleep disturbances are very common in patients with
GERD, and it has been reported that up to 50% of patients with GERD suffer
from nocturnal symptoms.

• According to a trail, patients receiving dexlansoprazole MR:

1. experienced 73.1% heartburn-free nights compared with 35.7% in those
receiving placebo.
2. (47.5%) had relief of nocturnal heartburn symptoms over the last week of
the study period when compared with the placebo group (19.6%).
3. was significantly better than placebo in controlling GERD-related sleep
disturbances (69.7% versus 47.9%).

33. Shaker R, Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a
gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003
 Nighttime Heartburn and Sleep
Distrubances33

Survey About Experiencing Heartburn Total Patients 1000

79% 75% 71%

63%

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33. Shaker R, Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a
gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003
Dexlansoprazole for Regurgitation 34

• An analysis was conducted to evaluate the impact of dexlansoprazole on

heartburn versus regurgitation in patients with either NERD or erosive
esophagitis.

• NERD patients receiving dexlansoprazole MR 30 mg and 60 mg

experienced significantly greater improvements in symptom severity
for both heartburn and regurgitation compared with placebo.

• The authors concluded that dexlansoprazole MR appears to be effective in

improving both heartburn and regurgitation in both EE and NERD patients and
this improvement is maintained throughout the duration of treatment.

34. Piura DA, Pilmer B, Hint B, et al. Distinguishing the impact of dexlansoprazole on heartburn vs regurgitation in patients with gastro-oesophageal reflux
disease. Aliment Pharmacol Ther 2013
On-Demand Therapy with Proton Pump Inhibitors for
Maintenance Treatment of Nonerosive Reflux
Disease or Mild Erosive Esophagitis: A Systematic
Review and Meta-Analysis 20%-
40%
On-demand PPI treatment is effective for
many patients with NERD or mild EE.

Different manifestations of GERD include nonerosive reflux

disease (NERD) and erosive esophagitis (EE).

NERD, the most frequent manifestation of GERD, is present in

around 70% of patients and characterized by the presence of
typical GERD symptoms associated with pathological acid
reflux but the absence of demonstrable esophageal mucosal
injury on endoscopy.
Estimated
Ref: Zubair Khan, Yaseen Alastal, Muhammad Ali Khan, Mohammad Saud Khan, Basmah Khalil, Shreesh
western adult
Shrestha, Faisal Kamal, Ali Nawras, Colin W. Howden, "On-Demand Therapy with Proton Pump Inhibitors for populations
Maintenance Treatment of Nonerosive Reflux Disease or Mild Erosive Esophagitis: A Systematic Review and
Meta-Analysis", Gastroenterology Research and Practice, vol. 2018, Article report chronic
ID 6417526, 10 pages, 2018. [Link]
heartburn or
regurgitation
 On-Demand Therapy with Proton Pump Inhibitors for
Maintenance Treatment of Nonerosive Reflux Disease
or Mild Erosive Esophagitis: A Systematic Review and
Meta-Analysis
Despite the absence of mucosal injury on endoscopy, many patients with NERD
experience severe symptoms and impairment in quality of life that may be
equivalent to, or greater than, seen in patients with EE.

Acid-suppressive therapy with proton pump inhibitors (PPI) has proved

to be the most effective treatment strategy for both NERD and EE.

PPIs have shown superiority over histamine H2-receptor antagonists for

controlling symptoms as well as for healing erosions and preventing
relapse.

Ref: Zubair Khan, Yaseen Alastal, Muhammad Ali Khan, Mohammad Saud Khan, Basmah Khalil, Shreesh Shrestha, Faisal Kamal, Ali Nawras, Colin W. Howden, "On-
Demand Therapy with Proton Pump Inhibitors for Maintenance Treatment of Nonerosive Reflux Disease or Mild Erosive Esophagitis: A Systematic Review and
Meta-Analysis", Gastroenterology Research and Practice, vol. 2018, Article ID 6417526, 10 pages, 2018. [Link]
Clinical efficacy of 60-mg dexlansoprazole and 40-mg
esomeprazole after 24 weeks for the on-demand treatment
of gastroesophageal reflux disease grades A and B: a
prospective randomized trial

Purpose:
 Research comparing the clinical efficacy of
dexlansoprazole, and esomeprazole has
been limited.

 A study aimed to compare the clinical

efficacy of single doses of dexlansoprazole
(modified-release 60 mg) and
esomeprazole (40 mg) after 24-week
follow-up in patients with mild erosive
esophagitis.
Ref: Chiang HH, Wu DC, Hsu PI, Kuo CH, Tai WC, Yang SC, Wu KL, Yao CC, Tsai CE, Liang CM, Wang YK, Wang JW, Huang CF, Chuah SK. Clinical efficacy of 60-mg
dexlansoprazole and 40-mg esomeprazole after 24 weeks for the on-demand treatment of gastroesophageal reflux disease grades A and B: a prospective randomized
trial. Drug Des Devel Ther. 2019;13:1347-1356. [Link]
 Dexlansoprazole
• Dexlansoprazole is a right-handed enantiomer of lansoprazole exhibiting greater efficacy in the inhibition of
gastric acid production.

• Compared to other PPIs, it has a unique mechanism of releasing the active ingredient.

• Consequently, the drug concentration in the blood and the proton pump inhibition effect are maintained for
much longer.

• Dexlansoprazole efficacy is not dependent on meal, which guarantees better compliance and cooperation
with the patient and high efficiency in everyday clinical practice.

• Crucial advantages of the drug include its optimum safety profile and low risk of adverse interactions with
concurrently taken medications
 Dexlansoprazole
An Advantage
Consequently, the drug achieves two peak concentrations in the blood, and the total serum concentration of
dexlansoprazole is three times higher than that of the left-handed enantiomer.

Also, dexlansoprazole has a lower elimination rate than S-lansoprazole and persists longer in the serum.

It inhibits acid secretion for a longer period, and its AUC (area under the curve) values are 3–5 times higher
than those determined for the racemic mixture or the left-handed isomer
Conclusion:
Study suggests that the symptom relief
effect for GERD after 24 weeks was similar
for dexlansoprazole and esomeprazole.

Dexlansoprazole exhibited fewer days with

reflux symptoms in the 24-week study
period, with better persistent
improvement in the GERDQ score in the on-
demand period.

Ref: Chiang HH, Wu DC, Hsu PI, Kuo CH, Tai WC, Yang SC, Wu KL, Yao CC, Tsai CE, Liang
CM, Wang YK, Wang JW, Huang CF, Chuah SK. Clinical efficacy of 60-mg dexlansoprazole
and 40-mg esomeprazole after 24 weeks for the on-demand treatment of
gastroesophageal reflux disease grades A and B: a prospective randomized trial. Drug
Des Devel Ther. 2019;13:1347-1356. [Link]
Side effects of Dexlansoprazole 35

• Overall, dexlansoprazole MR is well tolerated with very few side effects.

• In one study, fewer patients receiving dexlansoprazole MR discontinued

therapy because of adverse events, when compared with placebo.

• The safety profile of dexlansoprazole was evaluated in six controlled trials that
included data from 4270 patients.

• In general, dexlansoprazole MR had fewer adverse events per 100

patient months compared with the lansoprazole and placebo groups.

35. Peura DA, Metz DC, Dabholkar AH, et al. Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel USAL delayed release formulation: global
clinical trial experience. Aliment Pharmacol Ther 2009.
Side effects of Dexlansoprazole 35

• The most commonly reported treatment-emergent adverse events related to

dexlansoprazole (with a frequency of >2%) were:
1. Nausea
2. Diarrhea
3. Abdominal pain
4. Flatulence
5. Vomiting

• Diarrhea was the most common adverse event leading to discontinuation of

dexlansoprazole MR therapy in 0.7% of the patients.

35. Peura DA, Metz DC, Dabholkar AH, et al. Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel USAL delayed release formulation: global
clinical trial experience. Aliment Pharmacol Ther 2009;
Summary

• Dexlansoprazole is a Proton Pump Inhibitor (PPI) that is clinically effective in

reducing symptoms of non-erosive reflux disease (NERD) and in the healing
of erosive esophagitis by preventing acid from rising up into the esophagus.

• Compared to other PPIs, Dexlansoprazole has a unique mechanism of

releasing the active ingredient.

• The proton pump inhibitory effect and drug concentration of Dexlansoprazole

is also maintained for longer than other PPIs.

• Dexlansoprazole is well tolerated with a good safety profile and few side
effects.
Thank you.