Optimal Management of GERD with Dexlansoprazole - Extended plasma concentration and dosing flexibility with a dual delayed release PPI

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1 Optimal Management of GERD with Dexlansoprazole - Extended plasma concentration and dosing flexibility with a dual delayed release PPI Jun Heng Lee, M.D. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

2 Prevalence of GERD in Korea - a population-based study in Asan-si Male Female Total Heartburn At least monthly At least weekly Acid regurgitation At least monthly At least weekly Heartburn and/or acid regurgitation At least monthly At least weekly Cho YS, Choi MG. Am J Gastroenterol 2005;100:

3 Prevalence of GERD in health checkup Erosive esophagitis Reflux symptoms 7% 3% 7% 83%

4 Average physiological phs in GI tract Site fasted fed Stomach Duodenum Average ph Average ph Jejunum Ileum fasted fed stomach duodenum jejunum ileum stomach duodenum jejunum ileum Dressman. Pharm Res 1998:15:11-22

5 History of gastric acid & PPI 1823 Prout W Discovery of gastric acid 1836 Schwann Discovery of pepsin 1938 Komarov SA Discovery of gastrin 1972 Black JW Development of H2RA 1979 Olbe Development of PPI

6 There are many zoles. Omeprazole Lansoprazole Rabeprazole Pantoprazole Esomeprazole Illaprazole

7 A big exception: Aripiprazole (Abilify) an new antipsychotic a dopamine system stabilizer

8 Today s topic is about a relatively new member of the PPI family Omeprazole Lansoprazole Rabeprazole Pantoprazole Esomeprazole Illaprazole Dexlansoprazole (Dexilant)

lansoprazole The R-enantiomer has a slower

circulating plasma concentrations than the

9 Lansoprazole Dexlansoprazole (R-enantiomer) Lansoprazole is a racemic mixture of R- and S-entantiomers Dexlansoprazole is the R-enantiomer of lansoprazole The R-enantiomer has a slower clearance rate and correspondingly higher circulating plasma concentrations than the S-enantiomer Choi KD, et al. J Gastroenterol Hepatol 2009;24:

11 Do you think our patients are happy enough? Jun Heng Lee, M.D. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

12 Patients are not satisfied as much as doctors. The proportion of very satisfied or well controlled is higher by doctors assessment (blue bar) than the patients assessment (green bar). ReQuest TM -GI questionnaire

13 Goh. J Gastroenterol Hepatol 2014;29:1969

14 Response to PPI therapy Goh. J Gastroenterol Hepatol 2014;29:1969

15 Ideal GERD medication - Asian patients perspective Goh. J Gastroenterol Hepatol 2014;29:1969

16 Areas of unmet needs - Dexilant is very useful for these areas. Night-time heartburn PPIs-dependence on food for efficacy Individual variation Advanced grades of erosive esophagitis Non-erosive reflux disease

17 1. Mangement of night-time symptoms or breakthrough symptoms with Dexlilant 성균관대학교의과대학내과이준행

18 American Gastroenterological Association. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; 2008.

19 Most Patients with breakthrough symptoms experience them at night At night 65% While sleeping 28% During the day 45% In the morning 16% 0% 20% 40% 60% 80% 100% Adapted from American Gastroenterological Association. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; Available at Accessed Apr 9, 2018

Percentage of respondents receiving twice-daily dosing 80 73.4 60 40 39.1 20 0 9.4 7.

20 Percentage of respondents receiving twice-daily dosing Symptoms not controlled Symptoms not controlled at night Insurance coverage change Other Chey WD Curr Med Res Opin 2009;25:1869

21 PPIs bind to active pumps only H 2 ACh H+ H+ H+ K+ K+ K+ K+ Unstimulated proton pumps in cytoplasmic tubules H+ Gastrin Inactive Parietal Cell

22 Plasma concentration Most PPIs have short half-life Proton pumps activated in this period are not blocked by PPI Effective plasma level Time

24 The DDR formulation results in a plasma concentration-time profile with two distinct peaks Granule 1 comprises 25% of total dose and is released at ph 5.5 within 2 hours of dosing 2 Release 1 Granule 2 comprises 75% of total dose and is released at ph 6.75 several hours after dosing Release 2 1. KAPIDEX (dexlansoprazole) Prescribing Information, Takeda, Deerfield, IL Data on file, Takeda Pharmaceuticals North America, Inc. Deerfield, IL.

Drug concentration (ng/ml) 2000 1800 1600 1400 1200 1000 Conventional PPI DEXILANT 30 mg DEXILANT

25 Drug concentration (ng/ml) Conventional PPI DEXILANT 30 mg DEXILANT 60 mg Time (hours) 125 ng/ml Vakily Curr Med Res Opin. 2009;25:627

26 Kukulka. Clin Exp Gastroenterol 2011;4:213-20

Median percentage 40 36.8 Dexlansoprazole MR 30mg 35 Placebo 30 25 22.2 26.1 20 22.2 15 11.1 16.7 16.7 10 5 6.9 9.7 6.2 6.1 7.

27 Median percentage Dexlansoprazole MR 30mg 35 Placebo Nights with GERDrelated Sleep disturbances Nights with Difficulty Falling asleep Nights with waking Nights with Difficulty Getting back to sleep Morning Waking too early Morning Waking up Feeling tired Nights with Sleep Disturbances Due to other reasons Fass R Am J Gastroenterol. 2011;106:421

28 Nights without GERD symptoms by Dexilants 100% 80% 60% 40% 20% 0% 24hr heartburn free day Nights without heartburn Placebo Dexlansoprazole 60mg Howden CW. Aliment Pharmacol Ther 2009;30:895

29 2. Dexilant can be taken after the meal Jun Heng Lee, M.D. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

30 Sub-optimal PPI dosing in 54% Gunaratnam NT. Aliment Pharmacol Ther. 2006;23;1473-7

Mean ph Level Mean intragastric ph on day 3

31 Mean ph Level Mean intragastric ph on day 3 while on Dexilant Fasting 30 min after high-fat breakfast 5 min before high-fat breakfast 30 min before high-fat breakfast Hours From Dosing Lee RD et al. Aliment Pharmacol Ther. 2009;29:824

32 3. Less influenced by CYP2C19 polymorphism Jun Heng Lee, M.D. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

33 Dexilant was not significantly influenced by CYP2C19 polymorphism in Cmax homozygous EMs heterozygous EMs PMs Genotype homozygous EMs (hom EMs) heterozygou s EMs (het EMs) Poor Metabolizers (PMs) C max (ng/ml) 1,957 ± 413 2,196 ± 405 2,516 ± 357 P-value (vs. PM) NS NS Reference Mean±SD plasma concentration time profiles of (R)-lansoprazole after a 60 mg oral dose of racemic lansoprazole for homozygous extensive metabolizers (EMs) (solid circles), heterozygous EMs (open circles), and poor metabolizers (PMs) (solid squares) Miura M.Eur J Clin Pharmacol 2004;60:623-8

0-5 -10-15 % decrease in IPA -0.2-7.2 % decrease in inhibition of PRI 0-4.7 IPA= inhibition of platelet aggregation; PRI= platelet reactivity index Dexlansoprazole 60mg Lansoprazole 30mg -20-25 -19.

34 % decrease in IPA % decrease in inhibition of PRI IPA= inhibition of platelet aggregation; PRI= platelet reactivity index Dexlansoprazole 60mg Lansoprazole 30mg Esomeprazole 40mg Omeprazole 80mg Dexlansoprazole and lansoprazole had no significant effect on the PD and antiplatelet activity of clopidigril, while esomeprazole and omeprazole did Frelinger AL et al. J Am Coll Cardiol 2012;59:

35 Dexilant a strong long-acting PPI with dual delayed release (DDR) technology 1. Excellent control of breakthrough symptoms including night-time heartburn 2. Can be taken after the meal 3. Less individual variation

GERD. From Clinician to Pharmacologist. Chien-Heng, Shen

GERD. From Clinician to Pharmacologist. Chien-Heng, Shen GERD From Clinician to Pharmacologist Chien-Heng, Shen 2014.9.24 Gastroesophageal Reflux Disease (GERD) when the reflux of gastric content causes troublesome symptoms or complications Esophageal Syndromes