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

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1 GERD From Clinician to Pharmacologist Chien-Heng, Shen

2 Gastroesophageal Reflux Disease (GERD) when the reflux of gastric content causes troublesome symptoms or complications Esophageal Syndromes Extraesophageal Syndromes Symptomatic Syndromes Syndromes with Esophageal injury Established Associations Proposed Associations 1.Typical Reflux Syndrome 2.Reflux Chest Pain Syndrome 1. Reflux Esophagitis 2. Reflux Stricture 3. Barrett s Esophagus 4. Esophageal adenoca 1. Reflux Cough Syndrome 2. Reflux Laryngitis Syndrome 3. Reflux Asthma Syndrome 4. Reflux Dental Erosion Syndrome 1. Pharyngitis 2. Sinusitis 3. Idiopathic Pulmonary Fibrosis 4. Recurrent Otitis Media Am J Gastroenterol 2006;101:1900

5 GERD : Treatment Diet and lifestyle modification Decrease Gastric acid PPI H2-blocker Antacid Protect Mucosa Alginate Decrease transient LES relaxation (tlesr) Baclofen Increase GI tract Motility (Prokinetic drugs) Mosapride, Metoclopramide

6 PPIs Are the Most Effective Acid-Suppressive Therapy PPI therapy provides the most effective healing and symptom relief in GERD patients 1,2,4 PPIs improve quality of life that has been impaired due to GERD symptoms 3,4 Percentage of patients totally healed 1. Chiba N, et al. Gastroenterology. 1997;112: Khan M, et al. Cochrane Database Syst Rev. 2007;(2):CD Havelund T, et al. Am J Gastroenterol. 1999;94: Katz P, et al. Am J Gastroenterol. 2013;108: PPIs H 2 RA Placebo Time (weeks)

13 PPI Efficacy for Potential Manifestations of GORD Based on RCTs Gut 2012; 61:

14 2008 American Gastroenterological Association Harris GERD PPI Survey

15 Nearly 40% of Patients on PPI Therapy have Breakthrough Symptoms N=1,064 Those with breakthrough symptoms most often have symptoms at night Breakthrough Symptoms 38% In the morning 16% In the middle of the day 45% No Breakthrough Symptoms 62% At night During sleep 28% 65% Only 23% of patients on a PPI reported that they were completely satisfied with their current therapy AGA. GERD Patient Study: Patients and Their Medications. Harris Interactive Inc; 2008.

16 GERD in Asia Patients Research Report Understanding the GAPS study in more detail (GERD in Asia Pacific Survey)

17 Current treatments are inadequate, especially at night 94% of PPI treated patients have some breakthrough symptoms 62% of PPI treated patients have experienced breakthrough symptoms at night *Prior to visiting a doctor GERD IN ASIA PACIFIC SURVEY (GAPS). Multi-country qualitative and quantitative study. December 2011-March IPSOS Healthcare

18 Why PPIs unsatisfactory?

19 At Least 25% of Acid Production Capacity May Not Be Shut Down by a PPI 1-3 PPIs only inhibit active proton pumps 3 Following a meal, a proportion of proton pumps are inactive and inaccessible, and therefore are unable to be shut down by a PPI dose 1,2 In addition, proton pumps are constantly being generated to provide acid production later in the day 1,2 PPIs have half-lives of approximately 1-2 hours 2 Any proton pumps activated after PPI concentrations fall below effective plasma levels may not be inhibited 2 1. Blair JA, et al. J Clin Invest. 1987;79: Sachs G. Pharmacotherapy. 1997;17: Del Valle J, et al. Acid peptic disorders. In: Yamada T, et al, eds. Textbook of Gastroenterology. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:

21 How to rescue

5 within 2 hours of dosing 2 Granule 2 comprises 75% of total dose and is released at ph 6.

23 Dual Delayed Release (DDR) Formulation Releases Drug in Two ph-dependent Phases 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 Granule 2 comprises 75% of total dose and is released at ph 6.75 several hours after dosing Release 1 Release 2 1. KAPIDEX (dexlansoprazole) Prescribing Information, Takeda Pharmaceuticals North America, Inc. Deerfield, IL Data on file, Takeda Pharmaceuticals North America, Inc. Deerfield, IL.

24 Effective Maintenance of Intragastric ph >4: Dexlansoprazole vs. Esomeprazole Kukulka M Clinical and Experimental Gastroenterology 2011:4 213

26 Dexlansoprazole MR Is Effective in Nocturnal Heartburn Fass R et al. Am J Gastroenterol 2011

34 Safety More than 4,500 patients studied in clinical trials Similar safety and tolerability to lansoprazole No dose adjustment required in patients with mild hepatic impairment Dexlansoprazole 30 mg should be considered for patients with moderate hepatic impairment Pregnancy category B No significant effects on QT intervals demonstrated with up to dexlansoprazole 300 mg 1. KAPIDEX (dexlansoprazole) Prescribing Information, Takeda Pharmaceuticals North America, Inc. Deerfield, IL Lee RD, Wu J, Vakily M, Mulford D. Effect of hepatic impairment on the pharmacokinetics of TAK-390MR (modified release). Poster presented at the American Society for Clinical Pharmacology and Therapeutics annual meeting; April 2-5, 2008; Orlando, FL. 3. Vakily M, Zhang W, Wu J, Mulford D. Effect of age and gender on the pharmacokinetics of a single oral dose of TAK-390MR (modified release). Poster presented at the American Society for Clinical Pharmacology and Therapeutics annual meeting; April 2-5, 2008; Orlando, FL. 4. Vakily M, Wu J,l Atkinson S. Effect of single oral doses (90 and 300 mg) of TAK-390MR (dexlansoprazole MR) on QT intervals. Poster presented at the American Society for Clinical Pharmacology and Therapeutics annual meeting; March 21-24, 2007; Anaheim, CA. 5. Zhang W, Wu J, Atkinson S. Effects of TAK-390MR (dexlansoprazole MR) on plasma gastrin levels in healthy adults. Poster presented at the American Society for Clinical Pharmacology and Therapeutics annual meeting; March 21-24, 2007; Anaheim, CA.

35 Recent FDA Label Updates clopidogrel Omeprazole and esomeprazole reduce the antiplatelet activity of clopidigrel Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidigrel than did omeprazole or esomeprazole lansoprazole and dexlansoprazole Concomitant administration of dexlansoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition No dose adjustment of clopidogrel is necessary when administered with an approved dose of dexlansoprazole

36 Recent Taiwan Label Updates

37 Conclusion Dexlansoprazole with a Dual Delayed Release (DDR) formulation provides a second release of drug Dosing flexibility: can be administered at any time of day without regard to food intake A safety and tolerability profile similar to lansoprazole

38 Conclusion 可改善病患的睡眠品質 2 長期使用 DEXILANT (6 個月 ), 可有效控制症狀與預防疾病再復發 3 DEXILANT 與 esomeprazole 相比, 其維持在高血漿濃度的時間與維持 ph>4 的時間亦較長 4 DEXILANT 可使將近 9 成的病患, 由原來一天使用 2 次其他的 PPIs,(ex: omepraozole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) 成功轉換成一天使用 1 次 dexlansoprazole 5 DEXILANT 與 clopidogrel 併用時, 相較於 omepraozle & esomeprazole, 對於血小板功能的抑制, 並無臨床顯著性影響因此, 使用 dexlansoprazole 時, 無須調整 clopidogrel 劑量 6 1. Aliment Pharmacol Ther 29, , Am J Gastroenterol 2011; 106: Aliment Pharmacol Ther 29, , Clinical and Experimental Gastroenterology 2011: CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: J Am Coll Cardiol 2012; 59: DEXILANT Taiwan Package Insert

40 Thanks for Your Attention

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

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