Context In addition to drug-drug interactions, "Food-drug interactions" can also cause adverse drug reactions or losses of efficacy and are thus important issues to consider in the evaluation of new drug candidates. This is why drug agencies recommend conducting food-drug studies early in the development of new drugs. For example, the FDA advises the administration of a high-fat meal with new drugs to investigate potential food effect. Aureus' Solutions Aureus Sciences has developed a highly structured Knowledgebase, AurSCOPE ADME/DDI®, containing pharmacokinetics, metabolism and drug interactions data including reliable information about "Food-Drug interaction" studies extracted from journal articles and FDA reviews. Knowledge from published data can help the pharmaceutical industry improve recommendations for regulatory agencies on how drugs should be taken when eating food, and to challenge prediction of food-drug interactions. What you will learn Similarities and differences of regulatory agencies recommendations on food-drug interaction New insights about food-drug interactions including herbal, fruit, and dietary interactions based on clinical outcomes Therapeutic classes, physico-chemical properties of drugs linked with high food-drug interactions

1. Make the right decisions with data you can trust

2. Instructionsforattendees Due to the High number of attendees : Before starting We will mute your microphone during the webinar Use your full name for Identification During the webinar Use the chat for questions At the End We will answer them either at the end or later on by email.

3. Revisiting Food-Drug interactionsusingthe ADME/DDI database® 19/04/2011 3 Cliquez ici pour changer le texte

4. Aureus at a Glance Aureus is a knowledge and information management solutions provider for the Life Science industry located in Paris. Over the past 10 years the company has developed a unique knowledge production platform which stores, indexes and organizes critical chemical and bioactivity information including experimental vitro and vivo protocols from the public or private literature. Aureus employees 20 highlevelscientists (PhD and MSc) includingscientific and IT project leaders and documentation analysts Aureus is funded by institutional investors like CDC Entreprise, AXA Provate Equity, OTC Asset Management and is part of the OSEO Excellence innovation team.

5. AUREUS Mission To help ourcustomers in the Life Science Industry to develop new innovative and safedrugs by providing Solutions whichenablethem to take the best advantage of the existingscientificknowledge and therefore Optimizeprocesses, predict new opportunities as well as new risks of their R&D projects 03/12/2010 5 Webinar « Makethe right decisionswith data youcantrust »

6. Aureus Value Proposition Weoffer a unique combination of scientific, IT, and knowledge management assets and experience to : Assistcompanies in the Life Science Industry to define the scope and scientifccontext of their information needs Weensure the development of highlevelscientificdatabasesfocusing on experimental data in the areas of medicinalchemistry, drugbiologics, drugsafety, ADME/TOX. Weassist on the integration of suchdatabases in customers IT infrastructure or other software applications for furtheranalysis, predictions or simulations Wedevelop applications to mine and visualise the data

7. Aureus Selected Customers & Main projects « KnowTox »

8. WeGenerate & Organize Data intoKnowledge 19/04/2011 8 Cliquez ici pour changer le texte

9. AurSCOPE ADME/DDI Knowledge Base March 2011

10. Food-drug, drug-dietary supplement, drug-citrus fruit interactions 19/04/2011 10 Cliquez ici pour changer le texte Dietary supplement - St John’s Wort - Echinacea - Ginkgo biloba Food - High fat meal - Standard meal - Other meal drug Fruitjuice - Grapefruit juice - Other fruitjuice

11. Food-drug, drug-dietary supplement, drug-juice interactions extracted from Aureus ADME/DDI database 19/04/2011 11 Cliquez ici pour changer le texte Drug Food Juice Dietary AUC ratio <0.5 AUC ratio >2

12. 19/04/2011 12 Cliquez ici pour changer le texte Food-drug, drug-dietary supplement, drug-juice interactions extracted from Aureus ADME/DDI database Drug Food Juice Dietary AUC ratio <0.5 AUC ratio >2

13. 19/04/2011 13 Cliquez ici pour changer le texte Food-drug interactions

15. 150, 250 and 500 calories from protein, carbohydrate and fat respectivelyComposition : 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter, 120 mL hash brown potatoes and 240 mL whole milk 2- Lighter meal for drug administrated with food

16. 19/04/2011 15 Cliquez ici pour changer le texte Drug regulatory agencies recommendations Procedure for food interaction studies: - Fasted 10h - Meal consumed in 30 min or less - Drug with 240 mL water at +30min Analysis: AUC, Cmax, Tmax , t1/2el … 90 percent CI (CL-90) in the equivalence limits of 80-125 percent for AUC and Cmax  Specific recommendation on the clinical significance if outside the limits. (1) Guidance for Industry: Food-effect bioavalaibility and fed bioequivallence studies (2002) (2) Guideline on the Investigation of Drug Interactions (2010)

17. Aureus ADME/DDI® Knowledgebase Query 19/04/2011 16 Cliquez ici pour changer le texte  To compare AUC ratio between drugs we focus on “High-Fat meal” interaction

18. Food interaction: Change in the extent of absorption (AUC) from Aureus ADME/DDI 19/04/2011 17 Cliquez ici pour changer le texte 149 drugs

19. Food effect mechanism Clinically relevant food-drug interactions are generally caused by food-induced change in the Bioavailability of the drug  Important pharmacokinetic effect Delay gastric emptying Stimulate blood flow Change gastrointestinal pH Increase splanchnic blood flow Change luminal metabolism of a drug Physically or chemically interact with a dosage form or a drug substance 19/04/2011 18 Cliquez ici pour changer le texte

20. Biopharmaceutical Classification System (BCS) BCS Fundamental parameters controlling the rate and extent of oral absorption : Solubility Gastrointestinal permeability 19/04/2011 19 Cliquez ici pour changer le texte High permeability: absorption >90% High solubility: soluble in 250 mL of aqueous media (pH 1-7.5) from Wu and Benet, Pharm. Res. vol.22 p.11

21. Biopharmaceutical Classification System (BCS) Cliquez ici pour changer le texte from Wu and Benet, Pharm. Res. vol.22 p.11

22. Assessment: transporters inhibition as the primary mechanism of food effect 19/04/2011 21 Cliquez ici pour changer le texte High-fat meal effect - Increase solubility and efflux transporter inhibition ( Fextent) - Delay gastric emptying ( Tmax, Cmax) - Delay gastric emptying ( Tmax, Cmax) - Influx transporter inhibition ( Fextent) - Delay gastric emptying ( Tmax, Cmax) - Increase solubility - Efflux and influx transporter inhibition - Delay gastric emptying

23. 19/04/2011 22 Cliquez ici pour changer le texte Food-dietarysupplement interactions

24. Drug-dietary supplement interactions 19/04/2011 23 Cliquez ici pour changer le texte Dietary supplements: What is a dietary supplement ? Vitamin Mineral Herb or botanical Amino acid Enzymes or tissues from organ or gland (to supplement diet) Concentrate, metabolite, constituent from FDA: http://www.fda.gov/food/dietarysupplements/consumerinformation/ucm110417.htm

25. Drug-dietary supplement interactions 19/04/2011 24 Cliquez ici pour changer le texte Dietary supplements with potential pharmacokinetic interactions 1- St John’s wort  use for depression Chronic administration induces CYP3A and P-gp  Consequently can alter the PK of CYP3A and P-gp substrates. 2- Ginkgo biloba  use for memory improvement Inducer of CYP2C19 Inhibitor of P-gp and or CYP3A4 ??

26. ADME/DDI®Knowledgebase Query 19/04/2011 25 Cliquez ici pour changer le texte

27. Drug - St John’s wortinteractions from Aureus ADME/DDI 19/04/2011 26 Cliquez ici pour changer le texte 30 drugs

28. Drug - Ginkgo bilobainteractions from Aureus ADME/DDI 19/04/2011 27 Cliquez ici pour changer le texte 10 drugs

29. 19/04/2011 28 Cliquez ici pour changer le texte Grapefruit juice interactions

30. 19/04/2011 29 Cliquez ici pour changer le texte Aureus ADME/DDI® Knowledgebase Query

31. Drug – grapefruit juice interactions from Aureus ADME/DDI 19/04/2011 30 Cliquez ici pour changer le texte 61 drugs

32. Grapefruit juice interaction mechanism Significant clinically interactions  Important pharmacokinetic effect CYP3A4 inhibition in the small intestine Pgp inhibition OATP inhibition (> Pgp inhibition) 19/04/2011 31 Cliquez ici pour changer le texte

33. Active components in grapefruit juice 19/04/2011 32 Cliquez ici pour changer le texte Flavonoids Naringin % Inhibition OATP2B1 = 39% (at 10µM) (1) % Inhibition CYP3A4 = 6% (at 100µM) (2) % Inhibition OATP2B1 = 28% (at 10µM) (1) IC50 CYP3A4 = 87 µM (3) Naringenin (1) Satoh et al. Drug Metab Dispos (2005) 33:518 (2) Ho et al. J Pharm Pharm Sci (2001) 4:217 (3) Haehner et al. Arzneimittelforschung (2004) 54:78

34. Active components in grapefruit juice 19/04/2011 33 Cliquez ici pour changer le texte Furanocoumarin Bergamottin Ki 3A4 (HIM) = 13.3 µM (4) KI (HIM) = 23.5 µM Kinact (HIM) = 0.36 min-1 (4) 6’,7’-Dihydroxybergamottin Ki 3A4 (HIM) = 3.5 µM (4) KI (HIM) = 3.5 µM Kinact (HIM) = 0.31 min-1 (4) (4) Paine et al. Drug Metab Dispos (2004) 32:1146

35. Mechanism of grapefruit juice interactions 19/04/2011 34 Cliquez ici pour changer le texte BLOOD _ CYP3A4 intestinal epithelium GFJ _ OATP Pgp _ GFJ drug LUMEN

36. Mechanism of grapefruit juice interactions 19/04/2011 35 Cliquez ici pour changer le texte CYP3A4 substrates

37. Mechanism of grapefruit juice interactions 19/04/2011 36 Cliquez ici pour changer le texte OATP and Pgp substrates celiprolol talinolol fexofenadine

38. AfterthisWebinar An individual account will be created for each of you on www.aureus-sciences.com It is unique in offering access to editorial content, Aureus data & applications and community networks. Your new account will allow you to access our data and our tools including Food-Drug Interaction through AurQUESTfor free during 2 days. 19/04/2011 37 Food-Drug Interactions Webinar

39. Special Offer for this Webinar After the 2 free-trial days, we offer a special Access through the web during 1 year to data related to: Metabolism PK (Pharmacokinetics) Drug-Drug interactions Food Drug interactions Our Offer: 5 000 €, one user, 12 months. 19/04/2011 38 Food-Drug Interactions Webinar

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