1. Issues and Challenges in the Evaluation and Labeling of Drug Interaction Potentials of NME Shiew-Mei Huang, Ph.D. Deputy Office Director for Science Office of Clinical Pharmacology & Biopharmaceutics, OPS CDER, FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee meeting April 23, 2003

2. Recent US Market Withdrawal/NA -Examples QT TdP Others Hepato- tox * reintroduced in 2002

3. 3 2,000,000 number of serious ADRs yearly 136,000,000,000 annual cost in dollars associated with ADRs 100,000 annual number of ADR-related deaths 4-6 ranking of serious ADRs as causes of death Adverse Drug Reactions- Marketed Drugs

4. 4 Why are there so many ADRs?

5. 5 “…drug interactions represent 3- 5% of preventable ADRs and are an important contributor to ER visits and hospital admissions.” “…elderly patients with digoxin toxicity were 12 times more likely to have been treated with clarithromycin”

6. 6 OCPB GRP Quality Review (Steps) 1. Evaluate drug interactions well 2. Evaluate the safety/efficacy database & explore exposure/response relationship 3. Use prominent warning early in labeling (project a level of risk in drug interactions) ;

7. 7 Recommendations: 4. Develop better means of communicating dosing information to practitioners and patients

8. What is optimal drug interaction information from NDA submissions? Elucidation of metabolic pathways; contribution of CYP; fraction metabolized Enzyme modulating potential (inhibition/induction by NME/metabolites) - Effect of other drugs - Effect on other drugs

9. 1-3,7: internet: http://www.fda.gov/cder/guidance/index.htm under “clinical pharmacological” 4-6: intranet 1. Preclinical: in vitro studies: 1997 guidance Relevant guidance/MaPP documents: 5. OCPB Good Review Practice draft MAPP; 2001 2. Early phase: in vivo studies: 1999 guidance 4. Cross-labeling draft MAPP : 1999 6. In vitro metabolism draft MAPP; 2002 7. Exposure-response: draft guidance; 2002 3. Late phase: population PK studies : 1999 guidance

10. 10 In Vitro Metabolism Data for each key CYP enzyme Substrate? Inhibitor/ inducer? No Stop- General Labeling* Stop- General Labeling* Pathway Major? Stop- General Labeling* Yes/ unknown No In vivo- Most Sensitive Substrates In vivo- Most Potent Inhibitor/inducer In vivo- Most Potent Inhibitor/inducer Obviate certain in vivo metabolic interaction studies Focus on in vivo investigations *Population PK studies Yes/ unknown Yes/ unknown OCPB GRP

11. 11 In Vitro Metabolism Data for each key CYP enzyme Substrate? Inhibitor/ inducer? No Stop- General Labeling* Stop- General Labeling* Pathway Major? Stop- General Labeling* Yes/ unknown No In vivo- Most Sensitive Substrates In vivo- Most Potent Inhibitor/inducer In vivo- Most Potent Inhibitor/inducer *Population PK studies Yes/ unknown Yes/ unknown OCPB GRP ** PhRMA White paper JCP 2003; 43 (2)

12. Ketoconazole Itraconazole Clarithromycin Saquinavir Erythromycin Diltiazem Fluconazole Verapamil Grapefruit juice Cimetidine Ranitidine Azithromycin % AUC vs. baseline MildModeratePotent Oral Midazolam as probe substrate 500 200

13. Classification system-potential use Used to guide in vivo studies Used in labeling inhibitors/substrates Concerns Potent inhibitors may affect other enzymes/transporters (UGT, P-gp) Substrates are also substrates of other enzymes/transporters Multiple drugs are prescribed Varied data from various study designs others

14. Discussion of drug interaction issues CDER Scientific rounds, February 26, 2003 Professional meetings - AAPS open forum, November 2002, Toronto - ASCPT annual meeting, April, 2003, Washington DC ACPS subcommittee meetings, 2003

15. Case 1- NME as a Substrate Drug interactions evaluated? Clinical significance (exposure- response)? Labeling language?

16. 16 In Vitro Metabolism Data for each CYP enzyme Substrate? Inhibitor/ inducer? No Stop- General Labeling* Stop- General Labeling* Pathway Major? Stop- General Labeling* Yes/ unknown No In vivo- Most Sensitive Substrates In vivo- Most Potent Inhibitor/inducer In vivo- Most Potent Inhibitor/inducer *Population PK studies Yes/ unknown Yes/ unknown

17. 17 Drug A with AUC Cmax Ketoconazole 6x4x NME - CYP3A substrate Erythromycin 4x3x Verapamil 4x3x Drug A

18. 18 Exposure-response data Proposed clinical dose 15, 30, 60 Approved 15, 30 How to label drug interactions?

19. 19 Potential labeling language Do not take with potent CYP3A inhibitors….. Ketoconazole, itraconazole, TAO, ritonavir, nelfinavir, nefazodone, clarithromycin Use lower doses with moderate CYP3A inhibitors….. erythromycin, verapamil, diltiazem...

20. Case 2- NME as an inhibitor Drug interactions evaluated? Clinical significance (exposure- response of the substrates)? Labeling language?

21. 21 In Vitro Metabolism Data for each CYP enzyme Substrate? Inhibitor/ inducer? No Stop- General Labeling* Stop- General Labeling* Pathway Major? Stop- General Labeling* Yes/ unknown No In vivo- Most Sensitive Substrates In vivo- Most Potent Inhibitor/inducer In vivo- Most Potent Inhibitor/inducer *Population PK studies Yes/ unknown Yes/ unknown

22. 22 Drug B with AUC Cmax Midazolam 6x3x NME - CYP3A inhibitor Simvastatin8x5x Cisapride3x2x Theophylline1x1x Warfarin1x1x

23. Ketoconazole Itraconazole Clarithromycin Saquinavir Erythromycin Diltiazem Fluconazole Verapamil Grapefruit juice Cimetidine Ranitidine Azithromycin % AUC vs. baseline MildModeratePotent Oral Midazolam as probe substrate 500 200 Potent

24. Sensitive substrates or substrates with “narrow” therapeutic range: Labeling language (e.g., contraindication) with the “strong inhibitors” midazolam, triazolam simvastatin, lovastatin, atorvastatin terfenadine, cisapride, astemizole, pimozide

25. 25 Potential Labeling Language The use of Drug B, a strong CYP3A inhibitor, is contraindicated with cisapride, pimozide, simvastain….… monitored..midazolam…others, such as sildenafil, budesonide…(those carrying ketoconazole labeling..)

26. Classification system-potential use Used to guide in vivo studies Used in labeling inhibitors/substrates Concerns Potent inhibitors may affect other enzymes/transporters (UGT, P-gp) Substrates are also substrates of other enzymes/transporters Multiple drugs are prescribed Varied data from various study designs others Potent inhibitors may affect other enzymes/transporters (UGT, P-gp)

27. P-gp based interactions

28. 28 CYP3A and P-gp inhibitors IC 50 ratios (CYP3A/P-gp) verapamil cyclosporine quinidinePSC833

29. 29 AUC Cmax Ketoconazole 2.7x2.4x P-gp substrates- fexofenadine Itraconazole2.4-2.8x 2.4-2.5x Rifampin0.3x0.5x < PDR for fexofenadine; Hamman MA, et al, Clin Pharmacol Ther 2001; Dresser GK, et al, Clin Pharmacolg Ther 2003; Dresser G, et al, Shon J, et al, Lemma GL, et al, ASCPT 2003; * compared to water or acute dosing; ** possible OATP involvement> Grapefruit juice**0.5x0.5x St John’s Wort*0.5x0.6-0.7 Erythromycin2.1x1.8x Verapamil--- 1.5,1.3,1x (C at days 1,10,38)

30. 30 AUC Cmax Quinidine --- 2.4x (Css,7) P-gp substrates- digoxin Verapamil --- 1.4-1.7x(Css,-) surveys indicated that cimetidine and digoxin most often studied in submissions reviewed in 1996 and 1987-1997 digoxin continued to be studied, if likely to be co-administered Rifampin0.7x0.5x St John’s Wort0.8x--- Aprepitant0.93-0.99x--- Grapefruit juice**1.09x---

31. Next Steps

32. Guidance revision Guidance for Industry In Vivo Drug Metabolism/Drug Interaction Studies — Study Design, Data Analysis, and Recommendations for Dosing and Labeling Draft Cross Labeling MAPP Draft In Vitro Metabolism/Transport MAPP

33. Questions for the Panel 1. What other factors to consider in implementing the classification system for CYP3A inhibitors in the labeling? - definition of sensitive substrates?

34. Questions for the Panel (2) 3. What about transporter-based interactions? - should we recommend routine evaluation? 2. Should we consider application of Classification systems to inhibitors of other CYP enzymes? Inducers?

35. Acknowledgement In vitro (in vivo) Metabolism/transport interaction working group and others involved in CDER rounds discussions Sophia Abraham Sayed Al Habet Debra Birnkrant Sang Chung Phil Colangelo Jerry Collins Barbara Davit John Duan Shiew-Mei Huang Russell Katz Ronald Kavanagh Lawrence J Lesko Atiqur Rahman Kellie Reynolds Solomon Sobel John M Strong Robert Temple Wei Qiu Ramana UppoorJim Xiaoxiong Wei Lei K Zhang Jenny H Zheng Jenny J Zheng