1. 1 Drug-Drug Interaction Concept Paper: Issues Related to CYP/Transporter- and Induction-Based Interactions and Multiple- Inhibitor Drug Interaction Studies: Relevant Principles of Drug Interaction Concept Paper Shiew-Mei Huang, Ph.D. Deputy Director for Science Office of Clinical Pharmacology & Biopharmaceutics CDER, FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee Meeting November 3, 2004

2. 2 Discussions on Drug Interactions Publications of in vitro and in vivo drug interaction guidance documents - http://www.fda.gov/cder/guidance/clin3.pdf (1997) - http://www.fda.gov/cder/guidance/2635fnl.pdf (1999) Advisory Committee meetings -April 20-21, 2003 (CYP3A inhibitor classification and P-gp inhibition) -November 17-18, 2003 (CYP2B6 and CYP2C8- related interactions) Various public workshops/CDER rounds - Tucker, Houston and Huang, Clin Pharm Ther August 2001; 70(2):103 PhRMA position paper/other publications - Bjornsson, Callaghan, Einolf, et al, J Clin Pharmacol, May 2003; 43(5):443

3. 3 Draft Drug Interaction Guidance (in internal review)- To replace two metabolism/drug interaction guidance documents published in 1997 and 1999 To update and include recent findings and discussions from conferences and publications To address recent labeling rule changes Labeling guideline. Federal Register 65[247], 81082-81131. December 22, 2000.

4. 4 Drug Interaction Studies — Study Design, Data Analysis, and Implications for Dosing and Labeling PRELIMINARY CONCEPT PAPER For Discussion Purposes Only

5. 5 Key principles: 1. Metabolism, drug-interaction info key to benefit/risk assessment

6. 6 Recent US Market Withdrawal (1998-2003) WithdrawnApproval Drug nameUseRisk 19981997Mibefradil High blood pressure/ Chronic stable angina Drug-drug interactions Torsades de Pointes 19981997Bromfenac NSAIDAcute liver failure 19981985Terfenadine AntihistamineTorsades de Pointes Drug-drug interactions 19991988Astemizole AntihistamineTorsades de Pointes Drug-drug interactions 19991997Grepafloxacin AntibioticsTorsades de Pointes 2000 Alosetron* Irritable bowel syndrome in women Ischemic colitis; complications of constipation 20001993Cisapride HeartburnTorsades de Pointes Drug-drug interactions 20001997Troglitazone DiabetesAcute liver failure 20011997Cerivastatin Cholesterol loweringRhabdomyolysis Drug-drug interactions 20011999 Rapacuronium AnesthesiaBronchospasm Huang SM, Miller M, Toigo T, Chen MC, Sahajwala C, Lesko LJ, Temple R, Evaluation of Drugs in Women: Regulatory Perspective– in Section 11, Drug Metabolism/Clinical Pharmacology (section editor: Schwartz, J), in “Principles of Gender-Specific Medicine”, Ed., Legato M, Academic Press (2004). Need to evaluate other drug’s effects on NME and the NME’s effects on other drugs Need to evaluate inhibition as well as induction

7. 7 Key principles: 1. Metabolism, drug-interaction info key to benefit/risk assessment 2. Integrated approach may reduce number of unnecessary studies and optimize knowledge

8. 8 Inhibition Evaluation of metabolic interactions CYP1A2, CYP2C9, CYP2C19, CYP3A, CYP2D6 InductionCYP1A2, CYP2C9, CYP2C19, CYP3A Metabolic Profiling CYP1A2, CYP2C9, CYP2C19, CYP3A, CYP2D6 Other CYPs/Phase 2 metabolism

9. 9 Design the in vivo evaluation based on in vitro data (rank order and evaluate the more potent ones, smaller Kis, first) NME (Cmax 1uM) IC50Ki CYP1A250 uM 40 uM CYP2C920uM 10 uM CYP2C19 >100 uM-- CYP2D6 >100 uM-- CYP3A4 7uM2 uM Evaluation of inhibition Evaluate in vivo first

10. 10 Evaluation of induction Induction can be addressed in vitro (new!) initial in vitro evaluation with 2 CYPs (CYP1A2, CYP3A) - negative results may preclude in vivo evaluation of CYP1A2, CYP3A, CYP2C9, CYP2C19 - positive control recommended - 40% of positive control suggest possible induction potential -> follow with in vivo evaluation <Bjornsson, et al, JCP May 2003 Sahi, et al, DMD 2004; Madan et al, DMD 2003; Fergusson, et al, Wang et al, ISSX 2004>

11. 11 Evaluation of induction (continued) (Frequently asked question) Is there a need to conduct an in vitro induction study for all NMEs? No, however, - there is a need to address induction potential (which can be done initially with in vitro methods or it can be done via in vivo studies) - positive in vitro to be followed with in vivo - induction can be evaluated in vivo; can be conducted as part of an inhibition evaluation in vivo (multiple dosing)

12. 12 Key Principles: 1. Metabolism, drug-interaction info key to benefit/risk assessment 2. Integrated approach may reduce number of unnecessary studies and optimize knowledge 3. Study design/data analysis key to important information for proper labeling

13. 13 Midazolam (keto)/ Midazolam (placebo) midazolam at 7.5 mg Olkkola et al., CPT 55:481, 1994 - Use the highest dose and shortest dosing interval of the inhibitor Design a study to maximize seeing an interaction - 400 mg vs. 200 mg of ketoconazole - - Literature data: inter-study comparison

14. 14 AUC ratio: Midazolam (keto)/ Midazolam (placebo) - 400 mg vs. 200 mg of ketoconazole - Design a study to maximize seeing an interaction (continued) - CDER/Indiana University study: within study comparison

15. 15 CYP3A inhibition after ketoconazole dosing is dose-dependent - 400 mg > 200 mg If a study has been conducted with 200 mg of ketoconazole; do we need to conduct another study with 400 mg? - look at the results and other information (e.g., exposure- response data) Design a study to maximize seeing an interaction (continued) Inhibition study with ketoconazole should be conducted at 400 mg dose

16. 16 (Frequently asked question): would a cocktail approach be acceptable for evaluating in vivo inhibition or induction? Yes, if properly designed - if negative, it can preclude further evaluation Other study design issues - if positive, may need additional evaluation (to provide quantitative info) it can provide useful information, when reviewed with other interaction data

17. 17 What substrates, inhibitors, inducers to use Other study design issues (continued) What experimental conditions (e.g., substrate, inhibitor or inducer concentrations to use in vitro) Tables of in vivo and in vitro probe substrates, inhibitors, and inducers - web link for future updates

18. 18 CYPSubstrateInhibitorInducer 1A2theophylline, caffeinefluvoxaminesmoking (3) 2B6efavirenzrifampin 2C8repaglinide, rosiglitazonegemfibrozilrifampin 2C9warfarin, tolbutamidefluconazole, amiodarone (use of PM subjects) (4) rifampin 2C19omeprazol, esoprazol, lansoprazol, pantoprasol omeprazole, fluvoxamine, moclobemide (use of PM subjects) (4) rifampin 2D6desipramine, atomoxetine dextromethorphan paroxetine, quinidine, (use of PM subjects) (4) None identified 2E1chlorzoxazonedisulfirumethanol 3A4/ 3A5 midazolam, buspirone, felodipine, simvastatin, Lovastatin, eletriptan, sildenafil, simvastatin, triazolam atanazavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole rifampin, carbamazepine In vivo probes

19. 19 Discussed PK evaluation in poor metabolizers (PM) or smokers in lieu of certain interaction studies - Evaluation of interaction based on one pathway in PM of the enzyme for another pathway Discussed protocol exclusion criteria to address possible herb-drug, juice-drug interactions Other study design issues (continued)

20. 20 P-gp transporter based interaction (1) If a NME is an inhibitor of P-gp in vitro, in vivo study using digoxin may be appropriate Quinidine Verapamil Grapefruit juice Rifampin St John’s wort Aprepitant Digoxin plasma AUC or Css (co-administration) Ritonavir

21. 21 Ritonavir Ketoconazole 200 mg Erythromycin Indinavir Vardenafil AUC (co-administration) P-gp transporter based interaction (2) If a NME is a substrate for P-gp and CYP3A -> a clinical study with a multi- inhibitor (e.g., ritonavir) may be appropriate <Data extracted from http://www.fda.gov/cder/approval/index.htmhttp://www.fda.gov/cder/approval/index.htm or Pysicians’ Desk Reference at http://pdrel.thomsonhc.com/pdrel/librarian >http://pdrel.thomsonhc.com/pdrel/librarian [ Ritonavir affects multiple pathways ]

22. 22 P-gp transporter based interaction (3) If a NME is a substrate for P-gp and NOT CYP3A4 -> a clinical study with a P-gp- inhibitor (e.g., cyclosporine, verapamil) may be appropriate Quinidine Verapamil Grapefruit juice Rifampin St John’s wort Aprepitant Digoxin plasma AUC or Css (co-administration) Ritonavir

23. 23 Multiple inhibitors/ multiple impaired system To obtain maximum exposure (telithromycine) - Use one strong inhibitor - Use multiple inhibitors (or one inhibitor for one patheway in PM of another pathway) Research ongoing (CDER/Indiana University) on multiple inhibitors of one pathway) When evaluating QT effects To define maximum exposure (vardenadil)

24. 24 Key principles: 1. Metabolism, drug-interaction info key to benefit/risk assessment 2. Integrated approach may reduce number of unnecessary studies and optimize knowledge 3. Study design/data analysis key to important information for proper labeling 4. Need to establish “Therapeutic equivalence boundaries”

25. 25 NME with Cmax Ketoconazole 4x Erythromycin 3x Verapamil 3x NME - CYP3A substrate NME Do not take with strong CYP3A inhibitors…. Ketoconazole, itraconazole, ritonavir, nelfinavir, nefazodone, clarithromycin. Use lower dose with moderate CYP3A inhibitors….. erythromycin, verapamil, diltiazem... [if approved]

26. 26 Key principles: 1. Metabolism, drug-interaction info key to benefit/risk assessment 2. Integrated approach may reduce number of unnecessary studies and optimize knowledge 3. Study design/data analysis key to important information for proper labeling 4. Need to establish “Therapeutic equivalence boundaries” 5. Labeling language needs to be useful and consistent

27. 27 Labeling If a drug has been determined to be a sensitive CYP3A substrate or a CYP3A substrate with a narrow therapeutic range, it does not need to be tested with all strong or moderate inhibitors of CYP3A to warn about an interaction with “strong” or “moderate” CYP3A inhibitors

28. 28 Examples of strong and moderate CYP3A inhibitors Strong CYP3A inhibitorsModerate CYP3A inhibitors atanazavir clarithromycin indinavir itraconazole ketoconazole nefazodone nelfinavir ritonavir saquinavir telithromycin voriconazole amprenavir aprepitant diltiazem erythromycin fluconazole fosaprenavir grapefruit juice(a) verapamil A “strong inhibitor” is one that caused a > 5-fold increase in the plasma AUC values of CYP3A substrates (not limited to midazolam) in clinical evaluations A “moderate inhibitor” is one that caused a > 2- but < 5-fold increase in the AUC values of sensitive CYP3A substrates when the inhibitor was given at the highest approved dose and the shortest dosing interval in clinical evaluations (a)The effect varies widely

29. 29 NME with Cmax Ketoconazole 4x Erythromycin 3x Verapamil 3x Labeling example - CYP3A substrate NME Do not take with strong CYP3A inhibitors…. Ketoconazole, itraconazole, ritonavir, nelfinavir, nefazodone, clarithromycin. Use lower dose with moderate CYP3A inhibitors….. erythromycin, verapamil, diltiazem... [if approved]

30. 30 Labeling If a drug has been determined to be a strong inhibitor of CYP3A, it does not need to be tested with all CYP3A substrates to warn about an interaction with “sensitive CYP3A substrates” and “CYP3A substrates with narrow therapeutic range”.

31. 31 Examples of sensitive CYP3A substrates or CYP3A substrates with NTR Sensitive CYP3A substrates CYP3A Substrates with Narrow therapeutic range budesonide, buspirone, eletriptan, felodipine, imatinab, lovastatin, midazolam, saquinavir, sildenafil, simvastatin, triazolam Alfentanil, astemizole(a), cisapride(a), cyclosporine, diergotamine, ergotamine, fentanyl, irinotecan, pimozide, quinidine, sirolimus, tacrolimus, terfenadine(a) “sensitive CYP3A substrates” refer to drugs whose plasma AUC values are increased 5-fold or more when co-administered with CYP3A inhibitors “CYP3A substrates with narrow therapeutic range” refer to drugs whose exposure-response data are such that increases in their exposure levels by the concomitant use of CYP3A inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes); (a) not available in US

32. 32 Telithromycin is a strong inhibitor of the cytochrome P450 3A4 system Labeling example- CYP3A inhibitor Telithromycin AUC Midazolam 6x http://pdrel.thomsonhc.com/pdrel/librarian Use of simvastatin, lovastatin, or atorvastatin concomitantly with KETEK should be avoided The use of KETEK is contraindicated with cisapride, pimozide Not studied

33. 33 Summary: 1. Metabolism, drug-interaction info key to benefit/risk assessment 2. Integrated approach may reduce number of unnecessary studies and optimize knowledge 3. Study design/data analysis key to important information for proper labeling 4. Need to establish “Therapeutic equivalence boundaries” 5. Labeling language needs to be useful and consistent

34. 34 Jerry Collins Soloman Sobel John Strong Sophia Abraham Sayed Al-Habet Raman Baweja Sang Chung Philip Colangelo Paul Hepp Shiew-Mei Huang Ron Kavanagh Lawrence Lesko Patrick Marroum Srikanth Nallani Wei Qiu Nam Atik Rahman Kellie Reynolds Xiaoxiong Wei Lei K Zhang Jenny H Zheng David M Green David Frucht Hon Sum Ko Toni Stifano Drug Interactions working group Robert Temple Janet Norden

35. 35

36. 36 Questions for the Committee: In Vitro and In Vivo Drug-Drug Interaction Concept Paper: Issues Related to Transporter- and Induction-Based Interactions and Multiple Inhibitor Drug Interaction Studies

37. 37 Questions associated with inhibition of CYP enzymes and transporters 1.If a NME is NOT an inhibitor of the following 5 major CYP enzymes (CYP1A2, 2C9, 2C19, 2D6, 3A) based upon in vitro data, then there is NO need to conduct in vivo interaction studies based on these CYPs. Yes or No 2. If a NME IS an inhibitor of P-gp in vitro, then there IS a need to conduct an in vivo study using digoxin or other suitable substrates. Yes or No

38. 38 Questions associated with inhibition of CYP enzymes and transporters 3. If a NME IS a substrate for P-gp in vitro AND a CYP3A4 substrate based on either in vitro and/or in vivo data, then a clinical study with a P-gp- and CYP3A4-inhibitor (e.g., ritonavir) should be conducted. Yes or No 4. If a NME IS a substrate for P-gp in vitro AND NOT a CYP3A4 substrate based on either in vitro and/or in vivo data, then a clinical study with a P-gp- inhibitor (e.g., cyclosporine, verapamil) should be conducted. Yes or No

39. 39 Questions associated with inhibition of CYP enzymes and transporters 5. Is the current evidence and in vitro methodologies sufficiently mature to recommend that drug-drug interactions be studied clinically for CYP2B6, CYP2C8, UGT1A1 or others for certain drugs? Yes or No 6. Does the current evidence support recommendations that drug-drug interactions based on OATP and/or MRP be recommended for clinical study during drug development? Yes or No

40. 40 Questions associated with induction of CYP enzymes 7. If the in vitro induction (increase in enzyme activity) is more than 40% of the positive control (e.g., rifampin), then there IS a need to recommend an in vivo induction study. Yes or No 8. If a NME’s induction effect on CYP3A4 in vitro is NEGATIVE, is it acceptable to NOT recommend any in vivo studies with substrates of CYP3A, CYP2C9, CYP2C19 and CYP2B6. Yes or No

41. 41 Questions associated with multiple-inhibitor studies 9. Is it acceptable to recommend that under certain conditions (e.g., to estimate QT effects) it is important to determine the maximum exposure of a NME that a patient may experience by increasing the exposure to the NME in the presence of either a) a single inhibitor, b) multiple inhibitors (when there are more than one pathway responsible for its metabolic clearance) or c) under multiple-impaired conditions (e.g., renal impairment and co-administration of an inhibitor? Yes or No 10.What issues should be considered before recommending the type of clinical study be conducted on a NME that is described in (9) above?

42. 42 Others 11. Are there other areas of drug interactions that should have been addressed in the concept paper?