Transporters and Their Role in Drug Interactions

1. Advisory Committee for Pharmaceutical Science - Clinical Pharmacology Subcommittee meeting Topic 2: Transporter-based interactions Rockville, MD, October 18, 2006 Transporters and Their Role in Drug Interactions Shiew-Mei Huang, Ph.D. Deputy Director for Science Office of Clinical Pharmacology CDER, FDA Shiewmei.huang@fda.hhs.gov

2. Outline • Messages of the draft drug interaction guidance (September 2006) - Outline of CYP- vs. transporter- based interaction evaluation • Proposed methods to evaluate transporter- based interaction - Current labeling examples • Questions for the committee

3. 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, 2003 (CYP3A inhibitor classification and P-gp inhibition) • -November 18, 2003 (CYP2B6 and CYP2C8- related interactions) • -November 3, 2004 (relevant principles of drug interactions) Concept paper published- October 2004

4. Guidance for Industry: Drug Interaction Studies — Study Design, Data Analysis, and Implications for Dosing and Labeling Draft published for public comment September 11, 2006 http://www.fda.gov/cder/guidance/6695dft.pdf

5. 1. Metabolism, transport, drug-interaction info key to benefit/risk assessment • Key messages: • 2. Integrated approach (in vitro and in vivo ) may reduce number of unnecessary studies and optimize knowledge • 3. Study design/data analysis key to important information for proper labeling

6. 4. Clinical significance of a PK-based interaction needs to be interpreted based on exposure-response data/analyses • Key messages (continued): • 5. Classification of CYP inhibitors and substrates can aid in study design and labeling • 6. Labeling language needs to be useful and consistent (new labeling rule, June 2006)

7. What’s New? < http://www.fda.gov/Cder/drug/drugInteractions/default.htm

8. What’s New?

9. What’s New? Others: • protocol restriction (juice, • dietary supplement use) • multiple- inhibitor study • cocktail approach

10. Why Study Transporters?

11. Brain Transporters: P-gp (MDR1), OAT3, OATP-A, MRP1, MRP3 Liver Sinusoidal Hepatic Uptake:OCT1, OATP-C, OATP-B, OATP8, NTCP, OAT2 Secretion:MRP1, MRP3 Liver Canalicular Biliary Excretion: P-gp, MRP2, BCRP, MDR3 Kidney Basolateral: OCT1, OCT2, OAT1, OAT2, OAT3, MRP1 Intestinal Luminal Absorption:PEPT1 Secretary:P-gp, OATP3 Kidney Apical Renal Secretion:P-gp, OAT4 Reabsorption:PEPT2 <Zhang L et al, Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006 >

12. The role of P-gp transporter?

13. Number of published papers/patents MDR1 BCRP OCT MRP2 OAT OATP1B1 Year <Survey via Biovista; courtesy: Aris Persidis>

14. Proposed decision trees to evaluate transporter-based interactions

15. Figure 1. Decision tree to determine whether an investigational drug is an inhibitor for P-gp and whether an in vivo drug interaction study with a P-gp substrate is needed Bi-directional transport assay Net flux with concn of drug Net flux with concn of drug Determine Ki or IC50 Poor or non-inhibitor [I]/IC50 (or Ki) > 0.1 [I]/IC50 (or Ki) < 0.1 An in vivo interaction study With a P-gp substrate (e.g., digoxin) is recommended An in vivo interaction study With a P-gp substrate is not needed

16. If a NME is an inhibitor of P-gp in vitro, in vivo study using digoxin may be appropriate Digoxin plasma AUC or Css (co-administration) Grapefruit juice St John’s wort Rifampin Quinidine Verapamil Aprepitant Ritonavir Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm

17. Figure 2. Decision tree to determine whether an investigational drug is a substrate for P-gp and whether an in vivo drug interaction study with a P-gp inhibitor is needed Alternatively, use a % value (relative to a probe substrate) Bi-directional transport assay Net flux ratio < 2 Net flux Ratio > 2 Is efflux significantly inhibited by 1 or more P-gp inhibitors Poor or non-substrate YES NO Likely a P-gp substrate Other efflux transporters are responsible An in vivo interaction study With a P-gp inhibitor may be warranted Further in vivo to determine which efflux transporters are involved may be warranted Note exceptions

18. If a NME is a substrate for P-gp in vitro: an in vivo study with a P-gp- inhibitor (e.g., ritonavir, cyclosporine, verapamil) may be appropriate

19. Cyclosporine affects multiple transporters, including OATP1B1 Fold AUC change With cyclosporine rosuvastatin pravastatin pitavastatin <Data from Table in Shitara and Sugiyama, Pharmacol Ther 112, 2006>

20. If a NME is a substrate for P-gp and CYP3A -> a clinical study with a strong inhibitor for both (e.g., ritonavir) may be appropriate

21. Ritonavir affects multiple pathways (enzymes and transporters) Vardenafil AUC (Fold-change) Ketoconazole 200 mg Ritonavir Indinavir Erythromycin Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm

22. How do we label transporter-based interactions?

23. “Class” labeling of drugs that are substrates of CYP3A [proposed in the 2006 draft guidance on “drug interactions”]

24. Labeling example - CYP3A substrate EletriptanAUCCmax Ketoconazole 8x 4x Should not be used within at least 72 hours with strong CYP3A inhibitors…. Ketoconazole, itraconazole, ritonavir, nelfinavir, nefazodone, clarithromycin. Not studied <(Relpax (eletriptan) PDR labeling May 2005>

25. “Class” labeling of drugs that are inhibitors of CYP3A [proposed in the 2006 draft guidance on “drug interactions”]

26. Labeling example- CYP3A inhibitor TelithromycinAUC Midazolam 6x • Telithromycin is a strong inhibitor of the • cytochrome P450 3A4 system • Use of simvastatin, lovastatin, or • atorvastatin concomitantly with • KETEK should be avoided Not studied • The use of KETEK is contraindicated with • cisapride, pimozide <Physicians’ Desk Reference at http://pdrel.thomsonhc.com/pdrel/librarian >

27. Do we have sufficient data or understanding for a similar “class” labeling of drugs that are inhibitors or substrates of transporters?

28. Labeling examples

29. Eplerenone Eplerenone is not a substrate or an inhibitor of P-glycoprotein at clinically relevant doses No clinically significant drug-drug pharmacokinetic interactions were observed when eplerenone was administered with digoxin http://www.fda.gov/cder/foi/label/2003/21437se1-002_inspra_lbl.pdff

30. Pramipexole Cimetidine:   Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12). Probenecid:   Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12). http://pdrel.thomsonhc.com/pdrel/librarian/PFDefaultActionId/pdrcommon.IndexSearchTranslator#PDRPRE01el/2004/21704lbl.pdf

31. Varenicline- in vitro • In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g. metformin -see below) are unlikely to be affected by varenicline. • In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter, OCT2. Co-administration with inhibitors of OCT2 may not require a dose adjustment …. as the increase in systemic exposure .. is not expected to be clinically meaningful (see Cimetidine interaction below).

32. Varenicline (2)- in vivo • Metformin:varenicline .. did not alter the steady-state pharmacokinetics of metformin .. which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics. • Cimetidine:Co-administration of an OCT2 inhibitor, cimetidine … with varenicline (2 mg single dose) … increased the systemic exposure of varenicline by 29% .. due to a reduction in varenicline renal clearance. <Chantix labeling, May 2006- http://www.fda.gov/cder/foi/label/2006/021928lbl.pdf>

33. Multiple - inhibitor interactions

34. Combination of CYP and transporter interactions Repaglinide AUC (fold-change) itraconazole gemfibrozil Gemfibrozil+ itraconazole < Data from Neuvonen: Niemi M et al, Diabetologia. 2003 Mar;46(3):347-51>

35. Repaglinide • Caution should be used in patients already on PRANDIN and gemfibrozil - blood glucose levels should be monitored and PRANDIN dose adjustment may be needed. Rare postmarketing events of serious hypoglycemia have been reported in patients taking PRANDIN and gemfibrozil together. Gemfibrozil and itraconazole had a synergistic metabolic inhibitory effect on PRANDIN. Therefore, patients taking PRANDIN and gemfibrozil should not take itraconazole. PDR on Orandin, December 2004

36. Summary

37. P-gp- based interactions • Most well developed • Information increasingly included in labeling • To determine when to evaluate in vivo: • need agreed-upon criteria to evaluate • in vitro (preclinical) data- presented in the • September 2006 draft guidance • Digoxin a clinically relevant substrate • Proposed general transporter inhibitors • Other issues

38. Other transporter- based interactions • In vitro methodologies being developed • Some information has been included in labeling • Need standardized procedures; need probe • substrates/inhibitors • Short-term recommendations may be drug- • or “therapeutic class-” specific

39. Questions for the Committee

40. 1. Are the criteria for determining whether an investigational drug is an inhibitor of P-gp and whether an in vivo drug interaction study is needed, as described in the following figure, are appropriate?

41. Figure 1. Decision tree to determine whether an investigational drug is an inhibitor for P-gp and whether an in vivo drug interaction study with a P-gp substrate is needed Bi-directional transport assay Net flux with concn of drug Net flux with concn of drug Determine Ki or IC50 Poor or non-inhibitor [I]/IC50 (or Ki) > 0.1 [I]/IC50 (or Ki) < 0.1 An in vivo interaction study With a P-gp substrate (e.g., digoxin) is recommended An in vivo interaction study With a P-gp substrate is not needed

42. 2. Are the criteria for determining whether an investigational drug is an substrate of P-gp and whether an in vivo drug interaction study is needed, as described in the following figure, are appropriate?

43. Figure 2. Decision tree to determine whether an investigational drug is a substrate for P-gp and whether an in vivo drug interaction study with a P-gp inhibitor is needed Alternatively, use a % value (relative to a probe substrate) Bi-directional transport assay Net flux ratio < 2 Net flux Ratio > 2 Is efflux significantly inhibited by 1 or more P-gp inhibitors Poor or non-substrate YES NO Likely a P-gp substrate Other efflux transporters are responsible An in vivo interaction study With a P-gp inhibitor may be warranted Further in vivo to determine which efflux transporters are involved may be warranted Note exceptions

44. 3. If a NME is a P-gp substrate and an in vivo interaction study is indicated, are the inhibitors listed in page 11 (i.e., ritonavir, cyclosporine, verapamil) appropriate? -- 3a. Should different inhibitors be considered, if NME is also a substrate for CYP3A? For example, a strong dual inhibitor of P-gp and CYP3A (e.g., ritonavir)

45. 4. Does the current knowledge base support the recommendation of drug interaction studies for other transporters such as OATP1B1, MRP2, BCRP, OCTs and OATs?

46. References • Lei Zhang, John M. Strong, Wei Qiu, Lawrence J. Lesko, and Shiew-Mei Huang. Scientific Perspectives on Drug Transporters and Their Role in Drug Interactions [PDF] [external link] Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006. • Guidance for industry: Drug Interaction Studies: Study design, Data analysis and Implications for Dosing and Labeling (Issued for public comment, September 11, 2006, http://www.fda.gov/cder/guidance/6695dft.pdf). • FDA Drug Development and Drug Interactions Website; http://www.fda.gov/Cder/drug/drugInteractions/default.htm, established May 2006

47. Drug Interactions working group Sophia Abraham Sayed Al-Habet Raman Baweja Sang Chung Philip Colangelo Paul Hepp Shiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei Qiu Nam Atik Rahman Kellie Reynolds Xiaoxiong Wei Sally Yasuda *Lei K Zhang Jenny H Zheng Jerry Collins Soloman Sobel *John Strong David M Green David Frucht Hon Sum Ko Toni Stifano Robert Temple Janet Norden Kenneth ThummelGilbert Burckart (on sabbatical at FDA, 2006)