This document discusses the evaluation and labeling of drug interactions mediated by drug transporters. It proposes decision trees to determine if in vitro studies suggest a drug is a substrate or inhibitor of P-glycoprotein (P-gp) and may require in vivo interaction studies. It also provides examples of labeling transporter-mediated interactions and evaluates current knowledge for interactions via other transporters. Key questions are asked about the proposed decision trees and selection of inhibitors for in vivo studies.

1. Transporters and Their Role in Drug Interactions

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

7. What’s New? < http://www.fda.gov/Cder/drug/drugInteractions/default.htm Major CYPs -specific substrates -specific inhibitors -inducers In vitro and in vivo CYP Enzymes P-gp - specific substrate - general inhibitors - inducers in vitro and in vivo Transporters Others transporters: OATP, BCRP, MRP2, OATs, OCTs -general substrates, inhibitors, inducers (in vitro/in vivo)

10. Why Study Transporters?

11. <Zhang L et al, Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006 > Kidney Basolateral: OCT1, OCT2, OAT1, OAT2, OAT3, MRP1 Kidney Apical Renal Secretion: P-gp, OAT4 Reabsorption: PEPT2 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 Intestinal Luminal Absorption: PEPT1 Secretary: P-gp, OATP3

12. The role of P-gp transporter?

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

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 Quinidine Verapamil Grapefruit juice Rifampin St John’s wort Aprepitant Digoxin plasma AUC or Css (co-administration) 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 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 Likely a P-gp substrate 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 YES NO Other efflux transporters are responsible Alternatively, use a % value (relative to a probe substrate) 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 pravastatin rosuvastatin pitavastatin Fold AUC change With cyclosporine <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 Ketoconazole 200 mg Erythromycin Indinavir Vardenafil AUC (Fold-change) Ritonavir affects multiple pathways (enzymes and transporters) 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. Eletriptan AUC Cmax Labeling example - CYP3A substrate Should not be used within at least 72 hours with strong CYP3A inhibitors…. Ketoconazole, itraconazole, ritonavir, nelfinavir, nefazodone, clarithromycin . Ketoconazole 8x 4x 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”]

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 is not a substrate or an inhibitor of P-glycoprotein at clinically relevant doses Eplerenone 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). http://pdrel.thomsonhc.com/pdrel/librarian/PFDefaultActionId/pdrcommon.IndexSearchTranslator#PDRPRE01el/2004/21704lbl.pdf Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter , did not noticeably influence pramipexole pharmacokinetics (N=12).

34. Combination of CYP and transporter interactions Repaglinide AUC (fold-change) itraconazole Gemfibrozil+ itraconazole gemfibrozil < 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

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 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 Likely a P-gp substrate 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 YES NO Other efflux transporters are responsible Alternatively, use a % value (relative to a probe substrate) 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?