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When to Conduct a Renal Impairment Study

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When to Conduct a Renal Impairment Study

  1. 1. Transporters and Their Role in Drug Interactions
  2. 2. <ul><li>Outline </li></ul><ul><li>Messages of the draft drug interaction guidance (September 2006) </li></ul><ul><li>Proposed methods to evaluate transporter- based interaction </li></ul>- Outline of CYP- vs. transporter- based interaction evaluation <ul><li>Questions for the committee </li></ul>- Current labeling examples
  3. 3. <ul><li>Discussions on Drug Interactions </li></ul><ul><li>Publications of in vitro and in vivo drug interaction guidance documents </li></ul><ul><li>- http://www.fda.gov/cder/guidance/clin3.pdf (1997) </li></ul><ul><li>- http://www.fda.gov/cder/guidance/2635fnl.pdf (1999) </li></ul><ul><li>Advisory Committee meetings </li></ul><ul><ul><li>-April 20, 2003 (CYP3A inhibitor classification and P-gp inhibition) </li></ul></ul><ul><ul><li>-November 18, 2003 (CYP2B6 and CYP2C8- related interactions) </li></ul></ul><ul><ul><li>-November 3, 2004 (relevant principles of drug interactions) </li></ul></ul>Concept paper published- October 2004
  4. 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. 5. <ul><ul><li>Key messages: </li></ul></ul><ul><ul><li>1. Metabolism, transport , drug-interaction info key to benefit/risk assessment </li></ul></ul><ul><ul><li>2. Integrated approach (in vitro and in vivo ) may reduce number of unnecessary studies and optimize knowledge </li></ul></ul><ul><ul><li>3. Study design/data analysis key to important information for proper labeling </li></ul></ul>
  6. 6. <ul><ul><li>Key messages (continued): </li></ul></ul><ul><ul><li>4. Clinical significance of a PK-based interaction needs to be interpreted based on exposure-response data/analyses </li></ul></ul><ul><ul><li>6. Labeling language needs to be useful and consistent (new labeling rule, June 2006) </li></ul></ul><ul><ul><li>5. Classification of CYP inhibitors and substrates can aid in study design and labeling </li></ul></ul>
  7. 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)
  8. 8. What’s New? <ul><li>A decision tree --- when </li></ul><ul><li>in vivo studies are recommended </li></ul><ul><li>per in vitro data </li></ul><ul><li>- substrate </li></ul><ul><li>inhibitor (I/Ki > 0.1) </li></ul><ul><li>inducer (40% control) </li></ul>CYP Enzymes Decision trees-- when in vivo studies are recommended per in vitro data - substrate (flux ratio) - inhibitor (I/Ki) - (inducer) Transporters (P-gp) <ul><li>Classification of </li></ul><ul><li>inhibitors </li></ul><ul><li>substrates </li></ul>No classification system
  9. 9. What’s New? Others: <ul><li>protocol restriction (juice, </li></ul><ul><li>dietary supplement use) </li></ul><ul><li>multiple- inhibitor study </li></ul><ul><li>cocktail approach </li></ul>
  10. 10. Why Study Transporters?
  11. 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. 12. The role of P-gp transporter?
  13. 13. Number of published papers/patents Year <Survey via Biovista; courtesy: Aris Persidis> MDR1 BCRP OCT MRP2 OAT OATP1B1
  14. 14. Proposed decision trees to evaluate transporter-based interactions
  15. 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. 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. 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. 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. 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. 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. 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. 22. How do we label transporter-based interactions?
  23. 23. “ Class” labeling of drugs that are substrates of CYP3A [proposed in the 2006 draft guidance on “ drug interactions”]
  24. 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. 25. “ Class” labeling of drugs that are inhibitors of CYP3A [proposed in the 2006 draft guidance on “ drug interactions”]
  26. 26. <ul><li>Telithromycin is a strong inhibitor of the </li></ul><ul><li>cytochrome P450 3A4 system </li></ul>Labeling example- CYP3A inhibitor Telithromycin AUC Midazolam 6x <Physicians’ Desk Reference at http://pdrel.thomsonhc.com/pdrel/librarian > <ul><li>Use of simvastatin, lovastatin, or </li></ul><ul><li>atorvastatin concomitantly with </li></ul><ul><li>KETEK should be avoided </li></ul><ul><li>The use of KETEK is contraindicated with </li></ul><ul><li>cisapride, pimozide </li></ul>Not studied
  27. 27. Do we have sufficient data or understanding for a similar “class” labeling of drugs that are inhibitors or substrates of transporters ?
  28. 28. Labeling examples
  29. 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. 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).
  31. 31. Varenicline- in vitro <ul><li>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. </li></ul><ul><li>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). </li></ul>
  32. 32. <ul><li>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. </li></ul>Varenicline (2)- in vivo <ul><li>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. </li></ul><Chantix labeling, May 2006- http://www.fda.gov/cder/foi/label/2006/021928lbl.pdf>
  33. 33. <ul><li>Multiple - inhibitor </li></ul><ul><li>interactions </li></ul>
  34. 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. 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. 36. Summary
  37. 37. P-gp- based interactions <ul><li>Information increasingly included in labeling </li></ul><ul><li>To determine when to evaluate in vivo: </li></ul><ul><li>need agreed-upon criteria to evaluate </li></ul><ul><li>in vitro (preclinical) data- presented in the </li></ul><ul><li>September 2006 draft guidance </li></ul><ul><li>Digoxin a clinically relevant substrate </li></ul><ul><li>Proposed general transporter inhibitors </li></ul><ul><li>Most well developed </li></ul><ul><li>Other issues </li></ul>
  38. 38. Other transporter- based interactions <ul><li>In vitro methodologies being developed </li></ul><ul><li>Need standardized procedures; need probe </li></ul><ul><li>substrates/inhibitors </li></ul><ul><li>Short-term recommendations may be drug- </li></ul><ul><li>or “therapeutic class-” specific </li></ul><ul><li>Some information has been included in labeling </li></ul>
  39. 39. Questions for the Committee
  40. 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. 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. 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. 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. 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. 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?

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