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Transporters and Their Role in Drug Interactions 1 Outline • Messages of the draft drug interaction guidance (September 2006) - Outline of CYP- vs. transporter- based interaction evaluation • Proposed methods to evaluate transporterbased interaction - Current labeling examples • Questions for the committee 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, 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 3 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 4 Key messages: 1. Metabolism, transport, drug-interaction info key to benefit/risk assessment 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 5 Key messages (continued): 4. Clinical significance of a PK-based interaction needs to be interpreted based on exposure-response data/analyses 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) 6 What’s New? CYP Enzymes Major CYPs -specific substrates -specific inhibitors -inducers In vitro and in vivo Transporters P-gp - specific substrate - general inhibitors - inducers in vitro and in vivo Others transporters: OATP, BCRP, MRP2, OATs, OCTs -general substrates, inhibitors, inducers (in vitro/in vivo) < http://www.fda.gov/Cder/drug/drugInteractions/default.htm 7 What’s CYP Enzymes New? A decision tree --- when in vivo studies are recommended per in vitro data - substrate - inhibitor (I/Ki > 0.1) - inducer (40% control) Classification of -inhibitors -substrates Transporters (P-gp) Decision trees-- when in vivo studies are recommended per in vitro data - substrate (flux ratio) - inhibitor (I/Ki) - (inducer) No classification system 8 What’s New? Others: • protocol restriction (juice, dietary supplement use) • multiple- inhibitor study • cocktail approach 9 Why Study Transporters? 10 Liver Sinusoidal Hepatic Uptake: OCT1, OATP-C, OATP-B, OATP8, NTCP, OAT2 Secretion: MRP1, MRP3 Brain Transporters: P-gp (MDR1), OAT3, OATP-A, MRP1, MRP3 Liver Canalicular Biliary Excretion: P-gp, MRP2, BCRP, MDR3 Intestinal Luminal Absorption: PEPT1 Secretary: P-gp, OATP3 Kidney Basolateral: OCT1, OCT2, OAT1, OAT2, OAT3, MRP1 Kidney Apical Renal Secretion: P-gp, OAT4 Reabsorption: PEPT2 <Zhang L et al, Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006 > 11 The role of P-gp transporter? 12 Number of published papers/patents 600 MDR1 500 400 300 BCRP OCT MRP2 200 100 OAT OATP1B1 0 76 81 86 91 Year <Survey via Biovista; courtesy: Aris Persidis> 96 '01 '06 13 Proposed decision trees to evaluate transporterbased interactions 14 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 [I]/IC50 (or Ki) > 0.1 An in vivo interaction study With a P-gp substrate (e.g., digoxin) is recommended Poor or non-inhibitor [I]/IC50 (or Ki) < 0.1 An in vivo interaction study With a P-gp substrate is not needed 15 Digoxin plasma AUC or Css (co-administration) If a NME is an inhibitor of P-gp in vitro, in vivo study using digoxin may be appropriate 2.5 2 1.5 1 0.5 0 Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm 16 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 YES Likely a P-gp substrate An in vivo interaction study With a P-gp inhibitor Note may be warranted exceptions Poor or non-substrate NO Other efflux transporters are responsible Further in vivo to determine which efflux transporters are involved may be warranted 17 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 18 Cyclosporine affects multiple transporters, including OATP1B1 Fold AUC change With cyclosporine 8 7 6 5 4 3 2 1 0 <Data from Table in Shitara and Sugiyama, Pharmacol Ther 112, 2006> 19 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 20 Vardenafil AUC (Fold-change) Ritonavir affects multiple pathways (enzymes and transporters) 50 45 40 35 30 25 20 15 10 5 0 Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm 21 How do we label transporter-based interactions? 22 “Class” labeling of drugs that are substrates of CYP3A [proposed in the 2006 draft guidance on “drug interactions”] 23 Labeling example - CYP3A substrate Eletriptan AUC Cmax 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> 24 “Class” labeling of drugs that are inhibitors of CYP3A [proposed in the 2006 draft guidance on “drug interactions”] 25 Labeling example- CYP3A inhibitor Telithromycin Midazolam AUC 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 > 26 Do we have sufficient data or understanding for a similar “class” labeling of drugs that are inhibitors or substrates of transporters? 27 Labeling examples 28 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 29 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#PDRP 30 RE01el/2004/21704lbl.pdf 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. Coadministration 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). 31 Varenicline (2)- in vivo • Metformin: varenicline .. did not alter the steadystate 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> 32 Multiple - inhibitor interactions 33 Repaglinide AUC (fold-change) Combination of CYP and transporter interactions 20 18 16 14 12 10 8 6 4 2 0 < Data from Neuvonen: Niemi M et al, Diabetologia. 2003 Mar;46(3):347-51> 34 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 35 Summary 36 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 37 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 drugor “therapeutic class-” specific 38 Questions for the Committee 39 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? 40 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 [I]/IC50 (or Ki) > 0.1 An in vivo interaction study With a P-gp substrate (e.g., digoxin) is recommended Poor or non-inhibitor [I]/IC50 (or Ki) < 0.1 An in vivo interaction study With a P-gp substrate is not needed 41 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? 42 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 YES Likely a P-gp substrate An in vivo interaction study With a P-gp inhibitor Note may be warranted exceptions Poor or non-substrate NO Other efflux transporters are responsible Further in vivo to determine which efflux transporters are involved may be warranted 43 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) 44 4. Does the current knowledge base support the recommendation of drug interaction studies for other transporters such as OATP1B1, MRP2, BCRP, OCTs and OATs? 45