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Background: Focus on P-gp Questions:
DRUG-DRUG INTERACTIONS IN VIVO AND IN VITRO STUDIES: Focus on Transporters Background: Focus on P-gp Other Transporters Questions:
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Multiple Membrane Transporters in Hepatocyte Work in Concert
With Enzymes to Mediate Drug Elimination SLC DME Drug Metabolite ABC
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Drug Interactions with P-gp
Mizuno, 2003
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Drug Interactions with P-gp
Mizuno, 2003
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Inhibitors of P-gp That Have Been
Associated with a Known Clinical Drug-Drug Interaction* Valspodar Cyclosporin Erythromycin Itraconazole Verapamil Quinidine Ketoconazole Propafenone Clarithromycin Talinolol Ritonavir Nelfinavir Diltiazem Atorvastatin * Mechanism may be more complicated than simple P-gp inhibition
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Substrates of P-gp That Have Altered Pharmacokinetic
Properties in Humans in the Presence of P-gp Inhibitors* Digoxin Paclitaxel Dexamethasone Atorvastatin Talinolol Fexofenadine Saquinavir Cyclosporine Quinidine Docetaxal Etoposide Tacrolimus Azithromycin * Mechanism may be more complicated than simple P-gp inhibition
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If an NME is an inhibitor of P-gp in vitro,
there is a need to conduct a clinical study. Yes or No What defines an inhibitor? What clinical study?
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If an NME is an inhibitor of P-gp in vitro,
there is a need to conduct a clinical study. Yes or No What defines an inhibitor? High Ratio of Therapeutic Unbound Concentration/Ki Range of Ki values for drugs that have known clinical drug-drug inhibition interactions with P-gp: 0.18 to 280 µM. Especially recommend that study be performed if therapeutic drug concentrations (unbound) of “P-gp inhibitor” is in the range of its in vitro Ki.
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If an NME is an inhibitor of P-gp in vitro,
there is a need to conduct a clinical study. Yes or No What defines an inhibitor? What clinical study?
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If an NME is an inhibitor of P-gp in vitro,
there is a need to conduct a clinical study. Yes or No What clinical study? Study with digoxin Other possibilities
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Multiple Levels of Evidence that P-gp is Important in Digoxin Pharmacokinetics (Poorly metabolized)
Evidence in cell culture (digoxin is a substrate, Km 50 µM) Evidence in mdr1 knockout mouse (i.e. quinidine increases digoxin levels in normal mice, but not P-glycoprotein knockout mice; digoxin levels in brain increase in mdr1 knockout mice). Clinical evidence of a quinidine-digoxin interaction Clinical evidence that rifampin/St. John’s Wort reduce digoxin levels (and increase P-gp expression in intestiine).
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Digoxin Levels (ng/ml)
Multiple Levels of Evidence Suggesting That P-gp is Important in Digoxin Pharmacokinetics Digoxin Levels (ng/ml) Quinidine Dose
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If an NME is an inhibitor of P-gp in vitro,
there is a need to conduct a clinical study. Yes or No What clinical study? Study with digoxin Other possibilities Consider clinical use of drug
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Substrates of P-gp That Have Altered Pharmacokinetic
Properties in Humans in the Presence of P-gp Inhibitors* Digoxin Paclitaxel Dexamethasone Atorvastatin Talinolol Fexofenadine Saquinavir Cyclosporine Quinidine Docetaxal Etoposide Tacrolimus Azithromycin * Mechanism may be more complicated than simple P-gp inhibition
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3. If an NME is a substrate of P-gp and
CYP3A4 in vitro, then a clinical study with a multi-inhibitor should be conducted. Yes or No Consider clinical use of drug Other: Demonstrate proof of concept
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Inhibitors of P-gp That Have Been
Associated with a Known Clinical Drug-Drug Interaction* Valspodar Cyclosporin Erythromycin Itraconazole Verapamil Quinidine Ketoconazole Propafenone Clarithromycin Talinolol Ritonavir Nelfinavir Diltiazem Atorvastatin * Mechanism may be more complicated than simple P-gp inhibition
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3. If an NME is a substrate of P-gp and
not a substrate of CYP3A4 in vitro, then a clinical study with a P-gp inhibitor should be conducted. Yes or No
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Inhibitors of P-gp That Have Been
Associated with a Known Clinical Drug-Drug Interaction* Valspodar Cyclosporin Erythromycin Itraconazole Verapamil Quinidine Ketoconazole Propafenone Clarithromycin Talinolol Ritonavir Nelfinavir Diltiazem Atorvastatin * Mechanism may be more complicated than simple P-gp inhibition
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Inducers of P-gp That Have Been
Associated with a Known Clinical Drug-Drug Interaction* Rifampicin Induction Study
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Other transporters… during drug development?
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Other Transporters
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Other Transporters: OAT1 and OAT3
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Other Transporters: OCT1 and OCT2
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Selected Clinical Examples of Cyclosporin-Statin Interactions
with OATP1B1 (OATP-C) and CYPs STATIN AUC or Cmax Increase In the Presence of Cyclosporin (fold) Presumed Mechanism Simvastatin 8.0 CYP3A4 Pravastatin OATP1B1 Atorvastatin 7.0 CYP3A4/OATP1B1 Pitavastatin 4.5 Genetic evidence for OATP1B1 variants and pravastatin
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Recommendation: If NME is substrate of OATP1B1, consider the following study: Cyclosporin effect on PK of NME If NME is inhibitor of OATP1B1, consider the following NME effect on PK of pravastatin
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Selected Clinical Examples of Renal Drug-Drug Interactions at OATs
Compound Inhibitors Cephalosporins Probenecid (OAT1 and OAT3) Furosemide Probenecid Hydrochlorthiazide Penicillins R. Bendayan M. Dresser et al. Y. Shitara et al.
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Selected Clinical Examples of Renal Drug-Drug Interactions
at OCTs Compound Inhibitors Procainamide Cimetidine Trimethoprim Various Dipyridamole R. Bendayan M. Dresser et al. Y. Shitara et al.
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Renal Organic Anion Transporters (OATs)
If NME is secreted (i.e., Clrenal > fu*GFR), has a low therapeutic index, and substrate of OATs, consider a probenecid-NME interaction study. If NME is secreted (i.e., Clrenal > fu*GFR), has low therapeutic index, and substrate of OCTs, consider a trimethoprim-NME interaction study.
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Some Selective Inhibitors of Renal Organic Anion Transporters (OATs)
Inhibitors of OAT1 and OAT3 Probenecid Ketoprofen Indomethacin Ki values below therapeutic concentrations of unbound drug.
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Background: Focus on P-gp Questions:
DRUG-DRUG INTERACTIONS IN VIVO AND IN VITRO STUDIES: Focus on Transporters Background: Focus on P-gp Other Transporters Questions:
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Kinetic Values of Substrates of P-gp
Compound Km (µM) Cyclosporin 3.8 Etoposide 119 Indinavir 140 Verapamil 29 Vinblastine 27 Digoxin 59 From Jiunn Lin
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Substrates of P-gp Cyclosporin Digoxin Indinavir Ivermectin Nelfinavir
Paclitaxel Quinidine Saquinavir Tacrolimus Verapamil Vinblastine
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