DRUG-DRUG INTERACTIONS

1
DRUG-DRUG INTERACTIONS IN VIVO AND IN VITRO
STUDIES Focus on Transporters
Background Focus on P-gp
Other Transporters
Questions
2
Multiple Membrane Transporters in Hepatocyte Work
in Concert With Enzymes to Mediate Drug
Elimination
SLC
DME
Drug
Metabolite
ABC
3
Drug Interactions with P-gp
Mizuno, 2003
4
Drug Interactions with P-gp
Mizuno, 2003
5
Inhibitors of P-gp That Have Been Associated with
a Known Clinical Drug-Drug Interaction
Valspodar Cyclosporin Erythromycin Itraconazole Ve
rapamil Quinidine Ketoconazole Propafenone Clarith
romycin Talinolol Ritonavir Nelfinavir Diltiazem A
torvastatin
Mechanism may be more complicated than simple
P-gp inhibition
6
Substrates of P-gp That Have Altered
Pharmacokinetic Properties in Humans in the
Presence of P-gp Inhibitors
Digoxin Paclitaxel Dexamethasone Atorvastatin Tali
nolol Fexofenadine Saquinavir Cyclosporine Quinidi
ne Docetaxal Etoposide Tacrolimus Azithromycin
Mechanism may be more complicated than simple
P-gp inhibition
7

• 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?

8

• 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.

9

• 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?

10

• 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. Johns Wort
  reduce
• digoxin levels (and increase P-gp expression in
  intestiine).

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Multiple Levels of Evidence Suggesting That P-gp
is Important in Digoxin Pharmacokinetics
Digoxin Levels (ng/ml)
Quinidine Dose
13

• 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 Tali
nolol Fexofenadine Saquinavir Cyclosporine Quinidi
ne 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
16
Inhibitors of P-gp That Have Been Associated with
a Known Clinical Drug-Drug Interaction
Valspodar Cyclosporin Erythromycin Itraconazole Ve
rapamil Quinidine Ketoconazole Propafenone Clarith
romycin Talinolol Ritonavir Nelfinavir Diltiazem A
torvastatin
Mechanism may be more complicated than simple
P-gp inhibition
17
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
18
Inhibitors of P-gp That Have Been Associated with
a Known Clinical Drug-Drug Interaction
Valspodar Cyclosporin Erythromycin Itraconazole Ve
rapamil Quinidine Ketoconazole Propafenone Clarith
romycin Talinolol Ritonavir Nelfinavir Diltiazem A
torvastatin
Mechanism may be more complicated than simple
P-gp inhibition
19
Inducers of P-gp That Have Been Associated with a
Known Clinical Drug-Drug Interaction
Rifampicin Induction Study
20

1. 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


24
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 8.0 OATP1B1
Atorvastatin 7.0 CYP3A4/OATP1B1
Pitavastatin 4.5 OATP1B1
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 study NME effect on PK
of pravastatin
26
Selected Clinical Examples of Renal Drug-Drug
Interactions at OATs
Compound Inhibitors
Cephalosporins Probenecid (OAT1 and OAT3)
Furosemide Probenecid
Hydrochlorthiazide Probenecid
Penicillins Probenecid
R. Bendayan M. Dresser et al. Y. Shitara et al.
27
Selected Clinical Examples of Renal Drug-Drug
Interactions at OCTs
Compound Inhibitors
Procainamide Cimetidine
Procainamide Trimethoprim
Trimethoprim Procainamide
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 gt fuGFR), has
a low therapeutic index, and substrate of
OATs, consider a probenecid-NME interaction study.
If NME is secreted (i.e., Clrenal gt fuGFR), has
low therapeutic index, and substrate of
OCTs, consider a trimethoprim-NME interaction
study.
29
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.
30
DRUG-DRUG INTERACTIONS IN VIVO AND IN VITRO
STUDIES Focus on Transporters
Background Focus on P-gp
Other Transporters
Questions
31
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
32
Substrates of P-gp
Cyclosporin Digoxin Indinavir Ivermectin Nelfinavi
r Paclitaxel Quinidine Saquinavir Tacrolimus Verap
amil Vinblastine