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DRUG-DRUG INTERACTIONS
IN VIVO AND IN VITRO STUDIES: Focus on Transporters
Background: Focus on P-gp
Other Transporters
Questions:
SLC
ABC
Drug MetaboliteDME
Multiple Membrane Transporters in Hepatocyte Work in ConcertWith Enzymes to Mediate Drug Elimination
Drug Interactions with P-gp
Mizuno, 2003
Drug Interactions with P-gp
Mizuno, 2003
Inhibitors of P-gp That Have BeenAssociated with a Known Clinical Drug-Drug Interaction*
ValspodarCyclosporin
ErythromycinItraconazoleVerapamilQuinidine
KetoconazolePropafenone
ClarithromycinTalinololRitonavirNelfinavirDiltiazem
Atorvastatin
* Mechanism may be more complicated than simple P-gp inhibition
Substrates of P-gp That Have Altered PharmacokineticProperties in Humans in the Presence of P-gp Inhibitors*
DigoxinPaclitaxel
DexamethasoneAtorvastatin
TalinololFexofenadine
SaquinavirCyclosporine
QuinidineDocetaxalEtoposideTacrolimus
Azithromycin
* Mechanism may be more complicated than simple P-gp inhibition
2.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?
2.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?
•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.
High Ratio of Therapeutic Unbound Concentration/Ki
2.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?
2.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
Multiple Levels of Evidence that P-gp is Important in Digoxin Pharmacokinetics (Poorly metabolized)
• Clinical evidence of a quinidine-digoxin interaction
• Evidence in mdr1 knockout mouse (i.e. quinidine increasesdigoxin levels in normal mice, but not P-glycoproteinknockout mice; digoxin levels in brain increase in mdr1 knockoutmice).
• Evidence in cell culture (digoxin is a substrate, Km 50 µM)
• Clinical evidence that rifampin/St. John’s Wort reducedigoxin levels (and increase P-gp expression in intestiine).
Multiple Levels of Evidence Suggesting That P-gp is Important in Digoxin Pharmacokinetics
Quinidine Dose
Dig
oxin
Levels
(n
g/m
l)
2.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
Substrates of P-gp That Have Altered PharmacokineticProperties in Humans in the Presence of P-gp Inhibitors*
DigoxinPaclitaxel
DexamethasoneAtorvastatin
TalinololFexofenadine
SaquinavirCyclosporine
QuinidineDocetaxalEtoposideTacrolimus
Azithromycin
* Mechanism may be more complicated than simple P-gp inhibition
3. If an NME is a substrate of P-gp andCYP3A4 in vitro, then a clinical study witha multi-inhibitor should be conducted.
Yes or No
Consider clinical use of drug
Other: Demonstrate proof of concept
Inhibitors of P-gp That Have BeenAssociated with a Known Clinical Drug-Drug Interaction*
ValspodarCyclosporin
ErythromycinItraconazoleVerapamilQuinidine
KetoconazolePropafenone
ClarithromycinTalinololRitonavirNelfinavirDiltiazem
Atorvastatin
* Mechanism may be more complicated than simple P-gp inhibition
3. If an NME is a substrate of P-gp andnot a substrate of CYP3A4 in vitro, then a clinical study with a P-gpinhibitor should be conducted.
Yes or No
Inhibitors of P-gp That Have BeenAssociated with a Known Clinical Drug-Drug Interaction*
ValspodarCyclosporin
ErythromycinItraconazoleVerapamilQuinidine
KetoconazolePropafenone
ClarithromycinTalinololRitonavirNelfinavirDiltiazem
Atorvastatin
* Mechanism may be more complicated than simple P-gp inhibition
Inducers of P-gp That Have BeenAssociated with a Known Clinical Drug-Drug Interaction*
Rifampicin Induction Study
2.Other transporters… during drug development?
Other Transporters
Other Transporters: OAT1 and OAT3
Other Transporters: OCT1 and OCT2
Selected Clinical Examples of Cyclosporin-Statin Interactions with OATP1B1 (OATP-C) and CYPs
STATINSTATIN AUC or CmaxAUC or Cmax
Increase In the Increase In the Presence of Presence of
Cyclosporin (fold)Cyclosporin (fold)
PresumedPresumed
MechanismMechanism
SimvastatinSimvastatin 8.08.0 CYP3A4CYP3A4
PravastatinPravastatin 8.08.0 OATP1B1OATP1B1
AtorvastatinAtorvastatin 7.07.0 CYP3A4/CYP3A4/OATP1B1OATP1B1
PitavastatinPitavastatin 4.54.5 OATP1B1OATP1B1
Genetic evidence for OATP1B1 variants and pravastatin
Recommendation:
If NME is substrate of OATP1B1, consider the followingstudy:
Cyclosporin effect on PK of NME
If NME is inhibitor of OATP1B1, consider the followingstudy:
NME effect on PK of pravastatin
Selected Clinical Examples of Renal Drug-Drug Interactions at OATs
CompoundCompound InhibitorsInhibitors
CephalosporinsCephalosporins Probenecid (OAT1 and Probenecid (OAT1 and OAT3)OAT3)
FurosemideFurosemide ProbenecidProbenecid
HydrochlorthiazideHydrochlorthiazide ProbenecidProbenecid
PenicillinsPenicillins ProbenecidProbenecid
R. BendayanM. Dresser et al.Y. Shitara et al.
Selected Clinical Examples of Renal Drug-Drug Interactions at OCTs
CompoundCompound InhibitorsInhibitors
ProcainamideProcainamide CimetidineCimetidine
ProcainamideProcainamide TrimethoprimTrimethoprim
TrimethoprimTrimethoprim ProcainamideProcainamide
VariousVarious DipyridamoleDipyridamole
R. BendayanM. Dresser et al.Y. Shitara et al.
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.
Inhibitors of OAT1 and OAT3
ProbenecidKetoprofenIndomethacin
Ki values below therapeutic concentrations ofunbound drug.
Some Selective Inhibitors of Renal Organic Anion Transporters (OATs)
DRUG-DRUG INTERACTIONS
IN VIVO AND IN VITRO STUDIES: Focus on Transporters
Background: Focus on P-gp
Other Transporters
Questions:
Kinetic Values of Substrates of P-gp
CompoundCompound Km (µM)Km (µM)
CyclosporinCyclosporin 3.83.8
EtoposideEtoposide 119119
IndinavirIndinavir 140140
VerapamilVerapamil 2929
VinblastineVinblastine 2727
DigoxinDigoxin 5959
From Jiunn Lin
Substrates of P-gp
CyclosporinDigoxin
IndinavirIvermectinNelfinavirPaclitaxelQuinidineSaquinavirTacrolimusVerapamil
Vinblastine