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