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Transporters and Their Role in Drug Interactions

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Outline

• Messages of the draft drug interaction guidance (September 2006)

• Proposed methods to evaluate transporter- based interaction

- Outline of CYP- vs. transporter- based interaction evaluation

• Questions for the committee

- Current labeling examples

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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

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Guidance for Industry:Drug Interaction Studies —

Study Design, Data Analysis, and Implications for Dosing and Labeling

Draft published for public commentSeptember 11, 2006

http://www.fda.gov/cder/guidance/6695dft.pdf

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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

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Key messages (continued):

4. Clinical significance of a PK-based interaction needs to be interpreted based on exposure-response data/analyses

6. Labeling language needs to be useful and consistent (new labeling rule, June 2006)

5. Classification of CYP inhibitors and substrates can aid in study design and labeling

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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

What’s New?

Others transporters:

OATP, BCRP, MRP2, OATs, OCTs

-general substrates,

inhibitors, inducers

(in vitro/in vivo)< http://www.fda.gov/Cder/drug/drugInteractions/default.htm

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CYP Enzymes

A decision tree --- when

in vivo studies are recommended

per in vitro data

- substrate- inhibitor (I/Ki > 0.1)- inducer (40% control)

Transporters (P-gp)

Decision trees-- when in vivo studies are

recommended

per in vitro data

- substrate (flux ratio)

- inhibitor (I/Ki)

- (inducer)

Classification of -inhibitors-substrates

What’s New?

No classification system

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What’s New?

Others:

• protocol restriction (juice, dietary supplement use)

• multiple- inhibitor study

• cocktail approach

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Why Study Transporters?

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Kidney Basolateral: OCT1, OCT2, OAT1, OAT2, OAT3, MRP1

Kidney Apical Renal Secretion: P-gp, OAT4Reabsorption: PEPT2

Brain Transporters: P-gp (MDR1), OAT3, OATP-A, MRP1, MRP3

Liver Sinusoidal Hepatic Uptake: OCT1, OATP-C, OATP-B, OATP8, NTCP, OAT2Secretion: MRP1, MRP3

Liver Canalicular Biliary Excretion: P-gp, MRP2, BCRP, MDR3

Intestinal Luminal Absorption: PEPT1Secretary: P-gp, OATP3

<Zhang L et al, Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006 >

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The role of P-gp transporter?

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Number of published papers/patents

0

100

200

300

400

500

600

76 81 86 91 96 '01 '06Year

<Survey via Biovista; courtesy: Aris Persidis>

MDR1

BCRPOCTMRP2

OATOATP1B1

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Proposed decision trees to evaluate transporter-

based interactions

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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 Poor or non-inhibitor

[I]/IC50 (or Ki) > 0.1 [I]/IC50 (or Ki) < 0.1

An in vivo interaction studyWith a P-gp substrate (e.g., digoxin) is recommended

An in vivo interaction studyWith a P-gp substrate is not needed

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If a NME is an inhibitor of P-gp in vitro, in vivo study using digoxin may be appropriate

0

0.5

1

1.5

2

2.5

Quinidine

Verapamil

Grapefruit

juice Rifampin

St John’s

wort

Aprepitant

Dig

oxin

pla

sma

AU

C o

r C

ss(c

o-ad

min

istr

atio

n)

Ritonavir

Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm

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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

Bi-directional transport assay

Net flux Ratio > 2 Net flux ratio < 2

Is efflux significantly inhibited by 1 or more P-gp inhibitors

Poor or non-substrate

Likely a P-gp substrate

An in vivo interaction studyWith a P-gp inhibitor may bewarranted

Further in vivo to determine which efflux transporters are involved may be warranted

YES NOOther efflux transporters are responsible

Alternatively, use a % value (relative to a probe substrate)

Note exceptions

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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

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Cyclosporine affects multiple transporters, including OATP1B1

0

1

2

3

4

5

6

7

8

pravastatin

rosuvastatin

pitavastatin

Fol

d A

UC

ch

ange

Wit

h c

yclo

spor

ine

<Data from Table in Shitara and Sugiyama, Pharmacol Ther 112, 2006>

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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

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05

10152025

3035404550

Ritonavir

Ketoconazole

200 mg

Erythromycin

Indinavir

Var

den

afil

AU

C(F

old

-ch

ange

)

Ritonavir affects multiple pathways (enzymes and transporters)

Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm

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How do we label transporter-based

interactions?

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“Class” labeling of drugs that are substrates of

CYP3A[proposed in the 2006 draft

guidance on “drug interactions”]

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Eletriptan AUC Cmax

Labeling example - CYP3A substrate

Should not be used within at least 72 hours with strong CYP3A inhibitors…. Ketoconazole, itraconazole, ritonavir, nelfinavir, nefazodone, clarithromycin.

Ketoconazole 8x 4x

Not studied

<(Relpax (eletriptan) PDR labeling May 2005>

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“Class” labeling of drugs that are inhibitors of

CYP3A[proposed in the 2006 draft

guidance on “drug interactions”]

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• Telithromycin is a strong inhibitor of the cytochrome P450 3A4 system

Labeling example- CYP3A inhibitor

Telithromycin AUCMidazolam 6x

<Physicians’ Desk Reference at http://pdrel.thomsonhc.com/pdrel/librarian >

• Use of simvastatin, lovastatin, or atorvastatin concomitantly with KETEK should be avoided

• The use of KETEK is contraindicated with cisapride, pimozide

Not studied

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Do we have sufficient data or understanding for a

similar “class” labeling of drugs that are inhibitors or substrates of transporters?

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Labeling examples

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Eplerenone is not a substrate or an inhibitor of P-glycoprotein at clinically relevant doses

Eplerenone

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

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PramipexoleCimetidine:   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).

http://pdrel.thomsonhc.com/pdrel/librarian/PFDefaultActionId/pdrcommon.IndexSearchTranslator#PDRPRE01el/2004/21704lbl.pdf

Probenecid:   Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).

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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. Co-administration 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).

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• Metformin: varenicline .. did not alter the steady-state pharmacokinetics of metformin .. which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.

Varenicline (2)- in vivo

• 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>

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Multiple - inhibitor interactions

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Combination of CYP and transporter interactions

024

68

1012

14161820

Rep

agli

nid

e A

UC

(fol

d-c

han

ge)

itraconazol

eGemfib

rozil

+itraconazolegemfib

rozi

l

< Data from Neuvonen: Niemi M et al, Diabetologia. 2003 Mar;46(3):347-51>

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RepaglinideCaution 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

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Summary

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P-gp- based interactions

• 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

• Most well developed

• Other issues

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Other transporter- based interactions

• In vitro methodologies being developed

• Need standardized procedures; need probe substrates/inhibitors

• Short-term recommendations may be drug- or “therapeutic class-” specific

• Some information has been included in labeling

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Questions for the Committee

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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?

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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 Poor or non-inhibitor

[I]/IC50 (or Ki) > 0.1 [I]/IC50 (or Ki) < 0.1

An in vivo interaction studyWith a P-gp substrate (e.g., digoxin) is recommended

An in vivo interaction studyWith a P-gp substrate is not needed

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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?

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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

Bi-directional transport assay

Net flux Ratio > 2 Net flux ratio < 2

Is efflux significantly inhibited by 1 or more P-gp inhibitors

Poor or non-substrate

Likely a P-gp substrate

An in vivo interaction studyWith a P-gp inhibitor may bewarranted

Further in vivo to determine which efflux transporters are involved may be warranted

YES NOOther efflux transporters are responsible

Alternatively, use a % value (relative to a probe substrate)

Note exceptions

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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)

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4. Does the current knowledge base support the recommendation of drug interaction studies for other transporters such as OATP1B1, MRP2, BCRP, OCTs and OATs?