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Advisory Committee for Pharmaceutical Science - Clinical Pharmacology Subcommittee meeting Topic 2: Transporter-based interactions Rockville, MD, October 18, 2006. Transporters and Their Role in Drug Interactions. Shiew-Mei Huang, Ph.D. Deputy Director for Science

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Advisory Committee for Pharmaceutical Science - Clinical Pharmacology Subcommittee meeting

Topic 2: Transporter-based interactions

Rockville, MD, October 18, 2006

Transporters and Their Role in Drug Interactions

Shiew-Mei Huang, Ph.D.

Deputy Director for Science

Office of Clinical Pharmacology

CDER, FDA

Shiewmei.huang@fda.hhs.gov


Outline

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

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

  • Proposed methods to evaluate transporter- based interaction

- Current labeling examples

  • Questions for the committee


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


Guidance for Industry:

Drug Interaction Studies —

Study Design, Data Analysis,

and Implications for

Dosing and Labeling

Draft published for public comment

September 11, 2006

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


  • 1. Metabolism, transport, drug-interaction info key to benefit/risk assessment

  • Key messages:

  • 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


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

  • Key messages (continued):

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

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


What’s

New?

< http://www.fda.gov/Cder/drug/drugInteractions/default.htm


What’s

New?


What’s

New?

Others:

  • protocol restriction (juice,

  • dietary supplement use)

  • multiple- inhibitor study

  • cocktail approach


Why Study Transporters?


Brain Transporters:

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

Liver Sinusoidal Hepatic Uptake:OCT1, OATP-C,

OATP-B, OATP8, NTCP, OAT2

Secretion:MRP1, MRP3

Liver Canalicular

Biliary Excretion:

P-gp, MRP2, BCRP, MDR3

Kidney Basolateral:

OCT1, OCT2, OAT1, OAT2, OAT3, MRP1

Intestinal Luminal

Absorption:PEPT1

Secretary:P-gp, OATP3

Kidney Apical

Renal Secretion:P-gp, OAT4

Reabsorption:PEPT2

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


The role of P-gp transporter?


Number of published papers/patents

MDR1

BCRP

OCT

MRP2

OAT

OATP1B1

Year

<Survey via Biovista; courtesy: Aris Persidis>


Proposed decision trees to evaluate transporter-based interactions


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 study

With a P-gp substrate

(e.g., digoxin) is recommended

An in vivo interaction study

With a P-gp substrate

is not needed


If a NME is an inhibitor of P-gp in vitro,

in vivo study using digoxin may be appropriate

Digoxin plasma AUC or Css

(co-administration)

Grapefruit

juice

St John’s

wort

Rifampin

Quinidine

Verapamil

Aprepitant

Ritonavir

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


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

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

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

YES

NO

Likely a P-gp substrate

Other efflux transporters are responsible

An in vivo interaction study

With a P-gp inhibitor may be

warranted

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

Note

exceptions


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


Cyclosporine affects multiple transporters, including OATP1B1

Fold AUC change

With cyclosporine

rosuvastatin

pravastatin

pitavastatin

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


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


Ritonavir affects multiple pathways (enzymes and transporters)

Vardenafil AUC

(Fold-change)

Ketoconazole

200 mg

Ritonavir

Indinavir

Erythromycin

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


How do we label transporter-based interactions?


“Class” labeling of drugs that are substrates of CYP3A

[proposed in the 2006 draft guidance on

“drug interactions”]


Labeling example - CYP3A substrate

EletriptanAUCCmax

Ketoconazole 8x4x

Should not be used within at least 72 hours with strong CYP3A inhibitors….

Ketoconazole,

itraconazole, ritonavir,

nelfinavir, nefazodone,

clarithromycin.

Not studied

<(Relpax (eletriptan) PDR labeling May 2005>


“Class” labeling of drugs that are inhibitors of CYP3A

[proposed in the 2006 draft guidance on

“drug interactions”]


Labeling example- CYP3A inhibitor

TelithromycinAUC

Midazolam 6x

  • Telithromycin is a strong inhibitor of the

  • cytochrome P450 3A4 system

  • Use of simvastatin, lovastatin, or

  • atorvastatin concomitantly with

  • KETEK should be avoided

Not studied

  • The use of KETEK is contraindicated with

  • cisapride, pimozide

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


Do we have sufficient data or understanding for a similar “class” labeling of drugs that are inhibitors or substrates of transporters?


Labeling examples


Eplerenone

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

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


Pramipexole

Cimetidine:   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).

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

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


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).


Varenicline (2)- in vivo

  • 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.

  • 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>


Multiple - inhibitor

interactions


Combination of CYP and transporter interactions

Repaglinide AUC

(fold-change)

itraconazole

gemfibrozil

Gemfibrozil+

itraconazole

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


Repaglinide

  • Caution 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


Summary


P-gp- based interactions

  • Most well developed

  • 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

  • Other issues


Other transporter- based interactions

  • In vitro methodologies being developed

  • Some information has been included in labeling

  • Need standardized procedures; need probe

  • substrates/inhibitors

  • Short-term recommendations may be drug-

  • or “therapeutic class-” specific


Questions for the Committee


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?


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 study

With a P-gp substrate

(e.g., digoxin) is recommended

An in vivo interaction study

With a P-gp substrate

is not needed


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?


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

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

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

YES

NO

Likely a P-gp substrate

Other efflux transporters are responsible

An in vivo interaction study

With a P-gp inhibitor may be

warranted

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

Note

exceptions


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)


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


References

  • Lei Zhang, John M. Strong, Wei Qiu, Lawrence J. Lesko, and Shiew-Mei Huang. Scientific Perspectives on Drug Transporters and Their Role in Drug Interactions [PDF] [external link] Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006.

  • Guidance for industry: Drug Interaction Studies: Study design, Data analysis and Implications for Dosing and Labeling (Issued for public comment, September 11, 2006, http://www.fda.gov/cder/guidance/6695dft.pdf).

  • FDA Drug Development and Drug Interactions Website; http://www.fda.gov/Cder/drug/drugInteractions/default.htm, established May 2006


Drug Interactions working group

Sophia Abraham Sayed Al-Habet Raman Baweja

Sang Chung Philip Colangelo Paul Hepp

Shiew-Mei Huang Ron Kavanagh Lawrence LeskoPatrick Marroum Srikanth Nallani Wei Qiu

Nam Atik Rahman Kellie Reynolds Xiaoxiong Wei

Sally Yasuda *Lei K Zhang Jenny H Zheng

Jerry Collins Soloman Sobel *John Strong

David M Green David Frucht

Hon Sum Ko Toni Stifano

Robert Temple Janet Norden

Kenneth ThummelGilbert Burckart

(on sabbatical at FDA, 2006)


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