Issues and Challenges in the Evaluation and Labeling of Drug Interaction Potentials of NME

Shiew-Mei Huang, Ph.D.

Deputy Office Director for Science

Office of Clinical Pharmacology & Biopharmaceutics, OPS

CDER, FDA

Advisory Committee for Pharmaceutical SciencesClinical Pharmacology Subcommittee meeting

April 23, 2003

Recent US Market Withdrawal/NA -Examples

QTTdP

1998 TerfenadineMibefradilBromfenac

1999 AstemizoleGrepafloxacinDrug X (NA)

2000 TroglitazoneCisaprideAlosetron*

2001 CerivastatinPapacuroniumDrug Y (NA)

OthersHepato-tox

* reintroduced in 2002

3

• 2,000,000number of serious ADRs yearly

< JAMA 1998;279:1200–1205; Arch Intern Med 1995;155(18):1949–1956>

• 136,000,000,000annual cost in dollars associated with ADRs

• 100,000annual number of ADR-related deaths

• 4-6ranking of serious ADRs as causes of death

Adverse Drug Reactions- Marketed Drugs

4

0

20

40

60

80

100

Use

, %

Total 18-44ymen

45-64ymen

> 65 ymen

18-44ywomen

45-64ywomen

> 65 ywomen

Use of Medications by Sex and Age

Any Use> 5 drugs> 10 drugs

< JAMA 2002;287:337-344 >

Why are there so many ADRs?

5

“…drug interactions represent 3-5% of preventable ADRs and are an important contributor to ER visits and hospital admissions.”

< JAMA 2003;289 (13):1652>

“…elderly patients with digoxin toxicity were 12 times more likely to have been treated with clarithromycin”

< JAMA 1995;274(1):35–43>

6

OCPB GRP Quality Review (Steps)

1. Evaluate drug interactions well

2. Evaluate the safety/efficacy database & explore exposure/response relationship

3. Use prominent warning early in labeling (project a level of risk in drug interactions)

< Lesko LJ, et al, OCPB QA/QC report, 1999 >; < Huang S-M, et al, Clin Pharmacol Ther 2000; 67(2): 148 >

7

Recommendations:

4. Develop better means of communicating dosing information to practitioners and patients

What is optimal drug interaction information from NDA submissions?

• Elucidation of metabolic pathways; contribution of CYP; fraction metabolized

• Enzyme modulating potential (inhibition/induction by NME/metabolites)

- Effect of other drugs

- Effect on other drugs

1-3,7: internet: http://www.fda.gov/cder/guidance/index.htm under “clinical pharmacological”4-6: intranet

1. Preclinical: in vitro studies: 1997 guidance

Relevant guidance/MaPP documents:

5. OCPB Good Review Practice draft MAPP; 2001

2. Early phase: in vivo studies: 1999 guidance

4. Cross-labeling draft MAPP : 1999

6. In vitro metabolism draft MAPP; 2002

7. Exposure-response: draft guidance; 2002

3. Late phase: population PK studies : 1999 guidance

10

In Vitro Metabolism Data

<Studies in Human Tissues>

for each key CYP enzyme

Substrate?Inhibitor/

inducer?

No

Stop-

General Labeling*

Stop-

General Labeling*

Pathway

Major?

Stop-

General Labeling*

Yes/

unknownNo

No

In vivo-

Most Sensitive

Substrates

In vivo-

Most Potent

Inhibitor/inducer

In vivo-

Most Potent

Inhibitor/inducer

• Obviate certain in vivo metabolic interaction studies• Focus on in vivo investigations

*Population PK studies

Yes/

unknown

Yes/

unknown

OCPBGRP

11

In Vitro Metabolism Data

<Studies in Human Tissues>

for each key CYP enzyme

Substrate?Inhibitor/

inducer?

No

Stop-

General Labeling*

Stop-

General Labeling*

Pathway

Major?

Stop-

General Labeling*

Yes/

unknownNo

No

In vivo-

Most Sensitive

Substrates

In vivo-

Most Potent

Inhibitor/inducer

In vivo-

Most Potent

Inhibitor/inducer*Population PK studies

Yes/

unknown

Yes/

unknown

OCPBGRP

** PhRMA White paper JCP 2003; 43 (2)

Ket

ocon

azol

e

Itra

con

azol

e

Cla

rit h

rom

ycin

Saq

uin

avir

Ery

thro

myc

in

Dil

tiaz

em

Flu

con

azol

e

Ver

apam

il

Gra

pef

rui t

ju

ice

Cim

etid

ine

Ran

itid

ine

Azi

t hro

myc

in

0

200

400

600

800

1000

1200

1400

1600

% A

UC

vs.

bas

elin

e

MildModeratePotent

Oral Midazolam as probe substrate

500

200

Classification system-potential use

• Used to guide in vivo studies

• Used in labeling inhibitors/substrates

• Concerns• Potent inhibitors may affect other enzymes/transporters (UGT, P-gp)• Substrates are also substrates of other enzymes/transporters

• Multiple drugs are prescribed

• Varied data from various study designs

• others

Discussion of drug interaction issues

• CDER Scientific rounds, February 26, 2003

• Professional meetings

- AAPS open forum, November 2002, Toronto

- ASCPT annual meeting, April, 2003, Washington DC

• ACPS subcommittee meetings, 2003

Case 1-NME as a Substrate

Drug interactions evaluated?

Clinical significance (exposure-response)?

Labeling language?

16

In Vitro Metabolism Data

<Studies in Human Tissues>

for each CYP enzyme

Substrate?Inhibitor/

inducer?

No

Stop-

General Labeling*

Stop-

General Labeling*

Pathway

Major?

Stop-

General Labeling*

Yes/

unknownNo

No

In vivo-

Most Sensitive

Substrates

In vivo-

Most Potent

Inhibitor/inducer

In vivo-

Most Potent

Inhibitor/inducer*Population PK studies

Yes/

unknown

Yes/

unknown

17

Drug A with AUC Cmax

Ketoconazole 6x 4x

NME - CYP3A substrate

Erythromycin 4x 3xVerapamil 4x 3x

Drug A

18

Exposure-response data

Proposed clinical dose 15, 30, 60

Approved 15, 30

How to label drug interactions?

19

Potential labeling language

Do not take with potent CYP3A inhibitors….. Ketoconazole, itraconazole, TAO, ritonavir, nelfinavir, nefazodone, clarithromycin

Use lower doses with moderate CYP3A inhibitors….. erythromycin, verapamil, diltiazem...

Case 2-NME as an inhibitor

Drug interactions evaluated?

Clinical significance (exposure-response of the substrates)?

Labeling language?

21

In Vitro Metabolism Data

<Studies in Human Tissues>

for each CYP enzyme

Substrate?Inhibitor/

inducer?

No

Stop-

General Labeling*

Stop-

General Labeling*

Pathway

Major?

Stop-

General Labeling*

Yes/

unknownNo

No

In vivo-

Most Sensitive

Substrates

In vivo-

Most Potent

Inhibitor/inducer

In vivo-

Most Potent

Inhibitor/inducer*Population PK studies

Yes/

unknown

Yes/

unknown

22

Drug B with AUC Cmax

Midazolam 6x 3x

NME - CYP3A inhibitor

Simvastatin 8x 5x

Cisapride 3x 2x

Theophylline 1x 1x

Warfarin 1x 1x

Ket

ocon

azol

e

Itra

con

azol

e

Cla

rith

rom

ycin

Saq

uin

avir

Ery

thro

myc

in

Dil

tiaz

em

Flu

con

azol

e

Ver

apam

il

Gra

pef

ruit

ju

ice

Cim

etid

ine

Ran

itid

ine

Azi

thro

myc

in

0

200

400

600

800

1000

1200

1400

1600

% A

UC

vs.

bas

elin

e

MildModeratePotent

Oral Midazolam as probe substrate

500

200

Potent

Sensitive substrates or substrates with “narrow” therapeutic range:

Labeling language (e.g., contraindication) with the “strong inhibitors”

midazolam, triazolamsimvastatin, lovastatin, atorvastatinterfenadine, cisapride, astemizole,pimozide

25

Potential Labeling Language

The use of Drug B, a strong CYP3A inhibitor, is

contraindicated with cisapride, pimozide, simvastain….… monitored..midazolam…others, such as sildenafil, budesonide…(those carrying ketoconazole labeling..)

Classification system-potential use

• Used to guide in vivo studies

• Used in labeling inhibitors/substrates

• Concerns• Potent inhibitors may affect other enzymes/transporters (UGT, P-gp)• Substrates are also substrates of other enzymes/transporters

• Multiple drugs are prescribed

• Varied data from various study designs

• others• •Potent inhibitors may affect other enzymes/transporters (UGT, P-gp)

P-gp based interactions

28

CYP3A and P-gp inhibitors

0

20

40

60

80

100

120

140

IC 50 ratios (CYP3A/P-gp)

verapamil

cyclosporine quinidine PSC833

<Wandel C et al, Cancer Res 1999 >

29

AUC CmaxKetoconazole 2.7x 2.4x

P-gp substrates- fexofenadine

Itraconazole 2.4-2.8x 2.4-2.5x

Rifampin 0.3x 0.5x

< PDR for fexofenadine; Hamman MA, et al, Clin Pharmacol Ther 2001; Dresser GK, et al, Clin Pharmacolg Ther 2003; Dresser G, et al, Shon J, et al, Lemma GL, et al, ASCPT 2003; * compared to water or acute dosing; ** possible OATP involvement>

Grapefruit juice** 0.5x 0.5xSt John’s Wort* 0.5x 0.6-0.7

Erythromycin 2.1x 1.8x

Verapamil --- 1.5,1.3,1x (C at days 1,10,38)

30

AUC Cmax

Quinidine --- 2.4x (Css,7)

P-gp substrates- digoxin

Verapamil --- 1.4-1.7x(Css,-)

< Belz GC, et al; Clin Pharmacol Ther 1982; Klein HO, et al, Circulation 1982; ; Lee Y, et al, ASCPT 2003; Durr, Clin Pharmacol Ther, 2000; Greiner B J Clin Invest 1999 > < Huang SM et al, JCP, 1999; Marroum PJ et al, CPT, 2000>

• surveys indicated that cimetidine and digoxin most often studied in submissions reviewed in 1996 and 1987-1997

• digoxin continued to be studied, if likely to be co-administered

Rifampin 0.7x 0.5x St John’s Wort 0.8x ---

Aprepitant 0.93-0.99x ---

Grapefruit juice** 1.09x ---

Next Steps

Guidance revision

Guidance for IndustryIn Vivo Drug Metabolism/Drug

Interaction Studies —Study Design, Data Analysis, and

Recommendations forDosing and Labeling

Draft Cross Labeling MAPP

Draft In Vitro Metabolism/Transport MAPP

Questions for the Panel

1. What other factors to consider in implementing the classification system for CYP3A inhibitors in the labeling? - definition of sensitive substrates?

Questions for the Panel (2)

3. What about transporter-based interactions? - should we recommend routine evaluation?

2. Should we consider application of Classification systems to inhibitors of other CYP enzymes? Inducers?

AcknowledgementIn vitro (in vivo) Metabolism/transportinteraction working group and othersinvolved in CDER rounds discussions

Sophia Abraham Sayed Al Habet Debra BirnkrantSang Chung Phil Colangelo Jerry CollinsBarbara Davit John Duan Shiew-Mei HuangRussell Katz Ronald Kavanagh Lawrence J LeskoAtiqur Rahman Kellie Reynolds Solomon SobelJohn M Strong Robert Temple Wei QiuRamana Uppoor Jim Xiaoxiong Wei Lei K ZhangJenny H Zheng Jenny J Zheng