issues and challenges in the evaluation and labeling of drug interaction potentials of nme shiew-mei...
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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
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Recent US Market Withdrawal/NA -Examples
QTTdP
1998 TerfenadineMibefradilBromfenac
1999 AstemizoleGrepafloxacinDrug X (NA)
2000 TroglitazoneCisaprideAlosetron*
2001 CerivastatinPapacuroniumDrug Y (NA)
OthersHepato-tox
* reintroduced in 2002
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• 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
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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?
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“…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>
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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 >
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Recommendations:
4. Develop better means of communicating dosing information to practitioners and patients
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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
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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
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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
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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)
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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
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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
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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
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Case 1-NME as a Substrate
Drug interactions evaluated?
Clinical significance (exposure-response)?
Labeling language?
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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
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Drug A with AUC Cmax
Ketoconazole 6x 4x
NME - CYP3A substrate
Erythromycin 4x 3xVerapamil 4x 3x
Drug A
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Exposure-response data
Proposed clinical dose 15, 30, 60
Approved 15, 30
How to label drug interactions?
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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...
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Case 2-NME as an inhibitor
Drug interactions evaluated?
Clinical significance (exposure-response of the substrates)?
Labeling language?
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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
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Drug B with AUC Cmax
Midazolam 6x 3x
NME - CYP3A inhibitor
Simvastatin 8x 5x
Cisapride 3x 2x
Theophylline 1x 1x
Warfarin 1x 1x
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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
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Sensitive substrates or substrates with “narrow” therapeutic range:
Labeling language (e.g., contraindication) with the “strong inhibitors”
midazolam, triazolamsimvastatin, lovastatin, atorvastatinterfenadine, cisapride, astemizole,pimozide
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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..)
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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)
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P-gp based interactions
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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 >
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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)
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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 ---
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Next Steps
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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
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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?
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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?
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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
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