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 Sciences Clinical Pharmacology Subcommittee meeting April 23, 2003
36
Embed
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.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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)
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>
< 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