First Previous Next Last Index Text

Slide 1 of 12

First Previous Next Last Index Text

Slide 2 of 12

First Previous Next Last Index Text

Slide 12 of 12

Drug-Induced Liver Injury A National and Global Problem

3/28/01

Click here to start

Table of Contents

Drug-Induced Liver Injury A National and Global Problem

Material presented here is based on the experiences of the author for 20 years in academic hepatology and gastroenterology, 5 years as a senior executive in the pharmaceutical industry, 11 years in private consulting to industry, and 5 years as a medical reviewer for new gastrointestinal drugs for the FDA. The points made do not reflect official policies or positions of the Agency, but are the personal opinions of the presenter based on the diverse experiences mentioned.

Two Pressing Problems of Drug-induced Hepatotoxicty

PPT Slide

Drug-induced Hepatotoxicity

Binary Relationship

Author: CDER USER

PPT Slide

PPT Slide

PPT Slide

PPT Slide

PPT Slide

PPT Slide

Drug-Induced Liver Injury A National and Global Problem

Introduction and Overview

John R. Senior, M.D.

Office of Post-marketing Drug Risk Assessment (OPDRA)

Food and Drug Administration (FDA)

Next slide Back to first slide View graphic version

First Previous Next Last Index Text

Slide 3 of 12

Material presented here is based on the experiences of the author for 20 years in academic hepatology and gastroenterology, 5 years as a senior executive in the pharmaceutical industry, 11 years in private consulting to industry, and 5 years as a medical reviewer for new gastrointestinal drugs for the FDA. The points made do not reflect official policies or positions of the Agency, but are the personal opinions of the presenter based on the diverse experiences mentioned.

Previous slide Next slide Back to first slide View graphic version

First Previous Next Last Index Text

Slide 11 of 12

PPT SlideFactors in Idiosyncracy

● genetic inheritance �❍ gender; racial traits �❍ cytochromes, enzymes, transport systems

● experience �❍ age, diseases, antigens, other drugs �❍ diet, obesity, dietary supplements

● ? to be discovered - need research!

Previous slide Back to first slide View graphic version

First Previous Next Last Index Text

Slide 4 of 12

First Previous Next Last Index Text

Slide 5 of 12

First Previous Next Last Index Text

Slide 6 of 12

First Previous Next Last Index Text

Slide 7 of 12

First Previous Next Last Index Text

Slide 8 of 12

First Previous Next Last Index Text

Slide 9 of 12

First Previous Next Last Index Text

Slide 10 of 12

Two Pressing Problems of Drug-induced Hepatotoxicty

1) for the FDA, - the “Agency”:

- need to withdraw approved drugs - how to detect hepatotoxic effects

2) for medical practice and patients:

- too high incidence of acute liver failure - how to prevent; advise doctors and patients

Previous slide Next slide Back to first slide View graphic version

PPT SlideWhy Are They Susceptible?

“idiosyncracy” ????? (idios) - one’s own, self ??? (syn) - together ?????? (crasis) - a mixing, or mixture

therefore,

a person’s own mixture [of characteristics, factors, nature and nurture, uniquely]

Previous slide Next slide Back to first slide View graphic version

PPT SlideHepatotoxicity has been the most common single adverse effect causing major drug problems

(withdrawal after marketing or non-approval)

Iproniazid (MARSILID?) - 1956

Ibufenac (in Europe only) - 1975

Ticrynafen (SELACRYN?) - 1979

Benoxaprofen (ORAFLEX?) - 1982

Perihexilene (in France) - 1985

Dilevalol (in Portugal, Ireland) - 1990

Bromfenac (DURACT?) - 1998

Troglitazone (REZULIN?) - 2000

R. Temple, personal communication, 2000

Previous slide Next slide Back to first slide View graphic version

Drug-induced Hepatotoxicity

● Bad for the FDA

● Bad for the pharmaceutical company

● Bad for the prescribing physician

● Worst of all for the patient.

A problem for all of us !

Previous slide Next slide Back to first slide View graphic version

Binary RelationshipFDA

CDER

PhRMA

Company

data

approval

review

NDA

Previous slide Next slide Back to first slide View graphic version

PPT SlideFDA

CDER

PhRMA

Company

NDA data

review approval

Academic and

Practicing MDs

ACs

prestige

advice

payment

Triangular Interrelationships

Previous slide Next slide Back to first slide View graphic version

PPT SlideFDA

CDER

PhRMA

Company

NDA data

review approval

285 million

U.S. PEOPLE

Academic and

Practicing MDs

ACs

prestige

advice

payment

Rx

care

fees

taxes

votes

protection

drugs

purchase

Tetrahedron of Interrelationships

Previous slide Next slide Back to first slide View graphic version

PPT Slide~ 1500 g (2-3% BW)*

bile ducts

portal veins

~700 mL/day bile

hepatic artery

7-8% cardiac output

17-19% cardiac output

via gut, stomach, spleen

* 80% hepatocytes (250 billion)

Previous slide Next slide Back to first slide View graphic version

PPT Slidefoods, nutrients

AAs, gluc, FAs

hormones,

cytokines

bilirubin

proteins

drugs

alcohol

OTC

remedies

environmental

chemicals

dietary supplements,

food additives,

herbal products

Previous slide Next slide Back to first slide View graphic version