Prevention:-
The Drug-Development Process
The
first opportunity to prevent hepatotoxicity arises in the early stages of drug
development, when animals are exposed to a drug and assessments with regard to
toxicity are made. Preclinical studies in animals are more useful for detecting
dose-related, predictable hepatotoxicity than they are for detecting
unpredictable hepatotoxicity in humans. Phase 1 safety studies provide the
first opportunity to identify drug-related hepatotoxicity in humans. These
studies are limited by their small number of participants — 12 to 30 healthy
subjects — and the brief exposure of these subjects to low doses of a given
drug. During efficacy testing, more patients are exposed to a drug, and the
likelihood that hepatotoxicity will become evident is higher; however, the
limited number of participants involved in controlled clinical trials means
that a 95 percent or greater chance of even one case of a rare event occurring
with a true incidence of 1 in 1000 subjects requires that almost 3000 be
observed.
The
case of troglitazone highlights the importance of recognizing signs of
hepatotoxicity during drug development. Troglitazone was the first
peroxisome-proliferator–activated receptor γ agonist approved for use in
achieving blood glucose control in patients with non-insulin-dependent
diabetes. During clinical trials, 12 of 2510 patients treated with troglitazone
had alanine aminotransferase levels of more than 10 times the upper limit of
the normal range, and 5 had levels of more than 20 times the upper limit of
normal; biopsies were performed in 2 patients, including 1 in whom jaundice
developed. These observations proved to be predictive of adverse events after
troglitazone was marketed, when liver failure developed in 94 of the nearly 2
million patients who used the drug. Ultimately, troglitazone was withdrawn from
the market, in March of 2000. This situation highlighted the need to appreciate
signals that predict hepatotoxicity while a drug is being developed.
Figure.12.1:- A
typical strategy used in drug development. A target receptor or enzyme is
established on the basis of knowledge about the biology for the disease of
interest. Lead compounds are developed, usually by screening procedures
(sometimes by rational design). These candidates enter a series of reiterative
development loops. Efficacy and selectivity testing involve pharmacological
assays based on the target; developing screening and predictions involve the
aspects shown at the right; design and synthesis involve more chemistry. The
goal of the process is to develop candidates that are less likely to fail in
the detailed later studies and the clinical trials.
Post-marketing
Surveillance
Currently, the period after a drug is
approved is the most important for identifying hepatotoxicity. At present, the
FDA’s MedWatch program is a good way to report suspected drug-related
hepatotoxicity. This voluntary reporting system is limited in the use and
adequacy of reported clinical details. Case reports that appear in the
literature also draw attention to potential hepatotox-ins, particularly substances that are not studied
by the manufacturer or regulated by the FDA, such as herbal and
over-the-counter complementary and alternative medications.
Monitoring of Liver tests in Clinical
Practice
There is no evidence to show that,
despite instructions and warnings on drug labels, routine monitoring of liver
enzymes prevents clinically significant hepatotoxicity, most of which is
unpredictable and quite uncommon. Thus, an argument can be made that a more
effective and efficient method of detecting and preventing hepatotoxicity would
involve vigilance on the part of the patients themselves in recognizing
symptoms, followed by prompt medical evaluation. Admittedly, such an approach
may not apply to all drugs.
Pharmacogenomics
Exploitation of the growing body of
knowledge of genetic polymorphisms, through the field of pharmacogenomics,
should revolutionize our ability to prevent hepatotoxicity. The emerging fields
of proteomics and metabonomics also promise insights into the mechanisms of
drug-related hep-atotoxicity.
It has been postulated that tailoring
drug therapy to individual patients may maximize therapeutic effects while
minimizing hepatotoxicity, but as yet no genetic tests have come into routine
clinical use.
Key Guidelines in the Recognition and
Prevention of Hepatotoxicity in Clinical Practice.
Do
not ignore symptoms When a drug is
being used, even vague symptoms such as nausea, anorexia, malaise, fatigue, and
right upper abdominal discomfort as well as specific symptoms such as itching
or jaundice should prompt consideration of hepatotoxicity. Testing for liver
injury and abnormal function should be performed.
No comments:
Post a Comment