[e-drug] New drugs' dosages often too high

[Kirsten Myhr <myhr@online.no>]

E-drug: New drugs' dosages often too high
-------------------------------------------------------------------------

[Not only is our knowledge about risks of new drugs limited on introduction,
but risks may in fact be increased due to too high doses being used. Copied
as fair use. KM]

JAMA 2002; 288(13): 1578 (2 October)
http://jama.ama-assn.org/issues/v288n13/ffull/jmn1002-3.html

New Drugs' Dosages Often Too High
Joan Stephenson, PhD

The initially recommended dosage of prescription drugs is often twice that
needed for safe and effective use in clinical practice, according to two new
studies by researchers in the United States and the Netherlands. Both
studies were recently published in the online version of the journal
Pharmacoepidemiology and Drug Safety.

In one study, researchers at the Food and Drug Administration (FDA) in
Rockville, Md, and Georgetown University Center for Drug Development Science
in Washington, DC, studied label changes for 354 "new molecular entities"
(new drugs containing an active substance not previously approved for
marketing in any form in the United States) that received FDA approval
between 1980 and 1999 (Pharmacoepidemiol Drug Saf. DOI: 10.1002/pds.744).
They discovered that the initially recommended dosage for 21% of the drugs
was later changed, and that the overwhelming proportion of such changes
(70%) were dosage decreases made for safety reasons.
[Abstract:
http://www3.interscience.wiley.com/cgi-bin/abstract/97517549/START]

Although the researchers had predicted that improvement in drug development
would have led to a smaller proportion of label changes after approval in
recent years, they found that the opposite had occurred. New drugs approved
in the late 1990s (1995-1999) were more than three times likelier to require
a dosage change than drugs approved in the early 1980s (1980-1984).

The finding that a substantial proportion of drugs required dose reductions
"may represent a systematic flaw in premarketing dosage evaluation," the
researchers suggest. The drug industry, they note, commonly launches phase 3
trials testing the experimental drug at or near the maximum tolerated doses
(MTDs) established in phase 1 and 2 studiesoften before dose or
concentration studies from phase 2 trials have been fully analyzed.

"Although the MTD approach may enable efficient demonstration of
effectiveness, it has led, as our data show, to frequent postmarketing
dosage reductions due to inadequate premarketing dose optimization," they
concluded.

The second study used a different approach, but reached similar conclusions
(Pharmacoepidemiol Drug Saf. DOI: 10.1002/pds.745). The researchers, at
Utrecht Institute for Pharmaceutical Sciences and Maastricht University, the
Netherlands, examined data compiled from 1982-2000 by the World Health
Organization, which monitors changes in the daily defined dose (DDD). The
DDD is a reflection of dosing regimens used in everyday clinical practice,
and an analysis of DDD changes over time reveals ways in which drug dosages
used in practice differ from the initially recommended dosing regimens for
newly marketed drugs.
[Abstract:
http://www3.interscience.wiley.com/cgi-bin/abstract/97517552/START]

The researchers found 115 instances of changes in the DDD of which 45
(39.1%) were increases and 70 (60.9%) were decreases. Drug classes that most
frequently had dosage changes were antibiotics (mostly increases, probably
reflecting response to the development of drug resistance by microbes) and
cardiovascular drugs (mostly decreases, especially for
angiotensin-converting enzyme inhibitors and antithrombotic agents).

One implication of the findings of both studies is that more research on the
process of drug dose selection is needed to help ensure that patients get
the optimal dose. A greater understanding of the interplay between genetic
variation and patient response to drugs may also lead to drug doses tailored
to a patient's genetic makeup.

"Hopes are high that pharmacogenetics may also contribute to a better
understanding of dosing dynamics, as genetically determined between-patient
variability in response to different doses is understood and systematically
measured," the Dutch group said.

Kirsten Myhr, MScPharm, MPH
Head, RELIS Ost Drug Information Centre
Ulleval University Hospital
0407 OSLO, Norway
Tel: +47 23 01 64 11  Fax: +47 23 01 64 10
kirsten.myhr@relis.ulleval.no (w)
www.relis.no




--
To send a message to E-Drug, write to: e-drug@usa.healthnet.org
To subscribe or unsubscribe, write to: majordomo@usa.healthnet.org
in the body of the message type: subscribe e-drug OR unsubscribe e-drug
To contact a person, send a message to: e-drug-help@usa.healthnet.org
Information and archives: http://www.healthnet.org/programs/edrug.html