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. An Oct. 2 article in the Journal of the American Medical Association looked at these studies, which were recently published in the on-line version of the journal Pharmacoepidemiology and Drug Safety.
In the U.S. study, researchers studied label changes for 354 "new molecular entities" that received FDA approval between 1980 and 1999. The researchers 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. In addition, new drugs approved in the late 1990s (1995-99) were more than three times likelier to require a dosage change than drugs approved in the early 1980s (1980-84).
These findings "may represent a systematic flaw in premarketing dosage evaluation," according to the researchers. They note that the drug industry commonly launches Phase III trials testing the experimental drug at or near the maximum tolerated doses established in Phase I and II studies, often before dose or concentration studies from Phase II trials have been fully analyzed.
The Dutch researchers examined data compiled during the period 1982-2000 by the World Health Organization, which monitors changes in the daily defined dose (DDD). 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) 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, says JAMA writer Joan Stephenson, PhD. A better 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.