The Pharmaceutical Journal
Vol 269 No 7214 p308
7 September 2002

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Safety fears cut doses after new drugs are launched

The recommended doses for as many as a fifth of approved drugs are changed after the drugs are marketed, a new study suggests. In most cases, the change is a reduction in the recommended dose brought about because of safety concerns.

Researchers looked at the number of dosage changes made between 1980 and 1999 for drugs approved by the United States Food and Drug Administration after hypothesising that advances in drug development and regulation would have resulted in a decrease in the rate of post-marketing changes. However, they found that dosage changes of newly approved drugs increased over each five-year interval between 1980 and 1999. They also found that dosage changes were being made earlier.

"This pattern may represent a systematic flaw in pre-marketing dosage evaluation," say the researchers. "It has been common practice in the pharmaceutical industry to undertake phase III trials evaluating drug effectiveness at or near maximum tolerated dosages. Dose or concentration response studies in phase II- generated data are not often fully analysed."

The researchers found that 73 of 354 newly approved drugs underwent a post-marketing dosage change. Of these changes, 79 per cent were safety-motivated reductions. New dosing restrictions associated with the cytochrome P450 3A4 metabolic pathway accounted for 12 per cent of all observed dosage changes. "The importance of describing a new drug's metabolism, pharmacokinetics and pharmacodynamics in special populations ... is confirmed by the observation that nearly one-quarter of all changes could be attributed to renal-hepatic impairment and CYP3A4-mediated drug interactions," they add.

In a second study, Dutch researchers used World Health Organization data to evaluate changes in approved dosing regimens. They found that, between 1982 and 2000, there were 115 instances of a change in defined daily dose and, like the American researchers, that changes were occurring earlier in the post-marketing period.

The researchers suggest that a contributing factor to this acceleration in the rate of dose changes could be more efficient processes for identifying and changing suboptimal doses. However, they add that a contributing factor could be increasing use of pharmacokinetic concepts during drug development. "[Such concepts] may have induced a certain exaggeration of the importance of maintaining drug concentrations above certain presumed minima thought to be needed for sustained drug action."

Antibiotics, angiotensin-converting enzyme (ACE) inhibitors, and antithrombotics were the three drug classes most often associated with changes in dosing regimens. Dosages for antibiotics were mainly increased, whereas, all dosages for ACE inhibitors were decreased.

Both studies are to be published in Pharmacoepidemiology and Drug Safety (2002;11 issue 6) and are available on-line.