Drug & Device Development

Low-dose flutamide doesn't eliminate hepatotoxicity risk

Last Updated: 2012-07-25 16:20:38 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Low or ultralow doses of flutamide don't entirely eliminate the drug's potential for injuring the liver, researchers saw in a study of women with polycystic ovary syndrome.

The women were taking the drug to treat hyperandrogenism. Nearly one in 10 had mild to severe increases in aminotransferases during treatment, according to Dr. Elena Peruzzi and colleagues from the University of Florence in Italy.

"However, we still believe flutamide is a key drug in the current treatment of hyperandrogenism and low- and ultralow-dose regimens represent the way forward," Dr. Peruzzi and her team wrote in a July 13th online paper in Fertility and Sterility.

"Our data suggest hepatotoxicity is a rare but possible event also with low- and ultralow-dose regimens and at present we are not able to predict which patients will develop it."

Most cases of severe flutamide hepatotoxicity have occurred in patients taking 750 to 1,500 mg/day, the researchers noted. While hepatotoxicity is usually mild, some cases have been fatal.

Low- and ultralow-dose flutamide regimens were introduced because people believed its hepatotoxicity to be dose-dependent, the authors say - but there is some evidence that the hepatotoxicity may depend on other factors, such as genetics and ethnicity.

"Some differences in clinical and biochemical hepatotoxicity may be related to inter-individual genetic variability based on polymorphism or epigenetic mechanisms and clinically defined as unpredictable or 'idiosyncratic,'" the researchers wrote.

To investigate whether lower dose flutamide regimens might also be associated with hepatotoxicity, they looked at 203 hyperandrogenic women who received 62.5 or 125 mg/daily. Nineteen women (9.4%) developed hepatotoxicity, which was mild in 16 (7.9%), moderate in two (1%) and severe in one (0.5%).

There was no association between risk of hepatotoxicity and flutamide dosage.

The median time to the development of hypertransaminasemia was 12 weeks and did not differ between the two dosage groups.

Elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) returned to normal in all 19 women with four weeks after flutamide was discontinued.

Factors linked to an increased risk of hepatotoxicity included body mass index before treatment, ALT basal level, and AST basal level.

"Given the complexity of PCOS and related conditions, it is obvious that some metabolic aspects have not been extensively investigated," Dr. Peruzzi and her colleagues write. "More than long-term data, we need larger study populations in order to recruit patients susceptible to develop early hepatotoxicity. These patients should be evaluated by clinical, biochemical and genetic investigations in order to identify risk patterns for hepatotoxicity development."

Dr. Peruzzi did not respond to a request for comment by press time.

SOURCE: http://bit.ly/NJZOhX

Fertil Steril 2012.