Research focus on drug-induced liver injury on the rise

PHILADELPHIA – Drug-induced liver injury (DILI) continues to be a hot topic, but new advances have helped increase the amount of research done and improve the quality of treatment for patients suffering from the condition.

“It’s been 10 years since the DILI Network was started at [the National Institutes of Health], and it’s giving us a lot of important information about what’s happening with [DILI] in the United States,” explained Dr. James H. Lewis of Georgetown University in Washington, D.C. “However, we are still playing catch up with many nations around the world, who have had similar registries for a longer time.”

While incidents of DILI and, more important, severe DILI, continue to be low in the United States, DILI is the leading cause of acute liver failure in Americans, and a major cause of emergency liver transplant. Further research into new drugs is stymied by hepatoxicity, which is “the main reason why many drugs are pulled from development.”

“When it comes to drugs that are causing injury, these are fairly old friends,” said Dr. Lewis. “They’ve been around for a long time and they don’t change a whole lot, Very interesting [is] that the TB drugs lead the list, especially INH [isoniazid] and pyrazinamide, as well as antibiotics, especially augmentin.”

Nevertheless, activity continues to increase in the DILI field. Looking at PubMed, said Dr. Lewis, there are already over 300 citations involving DILI from January through April of this year, over 1,500 in all of 2014, and over 6,000 from 2010 to 2014. Compared to that, there were around 7,000 in total from 2000 to 2009.

The relationship between dosage and likelihood of liver injury still needs examination, declared Dr. Lewis, citing separate works done by Dr. Hy Zimmerman and Dr. Jack Uetretcht. The former determined that there were certain drugs for which the likelihood of liver injury could be predicted, such as acetaminophen, and those for which such risk was idiosyncratic.

Dr. Uetrecht determined that 10-mg doses were the cutoff at which liver injury became possible. In 2008, work by Lammert et al., published in Hepatology, revealed that doses of 10 mg or less resulted in a 9% risk of DILI, compared with 14.2% for doses of 11-49 mg, and 77% for doses at or above 50 mg. “There are over 200 drugs that have been found to cause DILI, but the top 10 alone account for 50% of all DILI, and the top 25 drugs account for [67%],” said Dr. Lewis. “This means that the other 175 drugs have maybe one case of DILI in the [DILI Network] entire database.”

What this means, concluded Dr. Lewis, is that DILI does not occur often with most drugs, and the ones that cause it are those that are already known.

Dr. Lewis disclosed receiving grant/research support from Ocera Therapeutics, Inc.; consultant relationships with GlaxoSmithKline, Otsuka Pharmaceutical Co. Ltd., Takeda Pharmaceuticals U.S.A. Inc., AstraZeneca, and Lundbeck Inc.; and being a member of the speaking bureau for Gilead Science, Inc.

[email protected]

PHILADELPHIA – Drug-induced liver injury (DILI) continues to be a hot topic, but new advances have helped increase the amount of research done and improve the quality of treatment for patients suffering from the condition.

“It’s been 10 years since the DILI Network was started at [the National Institutes of Health], and it’s giving us a lot of important information about what’s happening with [DILI] in the United States,” explained Dr. James H. Lewis of Georgetown University in Washington, D.C. “However, we are still playing catch up with many nations around the world, who have had similar registries for a longer time.”

While incidents of DILI and, more important, severe DILI, continue to be low in the United States, DILI is the leading cause of acute liver failure in Americans, and a major cause of emergency liver transplant. Further research into new drugs is stymied by hepatoxicity, which is “the main reason why many drugs are pulled from development.”

“When it comes to drugs that are causing injury, these are fairly old friends,” said Dr. Lewis. “They’ve been around for a long time and they don’t change a whole lot, Very interesting [is] that the TB drugs lead the list, especially INH [isoniazid] and pyrazinamide, as well as antibiotics, especially augmentin.”

Nevertheless, activity continues to increase in the DILI field. Looking at PubMed, said Dr. Lewis, there are already over 300 citations involving DILI from January through April of this year, over 1,500 in all of 2014, and over 6,000 from 2010 to 2014. Compared to that, there were around 7,000 in total from 2000 to 2009.

The relationship between dosage and likelihood of liver injury still needs examination, declared Dr. Lewis, citing separate works done by Dr. Hy Zimmerman and Dr. Jack Uetretcht. The former determined that there were certain drugs for which the likelihood of liver injury could be predicted, such as acetaminophen, and those for which such risk was idiosyncratic.

Dr. Uetrecht determined that 10-mg doses were the cutoff at which liver injury became possible. In 2008, work by Lammert et al., published in Hepatology, revealed that doses of 10 mg or less resulted in a 9% risk of DILI, compared with 14.2% for doses of 11-49 mg, and 77% for doses at or above 50 mg. “There are over 200 drugs that have been found to cause DILI, but the top 10 alone account for 50% of all DILI, and the top 25 drugs account for [67%],” said Dr. Lewis. “This means that the other 175 drugs have maybe one case of DILI in the [DILI Network] entire database.”

What this means, concluded Dr. Lewis, is that DILI does not occur often with most drugs, and the ones that cause it are those that are already known.

Dr. Lewis disclosed receiving grant/research support from Ocera Therapeutics, Inc.; consultant relationships with GlaxoSmithKline, Otsuka Pharmaceutical Co. Ltd., Takeda Pharmaceuticals U.S.A. Inc., AstraZeneca, and Lundbeck Inc.; and being a member of the speaking bureau for Gilead Science, Inc.

[email protected]

PHILADELPHIA – Drug-induced liver injury (DILI) continues to be a hot topic, but new advances have helped increase the amount of research done and improve the quality of treatment for patients suffering from the condition.

“It’s been 10 years since the DILI Network was started at [the National Institutes of Health], and it’s giving us a lot of important information about what’s happening with [DILI] in the United States,” explained Dr. James H. Lewis of Georgetown University in Washington, D.C. “However, we are still playing catch up with many nations around the world, who have had similar registries for a longer time.”

While incidents of DILI and, more important, severe DILI, continue to be low in the United States, DILI is the leading cause of acute liver failure in Americans, and a major cause of emergency liver transplant. Further research into new drugs is stymied by hepatoxicity, which is “the main reason why many drugs are pulled from development.”

“When it comes to drugs that are causing injury, these are fairly old friends,” said Dr. Lewis. “They’ve been around for a long time and they don’t change a whole lot, Very interesting [is] that the TB drugs lead the list, especially INH [isoniazid] and pyrazinamide, as well as antibiotics, especially augmentin.”

Nevertheless, activity continues to increase in the DILI field. Looking at PubMed, said Dr. Lewis, there are already over 300 citations involving DILI from January through April of this year, over 1,500 in all of 2014, and over 6,000 from 2010 to 2014. Compared to that, there were around 7,000 in total from 2000 to 2009.

The relationship between dosage and likelihood of liver injury still needs examination, declared Dr. Lewis, citing separate works done by Dr. Hy Zimmerman and Dr. Jack Uetretcht. The former determined that there were certain drugs for which the likelihood of liver injury could be predicted, such as acetaminophen, and those for which such risk was idiosyncratic.

Dr. Uetrecht determined that 10-mg doses were the cutoff at which liver injury became possible. In 2008, work by Lammert et al., published in Hepatology, revealed that doses of 10 mg or less resulted in a 9% risk of DILI, compared with 14.2% for doses of 11-49 mg, and 77% for doses at or above 50 mg. “There are over 200 drugs that have been found to cause DILI, but the top 10 alone account for 50% of all DILI, and the top 25 drugs account for [67%],” said Dr. Lewis. “This means that the other 175 drugs have maybe one case of DILI in the [DILI Network] entire database.”

What this means, concluded Dr. Lewis, is that DILI does not occur often with most drugs, and the ones that cause it are those that are already known.

Dr. Lewis disclosed receiving grant/research support from Ocera Therapeutics, Inc.; consultant relationships with GlaxoSmithKline, Otsuka Pharmaceutical Co. Ltd., Takeda Pharmaceuticals U.S.A. Inc., AstraZeneca, and Lundbeck Inc.; and being a member of the speaking bureau for Gilead Science, Inc.

[email protected]