Goodbye to LD50?
Drug companies should stop using a classic toxicity test, lethal dose 50 (LD50), to inform clinical trials, according to authors in an upcoming journal of Regulatory Toxicology and Pharmacology linkurl:report.;http://www.sciencedirect.com/science?
Drug companies should stop using a classic toxicity test, lethal dose 50 (LD50), to inform clinical trials, according to authors in an upcoming journal of Regulatory Toxicology and Pharmacology linkurl:report.;http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WPT-4R8WK2M-1-1&_cdi=6999&_user=10&_orig=browse&_coverDate=12%2F05%2F2007&_sk=999999999&view=c&wchp=dGLbVlz-zSkWW&md5=db03ae20cfcfde5f302c238ad0633bbc&ie=/sdarticle.pdf
Mouse data of a drug's LD50, the dose of a drug that kills 50% of the test population, is often required by regulatory agencies for drugs intended for humans use. However, many have questioned whether toxicity in mice and other animal models accurately predicts human outcomes (read our story about problems with animal models linkurl:here;http://www.the-scientist.com/article/display/53306/ ). A European group of 18 pharma, biotech and clinical contract companies surveyed their scientists to determine whether the LD50 test was necessary to the drug development process.
Looking at data pooled from 74 compounds through the development process, the working group determined that companies usually use other tests to collect pre-clinical information.
LD50 data was NOT used:
* for selecting a starting dose in human trials. Companies used either non-rodent data or repeat-dose studies in mice instead. * in determining the most affected organ. Companies used safety pharmacology studies instead. * for predicting acute overdose situations. Although the data helps determine a lethal does range, it doesn't inform what should be done in the event of human overdose. * as the main reason for terminating a compound in the development process.
The report recommends that LD50 data not be required for most situations in drug development, and says their suggestions have been well received by US, European and Japanese regulatory bodies.
Should companies wait until their government regulations change before cutting their LD50 tests? Maybe. But some companies in the study have already reduced the number of mice they use for LD50 studies and one even eliminated the test entirely.
January 10, 2008
This blog makes a quite valid proposal. In 17 years in drug development at 2 major pharma companies and 3 biotechs, I cannot think of a single instance where rodent LD50 data were determinant. These studies are usually conducted quite early in Phase 0 (IND enabling studies), well before one normally has a decent handle on likely therapeutic exposures. There is a need to evaluate single-dose tox to inform the doses chosen for multiple-dose tox, but even a few deaths from SD would set a lower top dose for the next MD study.\n\nDavid B. Karpf,MD
January 10, 2008
While I agree that LD50s are not useful to drug companies in dose-finding or for human trials, they may nevertheless, when taken together, inform researchers and regualtors about relative potencies among similar drugs.
January 20, 2008
I believe that eliminating the LD-50 test will deprive researchers of vital information concerning the safety and effects of newly created drugs. While critics may say that the physiology of rats and mice may be different from human physiology and therefore useless in extracting meaningful data, that is not the purpose of an LD-50 test. The LD-50 test is to determine the relative toxicity of a substance normalized to the variation of the animals? size. Knowing how toxic a substance is compared to other known compounds enables researchers to extrapolate what dosage may result in death for humans.\n\nTo say that the LD-50 test is not relevant is like saying that the damage sustained by an insect hit by a marble dropped from 10 stories is not relevant to determining the damage that a human would sustain from that same marble. That is ludicrous. If the LD-50 test is eliminated, another test, such as the Fixed Dose Procedure, must be put in its place to determine the toxicity of these drugs. Are the drug companies suggesting that we replace the rats with people? Anyone for a dose of Warfarin?