How Predictive Are Animal Studies Of Human Toxicity

In 1962, Litchfield reviewed six diverse drugs being developed by one company and found that toxicities that occurred in rats only were rarely observed in humans and those that occurred in dogs only slightly more frequently. Toxicities that occurred in rats and dogs showed about a 70% correlation with human toxicity.

In general, cytotoxic anticancer agents cause qualitatively similar toxicity in animals and humans with data from dogs predicting gastrointestinal toxicity well but overpredicting hepatic and renal toxicity.

In a survey of 139 drugs approved in Japan from 1987 to 1991 (Igarashi, 1994), animal toxicity data were drawn from 468 repeated dose studies, mainly in rats and dogs but with a few mice and monkeys. Forty-three percent of clinical toxicities from 69 marketed drugs were not predicted from animal studies. The best predictability was for cardiovascular events and the poorest was for skin and hypersensitivity. In reviews of clinical toxicity resulting in withdrawal from marketing, only 4 of 24 cases and 6 of 114 cases could have been predicted from animals. This is not surprising as late-onset toxic effects are of low incidence, usually idiosyncratic and not related to the drug's pharmacology.

In a review from 12 pharmaceutical companies who supplied data to the International Life Sciences Institute an attempt was made to identify how well toxicities seen in pre-clinical animal studies would predict actual human toxicities for a number of specific target organs (Olson et al, 2000). In addition, the duration of dosing necessary was studied.

A database of 221 human toxicities from 150 compounds was available for study. Over 50% of these became manifest during Phase I trials. Sixty-two cases were seen after single doses and 158 cases were seen after multiple doses. If the human toxicity led to project termination, then 39% were terminated at Phase I, 43% in Phase II and 10% were terminated in Phase III. Only four toxicities were considered to be idiosyncratic.

Overall, the true positive concordance rate was 70% for the pre-clinical animal species to show target organ toxicity in the same organ system as the human toxicity. For the remaining 30% of human toxicities, there was no relationship between toxicities seen in animals and those observed in humans. Concordance was seen in 63% of non-rodent species (particularly the dog) and 43% of rodent species (usually the rat).

The best predictability was for haematological, gastrointestinal and cardiovascular toxicities and the least for skin toxicity. The prediction rate when the human toxicity was observed first was 75% (Phase I), 58% (Phase II) and 52% (Phase III).

Overall, 94% of animal target organ toxicities which correlated with human toxicity was observed first in studies equal or less than one month in duration.

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