There are many potential reasons for incorrect predictions from animals to man. These include differences in the way the toxicity is elicited (verbally is not possible in animals), the presence or absence of concomitant medication, pharmacokinetic and metabolic differences, age (animals are young and humans may be old), state of health (animals are free from disease), homogeneity of the animals studied compared with the heterogeneity of the humans, dose differences, housing and nutrition (optimal in animal studies) as well as timing differences.
A significant message from Olson's review is that the human toxicities with the poorest correlation with animal studies (hepatic toxicity and hypersensitivity/skin reactions) were the two toxicities that led most often to termination of clinical development. Further study of mechanisms is required.
It is worthy of note that the pharmacokinetics in any one animal species may be very different from those in other species or in humans (Nimmo and Watson, 1994). This may result in low bioavailability in the animals or a first pass metabolism that results in insufficient target organ concentrations to produce any adverse effects reliably. Toxicokinetic data generated as an integral component of pre-clinical toxicology studies and the use of the data in the interpretation of toxicological findings may improve the predictive value of a particular species. A sensible approach to drug development would be to conduct a single dose tolerability/pharmaco-kinetic study in humans as soon as possible and to compare concentrations achieved with those observed in the different animal species studied. This would allow interpretation of the findings in the most appropriate animal species with similar concentrations before conducting a multiple dose tolerability or a Phase II study. Toxicokinetic data should contribute to the design of pre-clinical studies after the first human study has been conducted.
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