Regulatory bodies, who grant permission to conduct studies with Investigational New Drugs (INDs), require that a battery of toxicity studies be conducted in animals to understand the potential of the drugs to induce unwanted effects or toxicities. Studies to understand the toxicity potential of test drugs are generally conducted in two species: rodent and non-rodent. The most commonly used rodent species is the rat, though the mouse may also be used provided a strong enough justification supports it use. The non-rodent species of choice are the dog, monkey and pig. The choice of species largely depends on the class of test drug under investigation and how closely the metabolism of a species mimics that in humans based on in vitro studies. It doesn’t always follow that the metabolism in a non-rodent species will mimic that in humans as the species is closer to humans in the evolutionary tree.
Depending on the class of the test drug and bioavailability, the species for the toxicity studies are chosen. In rodents, generally, a multiple of the efficacy dose is administered and depending on the mortality observed, the dose is either increased or decreased till a dose that is lethal to approximately 50% of the population is established. A 7- or 14-day repeat dose toxicity study is then performed prior to the studies of longer duration. The maximum tolerated dose (MTD) in the non-rodent species is established by administering single increasing doses of the test drug to the animals. This is followed by a 7-day toxicity study at 1 or 2 doses below the MTD. The outcome of this study will help in designing the pivotal repeat dose studies.
The Preclinical Toxicity or IND package is designed to profile the toxicity potential of the test drug with respect to repeat dosing, effect on major systems (safety pharmacology) and genotoxicity. In addition, studies which elucidate or negate any class-specific toxicity are also required. Special characteristics of the test drug or test drug formulation may necessitate additional studies, for e.g. effect of food or beverages on bioavailability. The route of administration of the test drug to animals is the same as that proposed for humans.
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