Acute toxicity studies nonrodents

The September 2000 draft guidance considers excipient databases associated with drug products with three different therapeutic durations. For a drug product intended for a 14-day therapy or less, and for infrequent use, the excipient should be tested in acute toxicity studies and in one-month, repeat-dose toxicity studies in two mammalian species (one being a nonrodent), using the intended route of therapeutic administration. 

Acute toxicity Acute toxicity studies are required for all drugs. These studies involve administration of single doses of the agent up to the lethal level in at least two species, eg, one rodent and one nonrodent. 

FIGURE 5.14. Example of pyramiding dose study for acute toxicity testing in a nonrodent species. 

Common Study Protocols. The dog is the most commonly used nonrodent species in safety assessment testing (i.e., acute, subchronic, and chronic studies). The exception to this is its use in developmental toxicity and reproductive studies. For developmental toxicity studies, the dog does not appear to be as sensitive an indicator of teratogens as other nonrodent species such as the monkey (Earl et al., 1973) or the ferret (Gulamhusein et al., 1980), and, for reproductive studies, the dog is not the species of choice because fertility testing is difficult to conduct (due to prolonged anestrus and the unpredictability of the onset of proestrus) and there is no reliable procedure for induction of estrus or ovulation. 

IPEC-Europe (intended clinical route)b ADME Acute toxicity (intended route) and skin sensitization. Ames, chromosome damage and micronucleus. Four weeks toxicity (2 species by intended route) Short-term use studies. Three-month toxicity (most appropriate species). Teratology (rat and rabbit). Genotoxicity assays Short-/midterm studies. Segment I reproduction. Six to nine months toxicity (rodent and nonrodent), segment III reproduction, and carcinogenicity (conditional)... 

Acute toxicology studies in rodent and nonrodent These studies are used to identify doses causing no adverse effects and doses causing significant life-threatening effects. In addition to toxicity these studies frequently include toxicokinetics to identify the disposition of the test article in the rodent and nonrodent. These studies also provide additional support for the dose levels to be used in longer term studies. 

These segments can be tested separately or in a combined manner. All stages of development from conception to maturity and the detection of acute and delayed effects of exposure through one complete life cycle should be examined. The standard species are rodents, rats as the preferred rodent species for all study types and, the rabbit as the second nonrodent species for the embryo-toxicity studies. In some rare cases mice or monkeys are used too, if special conditions - usually kinetic data - justify such species. 

Preclinical toxicology studies should address the standard systemic and local reactogenicity, histopathology, and toxicity (acute and chronic dosage) in rodent and nonrodent animals. Since the FDA and some European authorities decided to classify mRNA-based therapies as no-gene therapy (for nonreplicative mRNA as depicted in this chapter), the implementation of clinical trials does not require additional specific toxicology testing. 

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