Animal studies preclinical trials

The preclinical trials are performed in in vitro and animal studies to assess the biological activity of the new compound. In phase 1 of the clinical trials the safety of a new drug is examined and the dosage is determined by administering the compound to about 20 to 100 healthy volunteers. The focus in phase II is directed onto the issues of safety, evaluation of efficacy, and investigation of side effects in 100 to 300 patient volimteers. More than 1000 patient volunteers are treated with the new drug in phase 111 to prove its efficacy and safety over long-term use. 

Preclinical studies should address the potential toxicity due to inappropriate release of the conjugated toxin. Preclinical toxicology of monoclonal antibodies may not require extensive animal studies but should be examined for cross-reactivity with antigenic epitopes present on normal cells in vitro and for the presence of human or rodent vimses. Early clinical trial should involve biodistribution studies with radiolabelled material. 

The efficacy of human G-CSF was initially evaluated in simian preclinical trials. Monkeys treated with subcutaneous injections of G-CSF showed a dose-related increase in polymorphonuclear neutrophils. These initial studies also evaluated two cyclophosphamide-treated animals. G-CSF... 

Before a drug may be tested on humans, it must first be tested on animals. Tests on humans are called clinical trials, and animal trials are often referred to as preclinical trials. Preclinical trials differ from the animal tests mentioned earlier in this chapter. The previously discussed animal tests help the drug discovery team determine and optimize the pharmacodynamic and pharmacokinetic behavior of a hit or lead. Preclinical trials, in contrast, are standardized, industrywide tests. The preclinical tests have technical names such as Segment II Reproductive Study in Rabbits or 6-Month Toxicity Study in Rats. The specific names suggest the exact nature of each study. Each trial seeks to answer predefined safety questions concerning a drug candidate. Preclinical trials do not address the therapeutic effectiveness of the drug candidate in any way. Preclinical trials examine exclusively safety issues. 

Many animal and preclinical studies have showed benefit of a variety of antiendotoxin therapies, but this effect has not been translated into human trials. Since both pre-clinical rationale and studies support the targeting of endotoxin to ameliorate the pro-inflammatory and pro-coagulation response of severe sepsis, we should continue to pursue therapeutic intervention in this area. 

In the future the FDA may develop guidance for preclinical toxicology studies but one has not been published at this time. The guidance recommending design of clinical studies can be used to model animal studies to support the various clinical trials. 

Several preclinical studies, originally designed to support the above clinical trials, have been carried out. From these it was determined that m-THPC is not metabolized in vivo and virtually all the drag is eliminated via the liver. Pharmacokinetic data derived from animal studies with m-THPC led to the prediction that this substance would show rapid clearance from plasma in humans. Surprisingly, however, this was only observed in the animal models (dog, rabbit, rat), not in the human populations. This dichotomy stands as a cogent reminder that caution must always be exercised in translating animal-model data into human-dosing decisions [225]. 

A variety of biomarkers have been shown to be valuable individually for one or several toxicant or disease situations. Few of these biomarkers have been systematically evaluated for the plethora of situations that might provoke false positive responses. Acceleration of the current pace of biomarker evaluation and qualification demands (a) the availability of panels of biomarker-assays that can be comparatively evaluated on well-defined common sample sets, (b) fit-for-purpose performance evaluation in controlled animal studies with carefully benchmarked histological endpoints and samples from well-defined focused clinical trial cohorts, and (c) ready availability of banked blood and urine sample archives from clinical trial populations with carefully documented morbidities such as the Framingham Heart Study,45 or the Drug-Induced Liver Injury Network (DILIN) prospective study,46 to name a few. Availability of such panels of validated biomarker assays and well-documented preclinical and clinical samples, as well as increased cooperation between animal model researchers and clinical researchers will enable individual biomarkers to be qualified for sensitivity of specifically defined adverse events, qualified for appropriate specificity using samples of defined benign events, and collected into panels that yield complementary information about the health and safety of animals and patients. 

Throughout drug development, preclinical animal studies are used to predict and assure the safety of human clinical trials. The preclinical program proceeds ahead of the clinical program to provide the necessary safety/toxicity information in a timely manner. The sponsor must relate the drug product... 

Data supplementation deals with the supplementation of data to enable the exploration of an aspect of the response surface that may not have been targeted for exploration in a completed trial. It also deals with the supplementation of data in preclinical animal studies where the destructive nature of the sampling design does not permit the construction of individual profiles for inaccessible tissues. A motivating example that deals with a targeted aspect of an unexplored region of the response surface is discussed next to provide clarity on the approach. Data supplementation in the preclinical animal setting is beyond the scope of this chapter. 

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