Preclinical in vivo animal model

Change in implant structure and preclinical in vivo animal model... 

Toxicology studies must be performed in at least two animal species. If the toxicity profile of the compound is acceptable, then it joins the hit or lead list of compounds to proceed. The metabolism of the compound must be understood and pharmacokinetic studies must be performed in small and large animals. Efficacy studies must be performed in relevant animal models, especially in chimpanzees when more than one candidate is identified and a choice has to be made before proceeding to studies in humans. The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others. 

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]. 

Only after all these exhaustive tests are a few candidates selected for preclinical in vivo studies using animal disease models. The current approach is to perform as much as possible of the tests based on tissue cultures or cell-based assays, as they are less costly and provide results more readily. At the end of this long process is the availability of selected drug candidates with sufficient efficacy and safety required for human clinical trial. 

In the early stages of preclinical development, metabolite profiling is performed using in vitro systems from animal and human, mainly to identify potential species-dependent metabolism early in the development process and to support the selection of the animal species employed in safety assessment studies. As the compound moves further into development, in vivo animal ADME studies are performed. The compound is usually dosed into a rodent and nonrodent species along with an efficacy model. Metabolism data from the animal studies are then used in species selection for safety assessment to insure that all expected human metabolic transformations will be represented in the animal models used in the safety study. 

Conclusion To date no in vitro models are available to study the physical dependence potential and the rewarding and reinforcing properties of novel CNS-active drug candidates in development. The preclinical abuse liability assessment represents the integrated data of in vivo animal studies to predict the abuse potential of CNS-active drug candidates. 

More than 500 different drugs have been formulated as SDDs at Bend Research and tested in various animal models. Absorption enhancement relative to crystalline drug ranges from around 1.5-fold to nearly 100-fold, but varies widely based on the dose and drug properties. Figure 9.12 shows representative preclinical in vivo data for BCS class II compounds. 

The introduction of a product designed for implantation into humans requires a comprehensive development program, structured to address issues of potential toxicity, safety, and efficacy in vitro, followed by preclinical in vivo testing in appropriate animal models. Only after safety and efficacy are established, can human trials be considered. Since the employment of the NovoSorb biodegradable polyurethane platform was entirely novel in both material and concept, we followed this strategy. All trial proposals were submitted to, and approved by, the relevant Animal or Human Research Ethics Conunittee. 

As a general rule, in vivo assays are more challenging than in vitro assays because the matrices for the samples are more complex. The most common use for in vivo assays is to measure the concentration of NCE dosed into a laboratory animal by collecting multiple sample time points, one can use the analytical results to plot the PK profile of the NCE and also obtain various PK parameters that help determine a test compound s PK properties. Preclinical PK parameters of a test compound are then used to predict its human PK parameters. Another use of in vivo assays is combining the results with pharmacodynamic (PD) observations to perform PK/PD modeling.77 82 PK/PD modeling is an important aspect of new drug discovery because it can be used to predict the exposures and durations required to determine clinical efficacy of a NCE. 

An evaluation of the various studies reported in the literature for preclinical assessment of drugs for nasal administrations indicated the usefulness of in situ, ex vivo, and in vivo approaches. Evidence from the literature also indicates that the choice of a particular model or animal species by different... 

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