Preclinical development summary

In summary, the examples mentioned in this chapter are a good representation of the outstanding chemical diversity exhibited by bioactive molecules produced by terrestrial actinomycetes discovered during the last few decades. This overview, necessarily limited in size, has omitted many other novel compounds with different modes of action that never reached preclinical development stages. These compounds could be the subject of another review. 

Improvement of sensitivity of the bioanalytical method is often needed to support PK evaluation of drug candidate during clinical development. This sensitivity requirement is mainly due to the fact that the phase I doses are usually much lower than the doses administrated during the preclinical development phase. An HPLC-MS/MS method had been validated in rat, dog, and mouse plasma for support of a preclinical development program. A summary of the validation parameters in rat plasma are given in Table 8.8. 

The linear range of concentration was 5.00-2000 ng/ mL and the lower LOQ was 5.00 ng/mL in all species tested. Intra- and interassay variation was less than 15%, the extraction recovery ranged from 101% to 110%, and the tested compounds were stable during the intended use of the method. The method was successfully applied to PK studies during the preclinical development of the candidate drug and IND application has been filed. A summary of the calculated PK parameters obtained from a dose escalation PK study in rats are given in Table 8.9 and the mean concentration-time profiles are illustrated in Figure 8.7. Dose-related linear trend was observed for AUC and Cmax in rats and there was a shift in the Uax with dose. 

II. Product Summaries Simulations Plus develops simulation and predictive modeling software for in silico compound screening and for preclinical and clinical drug development in the area of Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET). The available applications include GastroPlus, ADMET Predictor, ADMET Modeler, DDDPlus, and MembranePlus. 

In summary, a well-designed preclinical program that addresses questions of toxicity conducted internally or at a well-qualified CRO is necessary for a satisfactory preclinical safety evaluation program to support successful clinical development. 

A brief summary of the preclinical and early clinical development and manufacturing of the Ad5FGF-4 gene therapy product for the facilitation of angiogenesis in patients with chronic myocardial ischemia (recurrent angina) is provided below for the purpose of illustrating the complex processes involved in the many stages of preclinical and clinical development of an HGT product. 

In summary, tracking active metabolites at the drug discovery stage is not only important to correctly interpret the pharmacological effects in preclinical species but may also lead to the discovery of a lead candidate with superior drug developability characteristics. 

In summary, while the last 10 years has seen considerable developments and innovations in the use of in vitro toxicity models, particularly for predicting acute drug toxicity, there is still no single system that would predict acute hepatotox-icity induced by an agent such as APAP. Prediction of chronic hepatotoxicity is even less advanced, and until it is possible to incorporate components of both the innate and adaptive immune systems into the models, it is unlikely that these types of toxicity will be routinely detected preclinically. 

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