Safety profiles preclinical data

In dmg discovery, preliminary PK studies are usually conducted in rodents to evaluate the extent of dmg exposure in vivo. This is commonly followed by PK studies in larger animals such as dog or monkey to better characterize the PK profile of the compound and to support safety studies. Pharmacokinetic scaling (also called allometry) is a discipline that is used to predict human PK profiles using preclinical data and is widely used in predicting the dmg human half-life, dose, and extent of absorption. Accurate prediction of a human PK profile is imperative to minimize dmg failure in development due to poor PK attributes. A detailed description of methods in predicting human PK is beyond the scope of this chapter but can be found in many excellent reviews (Obach et al., 1997 Miners et al., 2004 Poggesi, 2004 Raunio et al., 2004 Thomas et al., 2006 Hurst et al., 2007). A more in-depth discussion of various PK concepts and their applications can be found in various references (Gibaldi and Perrier, 1982 Rowland and Tozer, 1995 Hurst et al., 2007). 

No adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine. Therefore preclinical and toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/ vaccine combination [60], Evaluation in preclinical studies is important for identifying the optimum composition and formulation process and also for allowing development of tests for quality control [61]. Data from these studies also helps plan protocols for subsequent clinical trials from which safety and efficacy in humans can be evaluated. 

Fig. 2 Tabular representation of preclinical and clinical testing phases of drug development at which new compounds have been showed to fail for toxicokinetic and safety reasons. The data show profiles between 1997 and 2001, and also indicate the proportional contribution of safety vs. efficacy testing during drug development.

Evidence from animal studies have suggested the potential utility of CCK-B antagonists in the treatment of CNS disorders such as anxiety and panic, with a seemingly specific advantage of a better safety profile over marketed anxiolytics, at least on the basis of the preclinical data. 

Agent TRO19622 featuring steroid template is under development by Trophos. It has successfully completed phase I studies in healthy volunteers and phase lb studies in SMA patients. The compound was well tolerated, featured good safety profile and PK suitable for once-daily oral dosing based on preclinical models. Unfortunately, very limited biochemical data are available on this molecule in the literature [55]. 

Figure 2.1 The evolution of the drug-likeness concept. Drug-likeness evolved from empirical rules such as Lipinski s rule of 5 through more sophisticated data mining algorithms into utilization of preclinical profiling and safety pharmacology data [3].

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. 

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