In vitro profiling

Extensions of BCS beyond the oral IR area has also been suggested, for example to apply BCS in the extended-release area. However, this will provide a major challenge since the release from different formulations will interact in different ways with in vitro test conditions and the physiological milieu in the gastrointestinal tract. For example, the plasma concentration-time profile differed for two felodipine ER tablets for which very similar in vitro profiles had been obtained, despite the fact that both tablets were of the hydrophilic matrix type based on cellulose derivates [70], This misleading result in vitro was due to interactions between the gel strength of the matrix and components in the dissolution test medium of no in vivo relevance. The situation for ER formulations would be further complicated by the need to predict potential food effects on the drug release in vivo. 

Froloff, N., Hamon, V., Dupuis, P., Otto-Bruc, A., Mao, B., Merrick, S. and Migeon, J. (2006) Construction of a homogeneous and informative in vitro profiling database for anticipating the clinical effects of drugs, in... 

The predicted concentration-time profiles for all three formulations are shown in Figure 5 (panel a). These simulations use the fitted in vitro profiles for input to the model. For comparison, the simulations assuming zero order release are shown in panel b. Although the zero order simulations may be useful for initial specification of target profiles, they offer little of value for selecting specific formulations for the in vivo study or for study design (e.g., selection of sampling times),... 

Sayes C, Marchione A, Reed K, Warheit DB (2007) Comparative pulmonary toxicity assessments of C60 water suspensions in rats Few differences in fullerene toxicity in vivo in contrast to in vitro profiles. Nano Lett. 7 2399-2403. 

As most of the 2500 compounds have a history of use in humans, a corollary dataset containing human adverse reactions and PK information has been compiled. These datasets are mined to develop quantitative relationships between in vitro profiles and in vivo effects. 

Single Test Compound Clustering with Several Marketed Drugs on the Basis of the Similarity of In Vitro Profile Results Including Human Absorption, Oral Bioavailability, Permeability, Solubility, Log D, and Metabolic Stability Characteristics... 

Construction of a Homogeneous and Informative In vitro Profiling Database for Anticipating the Clinical Effects of Drugs... 

In this chapter we have described the construction of a high-quality, homogeneous and informative in vitro profiling database and its applications both to drug discovery and development. 

Arrays of biological data can form the basis for uniquely informative molecular descriptors. By defining the relationships between compounds using biological descriptors (in vitro profiles) in addition to chemical structures, medicinal chemists are given new perspectives to support lead optimization. 

Tables.3 Hepatic metabolism, measured in liver microsomes and hERG IC50 (patch clamp data) of terfenadine and fexofenadine, determined and compared in early, routinely used in vitro profiling assays.

Using Data from In Vitro Profiling Confirmatory Tests, Follow-Up Tests, and the Link to Safety Assessment and In Vivo Models... 

Table 17.1 lists non-oncology compounds from diverse therapeutic, chemical, pharmacological areas and structures that induce clinical hematotoxicity. This demonstrates that bone marrow toxicity is not restricted to a small number of pharmacological or structural classes, thereby making it more difficult to understand specific mechanisms of toxicity. However, there are three classes of mechanisms of hematotoxicity, including antiproliferative, immune-mediated and other. Immune-mediated hematotoxicity and other indirect toxicities (e.g., a decrease of erythropoietin in kidney, leading to an impeded red cell production in the bone marrow) are not discussed in detail in this chapter as it requires involvement of the immune system or remote interactions and in vitro profiling assays have not been developed to detect these mechanisms. 

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