In vivo response

Routledge, E.J., Sheahan, D., and Desbrow, C. et al. (1998). Identification of estrogenic chemicals in STW effluent. 2. In vivo responses in trout and roach. Environmental Science and Technology 32, 1559-1565. 

Drysdale CM, McGraw DW, Stack CB et al. Complex promoter and coding region beta 2-adrenergic receptor haplo-types alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000 97 10483-10488. 

Drysdale, C.M., et al., "Complex Promoter and Coding Region Beta 2-Adrenergic Receptor Haplotypes Alter Receptor Expression and Predict in Vivo Responsiveness," Proc. Natl. Acad. Sci. U.S.A., 97, 10483-10488 (2000). 

Because DMPK properties vary among different species, in vitro human and animal data and in vivo animal data cannot always be extrapolated to human in vivo responses. The three main reasons that drugs fail during clinical trials are (1) lack of efficacy, (2) unacceptable adverse effects, and (3) unfavorable ADME properties. Hence, clinical development is necessary to establish solid experiment-based human exposure and safety data through both short- and long-term monitoring. 

Finally, as previously stated, if in vitro models are to be fully effective, the underlying mechanisms of ocular irritation need to be identified. Many of the in vitro assays proposed as alternatives to in vivo testing are based on correlations rather than mechanisms of irritation. The scoring or ranking of substances utilizing the in vitro endpoint may correlate with the severity of the in vivo response, but the reason for the agreement may be unclear and strictly fortuitous for the compounds evaluated. The ideal assay would monitor several biochemical or biological events specifically... 

The modeling discussed here depends on being able to describe the entire concentration-time curve. This can only be done using a Level A IVIVC (i.e., a point-to-point relationship between in vitro release and in vivo release/absorption). In fact, the U.S. Food and Drug Administration (FDA) defines a Level A IVIVC as a predictive mathematical model for the relationship between the entire in vitro dissolution-release time course and the entire in vivo response time course. 

T cells could suppress the in vivo response. Moreover, immunization of the donors of suppressor T cells increases the number of splenic CD8-I- suppressor T cells that suppress specifically DTH in the LTS [R.E. Cone, Y. Lemire, and R. Sharafieh, unpubl. observations]. These observations are consistent with those demonstrating that antigen-specific CD8+ suppressor T cells are amplified by immunization [3]. 

Pharmaceutical development of a medicinal product must retain the drug s promising in vitro pharmacological activity and provide a predictable in vivo response. The marketed product must be stable, correctly packaged, labelled and easily administered, preferably by self-administration. The product must also be economical to manufacture on a large scale by a method that ensures product quality. In addition, development and eventual production processes must comply with the regulatory requirements of proposed market countries, and all development studies must be performed to acceptable levels of quality assurance. 

Compounds tested in a more physiological 3-D environment show increased predictability of in vivo responses and help to span the gap between 2-D tissue culture and animal models. There is also evidence that 3-D cultures can identify active compounds that would fail to show their potential in 2-D (56, 57). The complexity of 3-D cultures can be increased by the addition of one or more cell types (fibroblasts, endothelial cells) and/or culture with different media, substrates, or oxygenation conditions. However, a disadvantage is that there is still a lack of simple, standardized, and reliable 3-D protocols that allow their incorporation into the pre-clinical high-throughput validation and drug evaluation process, although there have been several advances in this area in recent years (30, 58-61). 

Increasingly the existence of multiresistant strains is reported, especially in the United States but also elsewhere. Also the occurrence of infections with difficult to treat, so called atypical mycobacteria like Mycobacterium avium intracellulare and Mycobacterium kansasii is on the rise. These infections are especially seen in patients with a compromised immune system. In vitro these atypical mycobacteria often show resistance against first-choice drugs. However this in vitro lack of sensitivity does not always correspond with in vivo responses. 

Van Gelder You have shown sufficiency, which is fantastic, but to fully demonstrate equivalence of in vitro and in vivo responses, you need to... 

T)ilation is the dominant in vivo response, owing to indirect effects. 

Binding kinetics should be proportional to the rate of the in vivo response and should yield an equilibrium constant equal to the dissociation rate constant divided by the association rate constant. 

E. J. Routledge et al., Identification of Estrogenic Chemicals in STW Effluent. 2. In vivo Responses in Trout and Roach, Environ. Sci. Technol. 52... 

Although we are perhaps still faced with an incomplete scheme of all the interactions required for enzyme or transporter induction to occur, experimental and theoretical approaches are being used to make predictions about the ultimate in vivo response based on an understanding of the binding pockets of the above-stated receptors. 

Anderson JM. Perspectives on the in vivo responses of biodegradable polymers. In Hollinger JO, ed. Biomedical Applications of Synthetic Biodegradable Polymers. Boca Raton, FL CRC Press, 1995 223-233. 

In Vitro-In Vivo Correlation A predictive mathematical model describing the relationship between an in vitro property of an oral dosage form (usually the rate or extent of drug dissolution or release) and a relevant in vivo response (e.g., plasma drug concentration or amount of drug absorbed). 

Analytical research receives the drug after synthesis and characterizes its physicochemical parameters to ensure that all pharmacological testing is done with pure material and to establish specifications so that future production lots will yield reproducible in vivo response. These specifications will include the purity of drug, identification and quantitation of other products of synthesis and... 

The term response can take a number of different forms. In a biochemical assay, the response may be determined by changes in something quantitative, such as changes in ion concentration, absorbance, or fluorescence. Quantifiable examples of in vivo response include changes in body temperature and blood pressure. With this type of data (graded response), the range of responses collected in the study will determine what defines a... 

Tincello DG, Saunders PT, Hodgins MB, Simpson NB, Edwards CR, Hargreaves TB, Wu FC. Correlation of clinical, endocrine and molecular abnormalities with in vivo responses to high-dose testosterone in patients with partial androgen insensitivity syndrome. Clin Endocrinol (Oxford) 1997 46(4) 497-506. 

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