Safety biomarkers

Cytotoxicity Evaluated for confounding interpretation of in vitro efficacy assays, for predicting potential for human toxicity especially in liver but also if warranted by other safety assessments in bone marrow, kidney, neurons, immu-nocytes and so on. Also used for developing understanding of biochemical mechanisms of toxicity. HCA has been repeatedly demonstrated to be an effective tool in predictive toxicology. May also be used for certain translational safety biomarkers of toxicity [37]... 

Compared to efficacy, safety is typically more multifactorial, as it is dependent on homeostasis of virtually all cellular processes. A wider number and diversity of potential molecular and cellular effects of compound interactions may affect safety than may affect efficacy or bioavailability. Accordingly, cytotoxicity assessment is less specific, more multi parametric and extrapolatable with less certainty, unless there are specific safety signals indicated by the chemical structure or by its precedents. Extrapolation of safety biomarker data needs a greater foundation of mechanistic understanding of both in vitro and in vivo pathogenesis of toxicities, as well as rigorous, empirical validation of models. 

Biomarkers Translational safety biomarkers (e.g., mitochondrial toxicity can be detected in vitro and in vivo), phospholipidosis [37]... 

O Brien, P.J. and Domingos, M.C. (2009) Use of high content analysis in toxicologic clinical pathology for identification and monitoring of translational safety biomarkers. American Drug Discovery... 

Empirical PD models describe the relationship between drug concentrations in body fluids and the observed drug effect (efficacy, safety, biomarker measurements). Similar to empirical PK models, PD models are relatively simple and a variety of drug effects can be described with a few P D models. Empirical PD mod-... 

Adding Predictive Safety Biomarkers into Standard Toxicology... 

ADDING PREDICTIVE SAFETY BIOMARKERS INTO STANDARD TOXICOLOGY PROTOCOLS FOR BIOPHARMACEUTICALS... 

Further, the imaging biomarkers identified in preclinical safety assessment studies can also be used in clinical drug safety studies, as MRI is widely available and safe to use in volunteer studies. This can be an advantage for the preclinical safety assessment function as it provides feedback on predictability of animal models to human disease using the same endpoint. Clearly, one would not run MRI on all clinical safety studies but in those cases where there is no cheaper, simpler safety biomarker available and there is doubt about the degree of risk posed in man, for example, because of species differences or because the effect size in the placebo group is expected to be very high. 

O Brien, P.J. (2008). Cardiac troponin is the most effective translational safety biomarker for myocardial injury in car-diotoxicity. Toxicology 245 206-18. 

Much research progress is also being made in safety biomarkers for renal tox-icities. Current clinical practice relies heavily on buildup of serum creatinine to determine whether the kidneys are functionally impaired. Since serum creatinine does not change until kidney function is reduced by over 50 percent, more sensitive biomarkers revealing subtle injury are needed.32... 

QUALIFYING NEW SAFETY BIOMARKERS TO FOSTER REGULATORY ACCEPTANCE... 

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