Safety pharmacology data analysis

Meta Analysis of Safety Pharmacology Data Predicting Compound Promiscuity 13.2.1... 

Anderson, H., Spliid, H., Larsen, S. and Dali, V (2000). Statistical analysis of time to event data from preclinical safety pharmacology studies. Tox. Methods 10 111-125. 

It is standard practice in safety pharmacology to conduct a power analysis (i.e. establishes the sensitivity of the statistical test or the ability of a test to detect an effect, if the effect exists) by using data derived from each nonclinical model in order to assess the minimum detectable difference (MDD) for the parameter to be investigated. With regard to blood pressure changes, an effect size of 14-16 % (Ewart et al. 2013) was calculated as the MDD for haemodynamic measurements... 

One of the most striking observations that can be made of the peptides as a class is their remarkable safety profile. Of all of the peptides currently on the market that were investigated for this analysis (Table 22.1), there was only one observation in the chronic toxicology studies that was not linked to exaggerated pharmacology. Admittedly, our analysis is biased by the fact that only approved compounds were included however, this data set is still very instructive. The observation in question was from enfuvirtide, a 36 amino acid linear peptide derived from the HIV-1 glycoprotein gp41 [15,16],... 

Perhaps a better approach than this arbitrary dose-driven escalation is pharmacokinetic or drug concentration-driven dose escalation. This requires flexibility in protocol design, rapid assay of plasma samples, and pharmacokinetic analysis of results between dosing escalations. However, there are many advantages with this approach. Issues related to bioavailabihty or nonlinear pharmacokinetics are immediately apparent and can be readily addressed. Selecting subsequent doses based on pharmacokinetic data from previous doses increases both safety and efficiency fewer dose escalation steps are usually required. Another potential advantage is better correlation with safety and pharmacological effects. 

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