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Exploring the nature of biomarker responses to various dosages of an FAAH inhibitor: application of s systems pharmacology model to evaluate possible project risks

Aim of the project:

To identify the molecular mechanisms underlying the observed dynamics of anandamide and ethanolamide responses measured in clinical trials of an FAAH inhibitor and to evaluate prospects for the continuation of clinical trials and potential risks.

Results:

A systems pharmacology model describing the synthesis, degradation, and distribution of ethanolamides and the pharmacokinetics and pharmacodynamics of an FAAH inhibitor (compound PF-04457845) was developed. The model allows us (1) to predict anandamide concentrations in the CNS and tissues on the basis of its concentration in the blood, (2) to reveal alternative clearance of ethanolamides (different from FAAH), and (3) to estimate the occupancy level of the CB1 receptor with anandamide in the brain. The predicted occupancy of the CB1 receptor changes from 3% to 26% after administration of PF-04457845 at high doses, an effect that is not sufficient for therapeutic purposes. The prediction model proposes that there are other processes (different from FAAH) responsible for the degradation of ethanolamides. Thus, the model allows us to conclude that continuation of clinical trials of PF-04457845 is associated with a fairly high risk in demonstration of the efficacy of the compound. On the basis of the mechanisms underlying the conclusion, several ways to increase the efficacy of the compound, including combination therapy, have been proposed. 

Initiator of the project:

Pfizer

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pain_killers.pdf