Abstract
Increasing use of therapeutic proteins (TP) in poly-pharmacy settings calls for more in-depth understanding of the biological interactions that can lead to increased toxicity or loss of pharmacological effect. Factors like patient population, medications that are likely to be co-administered in that population, clearance mechanisms of a TP and concomitant drugs have to be taken into account in order to determine potential for drug-drug interactions (DDI). The most well documented TP DDI mechanism involves cytokine-mediated changes in drug metabolizing enzymes. This type of DDI can be described as a "High probability mechanism" of interaction. Due to the limitations of the current pre-clinical models for addressing this type of DDI, clinical evaluation is currently the most reliable approach. "Low-Medium" probability DDI mechanisms need to be addressed on a case-by-case basis. These DDI mechanisms include altered clearance of TP resulting from the changes in the target protein levels by the concomitant medication, displacement of TP from binding proteins, modulation of Fcγ receptor expression, or others. The purpose of this paper is to introduce the approach used by Pfizer scientists for evaluation of the DDI potential of novel TP products during drug discovery and development.
- Received May 23, 2011.
- Accepted July 18, 2011.
- The American Society for Pharmacology and Experimental Therapeutics