Quantitative characterization of the relationship between drug exposure and target occupancy at its site of action is essential in drug development. PK/PD modelling based on preclinical occupancy studies is commonly used to project human doses needed for efficacy for CNS targets. We have been interested in extending this approach to peripheral targets, and have established enzyme occupancy assays using an LC/MS/MS approach in peripheral tissues. Here we exemplify a PK/PD approach for peripheral targets using PDE5 enzyme occupancy as an example and looking at lung enzyme occupancy at the efficacious sildenafil clinical doses in pulmonary arterial hypertension.

Preclinical peripheral enzyme occupancy and PK/PD modelling: A retrospective analysis of sildenafil

249th National Meeting (2015)

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