Mechanism-based PK/PD modeling of selective serotonin reuptake inhibitors

Abstract

The main objective of the investigations was to explore the PK/PD correlations of fluvoxamine, as a prototype for the Selective Serotonin Reuptake Inhibitors (SSRIs). In the various investigations, a spectrum of different biomarkers was used, each reflecting a specific process on the causal path between drug administration and response. The effects of fluvoxamine have been explored in six investigation steps; from the relatively simple description of the pharmacokinetics of fluvoxamine in plasma and brain to the more complex relationships with the effects on SERT occupancy, 5-HT and 5-HIAA levels and REM sleep. In the PCA study, a categorical PK/PD model was proposed for the effects of fluvoxamine on PCA induced behavioral effects as a kind of intermediary biomarker. There appeared to be important aspects in the PK/PD relationships of fluvoxamine, which was already indicated in the well-known delayed therapeutic effect of SSRIs. The cascading PK/PD model enables the prediction of the effects of functional adaptation upon long-term administration. For SSRIs, adaptation may occur at various levels in the biological system. The various studied biomarkers provide a basis to determine at which level of the biological system functional adaptation occurs (i.e. target site distribution, target expression, turnover of neurotransmitters, transduction mechanisms).Johnson & Johnson, Pharmaceutical Research and Development, a Division of Janssen Pharmaceutica N.V. (Beerse, Belgium)UBL - phd migration 201