Nathalie Perdaems, Kathryn Ball, François Bouzom
Technologie Servier, Orléans, France
Objectives: To develop a semi-mechanistic PBPK model to predict blood, cerebrospinal (CSF) and brain concentrations acrossdifferent species.
Methods: PK studies in the different species were performed: blood and brain were sampled in mice – blood, CSF and brain were sampled in rat and extracellular fluid in brain (ECF) and plasma samples from a microdialysis study in rat – blood and CSF were sampled in monkey & blood and CSF were sampled in human. A semi-mechanistic model was developed usingacslX 2.5.0.6 and Phoenix WinNonlin 6.3.
Results: A PK model to describe blood concentrations in each specieswas developed. Then, a semi‑mechanistic PBPK model usingblood concentrations and CSF, brain and/or ECF concentrations was built in rat. The semi-mechanistic model parameters weretransposed toenable simulations in theother species, and the observed concentrations were compared with the model predictions.
Conclusions: The semi-mechanistic model allows the description of concentrations in the various CNS compartments in the rat. The transposition between species is ongoing.
References:
[1] Kielbasa et al., Drug Metabolism and Disposition, 2012, 40(5), 877-83.
[2] De Lange et al., Journal of Pharmacokinetics and Pharmacodynamics, 2013,Feb [Epub ahead of print]
Reference: PAGE 22 () Abstr 2728 [www.page-meeting.org/?abstract=2728]
Poster: CNS