Pharmacokinetic-pharmacodynamic modeling of the D-2 and 5-HT2A receptor occupancy of risperidone and paliperidone in ratsReport as inadecuate




Pharmacokinetic-pharmacodynamic modeling of the D-2 and 5-HT2A receptor occupancy of risperidone and paliperidone in rats - Download this document for free, or read online. Document in PDF available to download.

(2012)PHARMACEUTICAL RESEARCH.29(7).p.1932-1948 Mark abstract A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D-2 and serotonin 5-HT2A receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats.A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D-2 and 5-HT2A RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D-2 receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT2A receptors in the frontal cortex.A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D-2 and 5-HT2A RO well. Inclusion of binding to 5-HT2A receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern.Binding to both D-2 and 5-HT2A receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D-2 and 5-HT2A receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.

Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-4325388



Author: Magdalena Kozielska, Martin Johnson, Venkatesh Pilla Reddy, An Vermeulen , Cheryl Li, Sarah Grimwood, Rik de Greef, Geny MM Grooth

Source: https://biblio.ugent.be/publication/4325388



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