Pharmacokinetic-Pharmacodynamic Modeling of the D-2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in RatsKozielska, M., Johnson, M., Reddy, V. P., Vermeulen, A., Li, C., Grimwood, S., de Greef, R., Groothuis, G. M. M., Danhof, M. & Proost, J. H., Jul-2012, In : Pharmaceutical Research. 29, 7, p. 1932-1948 17 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||17|
|Publication status||Published - Jul-2012|
- dopamine D-2 receptor occupancy, mechanism-based PK-PD, paliperidone, risperidone, serotonin 5-HT2A receptor occupancy, SPONTANEOUSLY HYPERTENSIVE-RATS, ATYPICAL ANTIPSYCHOTIC-DRUGS, PLASMA-PROTEIN BINDING, CENTRAL-NERVOUS-SYSTEM, P-GLYCOPROTEIN, IN-VITRO, SEROTONIN RECEPTORS, BRAIN, VIVO, SCHIZOPHRENIA