Publication

Pharmacokinetic-Pharmacodynamic Modeling of the D-2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats

Kozielska, 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 journalArticleAcademicpeer-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.

Original languageEnglish
Pages (from-to)1932-1948
Number of pages17
JournalPharmaceutical Research
Volume29
Issue number7
Publication statusPublished - Jul-2012

    Keywords

  • 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

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