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Pharmacokinetic-pharmacodynamic modeling of the D₂ and 5-HT (2A) receptor occupancy of risperidone and paliperidone in rats.

Kozielska M, Johnson M, Pilla Reddy V, Vermeulen A, Li C, Grimwood S, de Greef R, Groothuis GM, Danhof M, Proost JH - Pharm. Res. (2012)

Bottom Line: A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone.This may stem from their high affinity for D₂ and 5-HT(2A) receptors.Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD, Groningen, The Netherlands.

ABSTRACT

Purpose: A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D₂ and serotonin 5-HT(2A) receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats.

Methods: A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D₂ and 5-HT(2A) RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D₂ receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT(2A) receptors in the frontal cortex.

Results: A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D₂ and 5-HT(2A) RO well. Inclusion of binding to 5-HT(2A) receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern.

Conclusion: Binding to both D₂ and 5-HT(2A) receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D₂ and 5-HT(2A) receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.

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Goodness-of-fit plots of the PK-PD model. Presented are scatter plots of plasma and brain concentrations and D2 and 5-HT2A RO versus population predictions and conditional weighted residuals (CWRES) versus time.
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Fig3: Goodness-of-fit plots of the PK-PD model. Presented are scatter plots of plasma and brain concentrations and D2 and 5-HT2A RO versus population predictions and conditional weighted residuals (CWRES) versus time.

Mentions: Goodness-of-fit plots did not show any systematic deviation between observations and population and individual predictions nor any trends in conditional weighted residuals versus time, which demonstrates that this model adequately describes the plasma PK of RIS and PALI (Fig. 3).Fig. 3


Pharmacokinetic-pharmacodynamic modeling of the D₂ and 5-HT (2A) receptor occupancy of risperidone and paliperidone in rats.

Kozielska M, Johnson M, Pilla Reddy V, Vermeulen A, Li C, Grimwood S, de Greef R, Groothuis GM, Danhof M, Proost JH - Pharm. Res. (2012)

Goodness-of-fit plots of the PK-PD model. Presented are scatter plots of plasma and brain concentrations and D2 and 5-HT2A RO versus population predictions and conditional weighted residuals (CWRES) versus time.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369128&req=5

Fig3: Goodness-of-fit plots of the PK-PD model. Presented are scatter plots of plasma and brain concentrations and D2 and 5-HT2A RO versus population predictions and conditional weighted residuals (CWRES) versus time.
Mentions: Goodness-of-fit plots did not show any systematic deviation between observations and population and individual predictions nor any trends in conditional weighted residuals versus time, which demonstrates that this model adequately describes the plasma PK of RIS and PALI (Fig. 3).Fig. 3

Bottom Line: A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone.This may stem from their high affinity for D₂ and 5-HT(2A) receptors.Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD, Groningen, The Netherlands.

ABSTRACT

Purpose: A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D₂ and serotonin 5-HT(2A) receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats.

Methods: A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D₂ and 5-HT(2A) RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D₂ receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT(2A) receptors in the frontal cortex.

Results: A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D₂ and 5-HT(2A) RO well. Inclusion of binding to 5-HT(2A) receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern.

Conclusion: Binding to both D₂ and 5-HT(2A) receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D₂ and 5-HT(2A) receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.

Show MeSH