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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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Observed and simulated brain-to-plasma ratios. Open circles in panels a-c represent observed brain-to-plasma ratios for total brain (a), brain excluding striatum - from D2 RO studies (b) and brain excluding frontal cortex - from 5-HT2A RO studies (c). In all the panels gray dots represent predictions of our final model. Black dots represent prediction of the model with only D2 receptor binding (a–b), or prediction of final model but assuming no efflux (d), kon and koff values 10 times higher (e) or koff values 10 times higher (f) than in the final model. Only total brain-to-plasma ratios are depicted in panels d-f. Qualitatively similar results were obtained for brain concentrations from D2 and 5-HT2A studies.
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Fig6: Observed and simulated brain-to-plasma ratios. Open circles in panels a-c represent observed brain-to-plasma ratios for total brain (a), brain excluding striatum - from D2 RO studies (b) and brain excluding frontal cortex - from 5-HT2A RO studies (c). In all the panels gray dots represent predictions of our final model. Black dots represent prediction of the model with only D2 receptor binding (a–b), or prediction of final model but assuming no efflux (d), kon and koff values 10 times higher (e) or koff values 10 times higher (f) than in the final model. Only total brain-to-plasma ratios are depicted in panels d-f. Qualitatively similar results were obtained for brain concentrations from D2 and 5-HT2A studies.

Mentions: The previously published hybrid physiology-based PK-PD model (9) fitted the data best after adjusting for binding to 5-HT2A receptors (Fig. 2). A model with only D2 receptor binding (9) led to high residual error (>60%) for brain concentration. Using a combined error model reduced the proportional error to some extent. However, this model did not explain the observed brain-to-plasma ratio adequately (Fig. 6a–b). These problems were overcome when the model was extended to include 5-HT2A receptor binding in frontal cortex.


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)

Observed and simulated brain-to-plasma ratios. Open circles in panels a-c represent observed brain-to-plasma ratios for total brain (a), brain excluding striatum - from D2 RO studies (b) and brain excluding frontal cortex - from 5-HT2A RO studies (c). In all the panels gray dots represent predictions of our final model. Black dots represent prediction of the model with only D2 receptor binding (a–b), or prediction of final model but assuming no efflux (d), kon and koff values 10 times higher (e) or koff values 10 times higher (f) than in the final model. Only total brain-to-plasma ratios are depicted in panels d-f. Qualitatively similar results were obtained for brain concentrations from D2 and 5-HT2A studies.
© Copyright Policy
Related In: Results  -  Collection

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

Fig6: Observed and simulated brain-to-plasma ratios. Open circles in panels a-c represent observed brain-to-plasma ratios for total brain (a), brain excluding striatum - from D2 RO studies (b) and brain excluding frontal cortex - from 5-HT2A RO studies (c). In all the panels gray dots represent predictions of our final model. Black dots represent prediction of the model with only D2 receptor binding (a–b), or prediction of final model but assuming no efflux (d), kon and koff values 10 times higher (e) or koff values 10 times higher (f) than in the final model. Only total brain-to-plasma ratios are depicted in panels d-f. Qualitatively similar results were obtained for brain concentrations from D2 and 5-HT2A studies.
Mentions: The previously published hybrid physiology-based PK-PD model (9) fitted the data best after adjusting for binding to 5-HT2A receptors (Fig. 2). A model with only D2 receptor binding (9) led to high residual error (>60%) for brain concentration. Using a combined error model reduced the proportional error to some extent. However, this model did not explain the observed brain-to-plasma ratio adequately (Fig. 6a–b). These problems were overcome when the model was extended to include 5-HT2A receptor binding in frontal cortex.

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