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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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Brain-to-plasma ratios against plasma concentrations. (a) Data from studies where total brain concentration was measured; circles - RIS, triangles -PALI. (b) Data from D2 RO studies where brain concentration was measured after removing striatum. (c) Data from 5-HT2A RO studies where brain concentration was measured after removing frontal cortex. For b and c only RIS data was available and different symbols represent different studies.
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Fig5: Brain-to-plasma ratios against plasma concentrations. (a) Data from studies where total brain concentration was measured; circles - RIS, triangles -PALI. (b) Data from D2 RO studies where brain concentration was measured after removing striatum. (c) Data from 5-HT2A RO studies where brain concentration was measured after removing frontal cortex. For b and c only RIS data was available and different symbols represent different studies.

Mentions: The observed brain-to-plasma ratios were higher at lower plasma concentrations and even out as plasma (or brain) concentration increases, both for RIS and PALI (Fig. 5). Even after multiplication of the brain-to-plasma ratio by fubrain/fuplasma = 0.876 and obtaining “free brain-to-plasma ratio”, the brain-to-plasma ratio at higher concentrations is lower than one due to active efflux from the brain. This brain-to-plasma ratio pattern was seen for both the total brain concentration and the concentration measured in brain excluding striatum (from the studies where D2 RO was measured) or excluding frontal cortex (from studies where 5-HT2A RO was measured). A model with only D2 receptor binding in striatum did not predict higher brain-to-plasma ratios for lower concentrations (Fig. 6a–b). Including binding to 5-HT2A receptors in the model predicted brain-to-plasma ratios well (Fig. 6a–c) over the entire concentration range.Fig. 5


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)

Brain-to-plasma ratios against plasma concentrations. (a) Data from studies where total brain concentration was measured; circles - RIS, triangles -PALI. (b) Data from D2 RO studies where brain concentration was measured after removing striatum. (c) Data from 5-HT2A RO studies where brain concentration was measured after removing frontal cortex. For b and c only RIS data was available and different symbols represent different studies.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3369128&req=5

Fig5: Brain-to-plasma ratios against plasma concentrations. (a) Data from studies where total brain concentration was measured; circles - RIS, triangles -PALI. (b) Data from D2 RO studies where brain concentration was measured after removing striatum. (c) Data from 5-HT2A RO studies where brain concentration was measured after removing frontal cortex. For b and c only RIS data was available and different symbols represent different studies.
Mentions: The observed brain-to-plasma ratios were higher at lower plasma concentrations and even out as plasma (or brain) concentration increases, both for RIS and PALI (Fig. 5). Even after multiplication of the brain-to-plasma ratio by fubrain/fuplasma = 0.876 and obtaining “free brain-to-plasma ratio”, the brain-to-plasma ratio at higher concentrations is lower than one due to active efflux from the brain. This brain-to-plasma ratio pattern was seen for both the total brain concentration and the concentration measured in brain excluding striatum (from the studies where D2 RO was measured) or excluding frontal cortex (from studies where 5-HT2A RO was measured). A model with only D2 receptor binding in striatum did not predict higher brain-to-plasma ratios for lower concentrations (Fig. 6a–b). Including binding to 5-HT2A receptors in the model predicted brain-to-plasma ratios well (Fig. 6a–c) over the entire concentration range.Fig. 5

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