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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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Predictive check of the PK-PD model. (a–c) Risperidone plasma concentration, risperidone brain concentration after removing striatum and D2 RO after IP administration of a 1 mg/kg dose of risperidone, respectively. (d–f) Risperidone plasma concentration, risperidone brain concentration after removing frontal cortex and 5-HT2A RO after IP administration of a 0.1 mg/kg dose of risperidone, respectively. Dots represent the observed data; the dashed line represents the median of the observed data; the shaded area represents 90% prediction interval based on 1000 simulated datasets; the grey line represents the median of the simulated data.
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Fig4: Predictive check of the PK-PD model. (a–c) Risperidone plasma concentration, risperidone brain concentration after removing striatum and D2 RO after IP administration of a 1 mg/kg dose of risperidone, respectively. (d–f) Risperidone plasma concentration, risperidone brain concentration after removing frontal cortex and 5-HT2A RO after IP administration of a 0.1 mg/kg dose of risperidone, respectively. Dots represent the observed data; the dashed line represents the median of the observed data; the shaded area represents 90% prediction interval based on 1000 simulated datasets; the grey line represents the median of the simulated data.

Mentions: Some of the predictive check results are depicted in Fig. 4. We present the result for the IP route of administration for doses of 0.1 and 1 mg/kg since for these doses there were time course data available for 5-HT2A and D2 RO and they had more data points than other doses. Practically all observations fall within the range of the 5-th and 95-th percentile. Median time course of D2 RO is predicted well. For 5-HT2A, RO seemed to be underestimated for later time points. Prediction intervals are very wide since the residual error in our model is also relatively big. However, it should be noted that the variability of the data is also large (see for example 5-HT2A RO at 1 h).Fig. 4


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)

Predictive check of the PK-PD model. (a–c) Risperidone plasma concentration, risperidone brain concentration after removing striatum and D2 RO after IP administration of a 1 mg/kg dose of risperidone, respectively. (d–f) Risperidone plasma concentration, risperidone brain concentration after removing frontal cortex and 5-HT2A RO after IP administration of a 0.1 mg/kg dose of risperidone, respectively. Dots represent the observed data; the dashed line represents the median of the observed data; the shaded area represents 90% prediction interval based on 1000 simulated datasets; the grey line represents the median of the simulated data.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3369128&req=5

Fig4: Predictive check of the PK-PD model. (a–c) Risperidone plasma concentration, risperidone brain concentration after removing striatum and D2 RO after IP administration of a 1 mg/kg dose of risperidone, respectively. (d–f) Risperidone plasma concentration, risperidone brain concentration after removing frontal cortex and 5-HT2A RO after IP administration of a 0.1 mg/kg dose of risperidone, respectively. Dots represent the observed data; the dashed line represents the median of the observed data; the shaded area represents 90% prediction interval based on 1000 simulated datasets; the grey line represents the median of the simulated data.
Mentions: Some of the predictive check results are depicted in Fig. 4. We present the result for the IP route of administration for doses of 0.1 and 1 mg/kg since for these doses there were time course data available for 5-HT2A and D2 RO and they had more data points than other doses. Practically all observations fall within the range of the 5-th and 95-th percentile. Median time course of D2 RO is predicted well. For 5-HT2A, RO seemed to be underestimated for later time points. Prediction intervals are very wide since the residual error in our model is also relatively big. However, it should be noted that the variability of the data is also large (see for example 5-HT2A RO at 1 h).Fig. 4

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