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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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A schematic representation of the plasma PK model. Plasma PK of both RIS and PALI follows a two-compartment model. IV and IP dosing goes directly to the central compartment. A fraction of the absorbed dose for IP RIS route of administration goes directly to the RIS central compartment and a fraction of the absorbed dose goes to the PALI central compartment (FrFPM) representing first pass metabolism. Absorption after SC dosing is described by consecutive zero- and first order processes for both RIS and PALI. DRSC is the duration of the zero-order process after SC dosing. Total elimination clearance of RIS is divided into metabolic clearance (CLmet) and the clearance by other routes of elimination (CLRIS).
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Fig1: A schematic representation of the plasma PK model. Plasma PK of both RIS and PALI follows a two-compartment model. IV and IP dosing goes directly to the central compartment. A fraction of the absorbed dose for IP RIS route of administration goes directly to the RIS central compartment and a fraction of the absorbed dose goes to the PALI central compartment (FrFPM) representing first pass metabolism. Absorption after SC dosing is described by consecutive zero- and first order processes for both RIS and PALI. DRSC is the duration of the zero-order process after SC dosing. Total elimination clearance of RIS is divided into metabolic clearance (CLmet) and the clearance by other routes of elimination (CLRIS).

Mentions: One- and two-compartment models for both RIS and PALI were tested. For SC and IP administration different absorption models were tested: zero-order and first-order absorption in combination with a lag time. For IP dosing of RIS we checked models with and without first pass metabolism by assuming that part of the administered RIS dose is converted to PALI before reaching the systemic circulation. Bioavailability for IP and SC doses were estimated relative to IV dosing. Since there were no data after IV administration of PALI, we assumed that RIS and PALI have the same bioavailability for the SC route of administration. This allows estimating the volume of distribution and other absorption parameters of PALI. To account for metabolite formation we divided the elimination clearance for RIS into two clearances: metabolic clearance to PALI (CLmet) and clearance by other routes of elimination (CLRIS) (Fig. 1). First-order conditional estimation method (FOCE) was used to obtain PK parameter estimates.Fig. 1


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)

A schematic representation of the plasma PK model. Plasma PK of both RIS and PALI follows a two-compartment model. IV and IP dosing goes directly to the central compartment. A fraction of the absorbed dose for IP RIS route of administration goes directly to the RIS central compartment and a fraction of the absorbed dose goes to the PALI central compartment (FrFPM) representing first pass metabolism. Absorption after SC dosing is described by consecutive zero- and first order processes for both RIS and PALI. DRSC is the duration of the zero-order process after SC dosing. Total elimination clearance of RIS is divided into metabolic clearance (CLmet) and the clearance by other routes of elimination (CLRIS).
© Copyright Policy
Related In: Results  -  Collection

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

Fig1: A schematic representation of the plasma PK model. Plasma PK of both RIS and PALI follows a two-compartment model. IV and IP dosing goes directly to the central compartment. A fraction of the absorbed dose for IP RIS route of administration goes directly to the RIS central compartment and a fraction of the absorbed dose goes to the PALI central compartment (FrFPM) representing first pass metabolism. Absorption after SC dosing is described by consecutive zero- and first order processes for both RIS and PALI. DRSC is the duration of the zero-order process after SC dosing. Total elimination clearance of RIS is divided into metabolic clearance (CLmet) and the clearance by other routes of elimination (CLRIS).
Mentions: One- and two-compartment models for both RIS and PALI were tested. For SC and IP administration different absorption models were tested: zero-order and first-order absorption in combination with a lag time. For IP dosing of RIS we checked models with and without first pass metabolism by assuming that part of the administered RIS dose is converted to PALI before reaching the systemic circulation. Bioavailability for IP and SC doses were estimated relative to IV dosing. Since there were no data after IV administration of PALI, we assumed that RIS and PALI have the same bioavailability for the SC route of administration. This allows estimating the volume of distribution and other absorption parameters of PALI. To account for metabolite formation we divided the elimination clearance for RIS into two clearances: metabolic clearance to PALI (CLmet) and clearance by other routes of elimination (CLRIS) (Fig. 1). First-order conditional estimation method (FOCE) was used to obtain PK parameter estimates.Fig. 1

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