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. 2012 Jul;29(7):1932-48.
doi: 10.1007/s11095-012-0722-8. Epub 2012 Mar 22.

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

Magdalena Kozielska  1 , Martin Johnson, Venkatesh Pilla Reddy, An Vermeulen, Cheryl Li, Sarah Grimwood, Rik de Greef, Geny M M Groothuis, Meindert Danhof, Johannes H Proost
Affiliations

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

Magdalena Kozielska et al. Pharm Res. 2012 Jul.

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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Figures

Fig. 1
Fig. 1
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).
Fig. 2
Fig. 2
(a) A schematic representation of the PK-PD model. The plasma PK has been omitted (see Fig. 1) and brain kinetics and receptor binding have been presented here for one drug only because of the complexity of the model. The same model structure applies for RIS and PALI. (b) Representation of the competitive binding to the same receptors by RIS and PALI. Measured RO is the sum of occupancies obtained by both drugs. Here only binding to D2 receptors is shown. The same principle applies for 5-HT2A receptors. [D2] - concentration of free D2 receptors, [R] – unbound concentration of RIS, [D2R] - concentration of D2 receptor complex with RIS, [P] – unbound concentration of PALI, [D2P] - concentration of D2 receptor complex with PALI. D2 receptor occupancy (RO) is the sum of RO exerted by both drugs.
Fig. 3
Fig. 3
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.
Fig. 4
Fig. 4
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.
Fig. 5
Fig. 5
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.
Fig. 6
Fig. 6
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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