Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats
Identifieur interne : 000751 ( Main/Exploration ); précédent : 000750; suivant : 000752Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats
Auteurs : Magdalena Kozielska [Pays-Bas] ; Martin Johnson [Pays-Bas] ; Venkatesh Pilla Reddy [Pays-Bas] ; An Vermeulen [Belgique] ; Cheryl Li ; Sarah Grimwood ; Rik De Greef [Pays-Bas] ; Geny M. M. Groothuis [Pays-Bas] ; Meindert Danhof [Pays-Bas] ; Johannes H. Proost [Pays-Bas]Source :
- Pharmaceutical Research [ 0724-8741 ] ; 2012.
Abstract
A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D2 and serotonin 5-HT2A receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats.
A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D2 and 5-HT2A 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-HT2A receptors in the frontal cortex.
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-HT2A RO well. Inclusion of binding to 5-HT2A receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern.
Binding to both D2 and 5-HT2A receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D2 and 5-HT2A receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.
Url:
DOI: 10.1007/s11095-012-0722-8
PubMed: 22437487
PubMed Central: 3369128
Affiliations:
- Belgique, Pays-Bas
- Groningue (province), Hollande-Méridionale
- Groningue (ville), Leyde
- Université de Groningue
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Le document en format XML
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M." last="Groothuis">Geny M. M. Groothuis</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Danhof, Meindert" sort="Danhof, Meindert" uniqKey="Danhof M" first="Meindert" last="Danhof">Meindert Danhof</name><affiliation wicri:level="3"><nlm:aff id="Aff5">Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Proost, Johannes H" sort="Proost, Johannes H" uniqKey="Proost J" first="Johannes H." last="Proost">Johannes H. Proost</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22437487</idno><idno type="pmc">3369128</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369128</idno><idno type="RBID">PMC:3369128</idno><idno type="doi">10.1007/s11095-012-0722-8</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000172</idno><idno type="wicri:Area/Pmc/Curation">000172</idno><idno type="wicri:Area/Pmc/Checkpoint">000311</idno><idno type="wicri:Area/Ncbi/Merge">000127</idno><idno type="wicri:Area/Ncbi/Curation">000127</idno><idno type="wicri:Area/Ncbi/Checkpoint">000127</idno><idno type="wicri:doubleKey">0724-8741:2012:Kozielska M:pharmacokinetic:pharmacodynamic:modeling</idno><idno type="wicri:Area/Main/Merge">000752</idno><idno type="wicri:Area/Main/Curation">000751</idno><idno type="wicri:Area/Main/Exploration">000751</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Pharmacokinetic-Pharmacodynamic Modeling of the D<sub>2</sub> and 5-HT<sub>2A</sub> Receptor Occupancy of Risperidone and Paliperidone in Rats</title><author><name sortKey="Kozielska, Magdalena" sort="Kozielska, Magdalena" uniqKey="Kozielska M" first="Magdalena" last="Kozielska">Magdalena Kozielska</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Johnson, Martin" sort="Johnson, Martin" uniqKey="Johnson M" first="Martin" last="Johnson">Martin Johnson</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Pilla Reddy, Venkatesh" sort="Pilla Reddy, Venkatesh" uniqKey="Pilla Reddy V" first="Venkatesh" last="Pilla Reddy">Venkatesh Pilla Reddy</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Vermeulen, An" sort="Vermeulen, An" uniqKey="Vermeulen A" first="An" last="Vermeulen">An Vermeulen</name><affiliation wicri:level="1"><nlm:aff id="Aff2">Advanced PK-PD Modeling & Simulation, Janssen Research and Development Janssen Pharmaceutica NV, Beerse, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Advanced PK-PD Modeling & Simulation, Janssen Research and Development Janssen Pharmaceutica NV, Beerse</wicri:regionArea><wicri:noRegion>Beerse</wicri:noRegion></affiliation></author><author><name sortKey="Li, Cheryl" sort="Li, Cheryl" uniqKey="Li C" first="Cheryl" last="Li">Cheryl Li</name><affiliation><nlm:aff id="Aff3">Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut USA</nlm:aff><wicri:noCountry code="subfield">Connecticut USA</wicri:noCountry></affiliation></author><author><name sortKey="Grimwood, Sarah" sort="Grimwood, Sarah" uniqKey="Grimwood S" first="Sarah" last="Grimwood">Sarah Grimwood</name><affiliation><nlm:aff id="Aff3">Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut USA</nlm:aff><wicri:noCountry code="subfield">Connecticut USA</wicri:noCountry></affiliation></author><author><name sortKey="De Greef, Rik" sort="De Greef, Rik" uniqKey="De Greef R" first="Rik" last="De Greef">Rik De Greef</name><affiliation wicri:level="1"><nlm:aff id="Aff4">Clinical PK-PD, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Sharp & Dohme, Oss, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Clinical PK-PD, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Sharp & Dohme, Oss</wicri:regionArea><wicri:noRegion>Oss</wicri:noRegion></affiliation></author><author><name sortKey="Groothuis, Geny M M" sort="Groothuis, Geny M M" uniqKey="Groothuis G" first="Geny M. M." last="Groothuis">Geny M. M. Groothuis</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Danhof, Meindert" sort="Danhof, Meindert" uniqKey="Danhof M" first="Meindert" last="Danhof">Meindert Danhof</name><affiliation wicri:level="3"><nlm:aff id="Aff5">Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Proost, Johannes H" sort="Proost, Johannes H" uniqKey="Proost J" first="Johannes H." last="Proost">Johannes H. Proost</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Pharmacokinetics, Toxicology and Targeting, University of Groningen, P.O. Box 196, 9700 AD Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author></analytic><series><title level="j">Pharmaceutical Research</title><idno type="ISSN">0724-8741</idno><idno type="eISSN">1573-904X</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><sec><title>Purpose</title><p>A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats.</p></sec><sec><title>Methods</title><p>A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D<sub>2</sub> and 5-HT<sub>2A</sub> RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D<sub>2</sub> receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT<sub>2A</sub> receptors in the frontal cortex.</p></sec><sec><title>Results</title><p>A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D<sub>2</sub> and 5-HT<sub>2A</sub> RO well. Inclusion of binding to 5-HT<sub>2A</sub> receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern.</p></sec><sec><title>Conclusion</title><p>Binding to both D<sub>2</sub> and 5-HT<sub>2A</sub> receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D<sub>2</sub> and 5-HT<sub>2A</sub> receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Carpenter, Wt" uniqKey="Carpenter W">WT Carpenter</name></author><author><name sortKey="Koenig, Ji" uniqKey="Koenig J">JI Koenig</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pani, L" uniqKey="Pani L">L Pani</name></author><author><name sortKey="Pira, L" uniqKey="Pira L">L Pira</name></author><author><name sortKey="Marchese, G" uniqKey="Marchese G">G Marchese</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Meltzer, Hy" uniqKey="Meltzer H">HY Meltzer</name></author><author><name sortKey="Matsubara, S" uniqKey="Matsubara S">S Matsubara</name></author><author><name sortKey="Lee, Jc" uniqKey="Lee J">JC 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Price</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Callado, Lf" uniqKey="Callado L">LF Callado</name></author><author><name sortKey="Meana, Jj" uniqKey="Meana J">JJ Meana</name></author><author><name sortKey="Grijalba, B" uniqKey="Grijalba B">B Grijalba</name></author><author><name sortKey="Pazos, A" uniqKey="Pazos A">A Pazos</name></author><author><name sortKey="Sastre, M" uniqKey="Sastre M">M Sastre</name></author><author><name sortKey="Garcia Sevilla, Ja" uniqKey="Garcia Sevilla J">JA Garcia-Sevilla</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Belgique</li><li>Pays-Bas</li></country><region><li>Groningue (province)</li><li>Hollande-Méridionale</li></region><settlement><li>Groningue (ville)</li><li>Leyde</li></settlement><orgName><li>Université de Groningue</li></orgName></list><tree><noCountry><name sortKey="Grimwood, Sarah" sort="Grimwood, Sarah" uniqKey="Grimwood S" first="Sarah" last="Grimwood">Sarah Grimwood</name><name sortKey="Li, Cheryl" sort="Li, Cheryl" uniqKey="Li C" first="Cheryl" last="Li">Cheryl Li</name></noCountry><country name="Pays-Bas"><region name="Groningue (province)"><name sortKey="Kozielska, Magdalena" sort="Kozielska, Magdalena" uniqKey="Kozielska M" first="Magdalena" last="Kozielska">Magdalena Kozielska</name></region><name sortKey="Danhof, Meindert" sort="Danhof, Meindert" uniqKey="Danhof M" first="Meindert" last="Danhof">Meindert Danhof</name><name sortKey="De Greef, Rik" sort="De Greef, Rik" uniqKey="De Greef R" first="Rik" last="De Greef">Rik De Greef</name><name sortKey="Groothuis, Geny M M" sort="Groothuis, Geny M M" uniqKey="Groothuis G" first="Geny M. M." last="Groothuis">Geny M. M. Groothuis</name><name sortKey="Johnson, Martin" sort="Johnson, Martin" uniqKey="Johnson M" first="Martin" last="Johnson">Martin Johnson</name><name sortKey="Pilla Reddy, Venkatesh" sort="Pilla Reddy, Venkatesh" uniqKey="Pilla Reddy V" first="Venkatesh" last="Pilla Reddy">Venkatesh Pilla Reddy</name><name sortKey="Proost, Johannes H" sort="Proost, Johannes H" uniqKey="Proost J" first="Johannes H." last="Proost">Johannes H. Proost</name></country><country name="Belgique"><noRegion><name sortKey="Vermeulen, An" sort="Vermeulen, An" uniqKey="Vermeulen A" first="An" last="Vermeulen">An Vermeulen</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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