Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of the Dopamine D2 Receptor Occupancy of Olanzapine in Rats
Identifieur interne : 000A54 ( Main/Exploration ); précédent : 000A53; suivant : 000A55Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of the Dopamine D2 Receptor Occupancy of Olanzapine in Rats
Auteurs : Martin Johnson [Pays-Bas] ; Magdalena Kozielska [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 ] ; 2011.
Abstract
A mechanism-based PK-PD model was developed to predict the time course of dopamine D2 receptor occupancy (D2RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug.
A population approach was utilized to quantify both the pharmacokinetics and pharmacodynamics of olanzapine in rats using the exposure (plasma and brain concentration) and D2RO profile obtained experimentally at various doses (0.01–40 mg/kg) administered by different routes. A two-compartment pharmacokinetic model was used to describe the plasma pharmacokinetic profile. A hybrid physiology- and mechanism-based model was developed to characterize the D2 receptor binding in the striatum and was fitted sequentially to the data. The parameters were estimated using nonlinear mixed-effects modeling .
Plasma, brain concentration profiles and time course of D2RO were well described by the model; validity of the proposed model is supported by good agreement between estimated association and dissociation rate constants and
This model includes both receptor binding kinetics and pharmacokinetics as the basis for the prediction of the D2RO in rats. Moreover, this modeling framework can be applied to scale the
Url:
DOI: 10.1007/s11095-011-0477-7
PubMed: 21647790
PubMed Central: 3170473
Affiliations:
- Belgique, Pays-Bas
- Groningue (province), Hollande-Méridionale
- Groningue (ville), Leyde
- Université de Groningue
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M." last="Groothuis">Geny M. M. Groothuis</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV 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">Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV 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">21647790</idno><idno type="pmc">3170473</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170473</idno><idno type="RBID">PMC:3170473</idno><idno type="doi">10.1007/s11095-011-0477-7</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000179</idno><idno 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Deusinglaan 1, 9713 AV Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV 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="Kozielska, Magdalena" sort="Kozielska, Magdalena" uniqKey="Kozielska M" first="Magdalena" last="Kozielska">Magdalena Kozielska</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV 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">Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV 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 and Simulation, Janssen Research and Development A Division of Janssen Pharmaceutica NV, Beerse, Belgium</nlm:aff><country xml:lang="fr">Belgique</country><wicri:regionArea>Advanced PK-PD Modeling and Simulation, Janssen Research and Development A Division of 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">Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3), Merck Sharp & Dohme, Oss, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3), 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">Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV 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">Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV 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="2011">2011</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 mechanism-based PK-PD model was developed to predict the time course of dopamine D<sub>2</sub> receptor occupancy (D<sub>2</sub>RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug.</p></sec><sec><title>Methods</title><p>A population approach was utilized to quantify both the pharmacokinetics and pharmacodynamics of olanzapine in rats using the exposure (plasma and brain concentration) and D<sub>2</sub>RO profile obtained experimentally at various doses (0.01–40 mg/kg) administered by different routes. A two-compartment pharmacokinetic model was used to describe the plasma pharmacokinetic profile. A hybrid physiology- and mechanism-based model was developed to characterize the D<sub>2</sub> receptor binding in the striatum and was fitted sequentially to the data. The parameters were estimated using nonlinear mixed-effects modeling .</p></sec><sec><title>Results</title><p>Plasma, brain concentration profiles and time course of D<sub>2</sub>RO were well described by the model; validity of the proposed model is supported by good agreement between estimated association and dissociation rate constants and <italic>in vitro</italic> values from literature.</p></sec><sec><title>Conclusion</title><p>This model includes both receptor binding kinetics and pharmacokinetics as the basis for the prediction of the D<sub>2</sub>RO in rats. Moreover, this modeling framework can be applied to scale the <italic>in vitro</italic> and preclinical information to clinical receptor occupancy.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Murray, Rm" uniqKey="Murray R">RM Murray</name></author><author><name sortKey="Lappin, J" uniqKey="Lappin J">J Lappin</name></author><author><name sortKey="Di, Fm" uniqKey="Di F">FM Di</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Laruelle, M" uniqKey="Laruelle M">M Laruelle</name></author><author><name sortKey="Bi Dargham, A" uniqKey="Bi Dargham A">A Bi-Dargham</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Natesan, S" uniqKey="Natesan S">S Natesan</name></author><author><name sortKey="Reckless, Ge" uniqKey="Reckless G">GE Reckless</name></author><author><name sortKey="Nobrega, Jn" uniqKey="Nobrega J">JN 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uniqKey="Gompel P">P Gompel</name></author><author><name sortKey="Lesage, As" uniqKey="Lesage A">AS Lesage</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Seeman, P" uniqKey="Seeman P">P Seeman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Danhof, M" uniqKey="Danhof M">M Danhof</name></author><author><name sortKey="Jongh, J" uniqKey="Jongh J">J Jongh</name></author><author><name sortKey="Lange, Ec" uniqKey="Lange E">EC Lange</name></author><author><name sortKey="Della, Po" uniqKey="Della P">PO Della</name></author><author><name sortKey="Ploeger, Ba" uniqKey="Ploeger B">BA Ploeger</name></author><author><name sortKey="Voskuyl, Ra" uniqKey="Voskuyl R">RA Voskuyl</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chien, Jy" uniqKey="Chien J">JY Chien</name></author><author><name sortKey="Friedrich, S" uniqKey="Friedrich S">S Friedrich</name></author><author><name sortKey="Heathman, Ma" uniqKey="Heathman M">MA Heathman</name></author><author><name sortKey="Alwis, Dp" uniqKey="Alwis D">DP Alwis</name></author><author><name sortKey="Sinha, V" uniqKey="Sinha V">V Sinha</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zuideveld, Kp" uniqKey="Zuideveld K">KP Zuideveld</name></author><author><name sortKey="Graaf, Ph" uniqKey="Graaf P">PH Graaf</name></author><author><name sortKey="Peletier, La" uniqKey="Peletier L">LA Peletier</name></author><author><name sortKey="Danhof, M" uniqKey="Danhof M">M Danhof</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Woo, S" uniqKey="Woo S">S Woo</name></author><author><name sortKey="Jusko, Wj" uniqKey="Jusko W">WJ Jusko</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Agoram, Bm" uniqKey="Agoram B">BM Agoram</name></author><author><name sortKey="Martin, Sw" uniqKey="Martin S">SW Martin</name></author><author><name sortKey="Graaf, Ph" uniqKey="Graaf P">PH Graaf</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="Johnson, Martin" sort="Johnson, Martin" uniqKey="Johnson M" first="Martin" last="Johnson">Martin Johnson</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="Kozielska, Magdalena" sort="Kozielska, Magdalena" uniqKey="Kozielska M" first="Magdalena" last="Kozielska">Magdalena Kozielska</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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