caa a22 4500 445313129 CHVBK 20180317142637.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s11095-011-0477-7 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0477-7 Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of the Dopamine D2 Receptor Occupancy of Olanzapine in Rats [Elektronische Daten] [Martin Johnson, Magdalena Kozielska, Venkatesh Pilla Reddy, An Vermeulen, Cheryl Li, Sarah Grimwood, Rik de Greef, Geny Groothuis, Meindert Danhof, Johannes Proost] ABSTRACT: Purpose: 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. Methods: 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 (0.01-40mg/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 . Results: 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 in vitro values from literature. Conclusion: 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 in vitro and preclinical information to clinical receptor occupancy. The Author(s), 2011 antipsychotic nationallicence dopamine D2 receptor occupancy nationallicence koff nationallicence mechanism-based PK-PD nationallicence olanzapine nationallicence translational model nationallicence BBB : blood-brain barrier nationallicence Bmax : dopamine D2 receptor density nationallicence CB : concentration of olanzapine bound to receptor nationallicence CEV : concentration in extravascular brain compartment nationallicence CL : systemic clearance nationallicence CLbev : brain-extravascular clearance nationallicence CLbv : brain-vascular clearance nationallicence D2RO : dopamine-2 receptor occupancy nationallicence FIP : bioavailability for intraperitoneal route of administration nationallicence FOCE : first order conditional estimation method nationallicence FSC : bioavailability for subcutaneous route of administration nationallicence fubrain : unbound fraction in brain nationallicence fuplasma : unbound fraction in plasma nationallicence GOF : goodness-of-fit plots nationallicence IAV : inter-animal variability nationallicence koff : receptor dissociation rate constant nationallicence kon : receptor association rate constant nationallicence MW : molecular weight nationallicence nM : nanomoles/litre nationallicence OFV : objective function value nationallicence PBPKPD : physiology-based pharmacokinetic and pharmacodynamic nationallicence PK-PD : pharmacokinetic and pharmacodynamic nationallicence Q : intercompartmental clearance nationallicence RSE : relative standard error nationallicence SSE : stochastic simulation and estimation nationallicence V1 : volume of the central compartment nationallicence V2 : volume of the peripheral compartment nationallicence Vbev : volume of brain-extravascular compartment nationallicence Vbv : volume of brain-vascular compartment nationallicence Johnson Martin Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut Kozielska Magdalena Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut Pilla Reddy Venkatesh Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut Vermeulen An Advanced PK-PD Modeling and Simulation, Janssen Research and Development A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut Li Cheryl Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut, USA aut Grimwood Sarah Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut, USA aut de Greef Rik Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3), Merck Sharp & Dohme, Oss, The Netherlands aut Groothuis Geny Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut Danhof Meindert Division of Pharmacology, Leiden/Amsterdam Center For Drug Research, Leiden, The Netherlands aut Proost Johannes Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2490-2504 0724-8741 28:10<2490 2011 28 11095 https://doi.org/10.1007/s11095-011-0477-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0477-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Johnson Martin Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Kozielska Magdalena Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Pilla Reddy Venkatesh Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Vermeulen An Advanced PK-PD Modeling and Simulation, Janssen Research and Development A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut NATIONALLICENCE 700 1- Li Cheryl Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut, USA aut NATIONALLICENCE 700 1- Grimwood Sarah Worldwide Research & Development, Pfizer, Inc., Groton, Connecticut, USA aut NATIONALLICENCE 700 1- de Greef Rik Pharmacokinetics, Pharmacodynamics & Pharmacometrics (P3), Merck Sharp & Dohme, Oss, The Netherlands aut NATIONALLICENCE 700 1- Groothuis Geny Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut NATIONALLICENCE 700 1- Danhof Meindert Division of Pharmacology, Leiden/Amsterdam Center For Drug Research, Leiden, The Netherlands aut NATIONALLICENCE 700 1- Proost Johannes Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/10(2011-10-01), 2490-2504 0724-8741 28:10<2490 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer