A Tutorial on Target-Mediated Drug Disposition (TMDD) Models

Target‐mediated drug disposition (TMDD) is the phenomenon in which a drug binds with high affinity to its pharmacological target site (such as a receptor) to such an extent that this affects its pharmacokinetic characteristics. The aim of this Tutorial is to provide an introductory guide to the mathematical aspects of TMDD models for pharmaceutical researchers. Examples of Berkeley Madonna code for some models discussed in this Tutorial are provided in the Supplementary Materials.

[1]  S. Yamazaki,et al.  Application of Target-Mediated Drug Disposition Model to Small Molecule Heat Shock Protein 90 Inhibitors , 2013, Drug Metabolism and Disposition.

[2]  Anson K. Abraham,et al.  Type I Interferon Receptor is a Primary Regulator of Target-Mediated Drug Disposition of Interferon-β in Mice , 2010, Journal of Pharmacology and Experimental Therapeutics.

[3]  D. Mager,et al.  Numerical validation and properties of a rapid binding approximation of a target-mediated drug disposition pharmacokinetic model , 2009, Journal of Pharmacokinetics and Pharmacodynamics.

[4]  D. Mager,et al.  Quasi-Equilibrium Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition , 2005, Pharmaceutical Research.

[5]  J. Treadway,et al.  The Application of Target Information and Preclinical Pharmacokinetic/Pharmacodynamic Modeling in Predicting Clinical Doses of a Dickkopf-1 Antibody for Osteoporosis , 2010, Journal of Pharmacology and Experimental Therapeutics.

[6]  Wojciech Krzyzanski,et al.  Population Pharmacokinetic Modelling of Filgrastim in Healthy Adults following Intravenous and Subcutaneous Administrations , 2009, Clinical pharmacokinetics.

[7]  Liang Zhao,et al.  Application of pharmacokinetics-pharmacodynamics/clinical response modeling and simulation for biologics drug development. , 2012, Journal of pharmaceutical sciences.

[8]  Leonid Gibiansky,et al.  Approximations of the target-mediated drug disposition model and identifiability of model parameters , 2008, Journal of Pharmacokinetics and Pharmacodynamics.

[9]  J. Balthasar,et al.  Application of pharmacokinetic-pharmacodynamic modeling to predict the kinetic and dynamic effects of anti-methotrexate antibodies in mice. , 2003, Journal of pharmaceutical sciences.

[10]  D. Mager,et al.  Mechanisms of Subcutaneous Absorption of Rituximab in Rats , 2013, Drug Metabolism and Disposition.

[11]  E. Kraynov,et al.  A Model-Based Approach to Predicting the Human Pharmacokinetics of a Monoclonal Antibody Exhibiting Target-Mediated Drug Disposition , 2012, Journal of Pharmacology and Experimental Therapeutics.

[12]  L. Gibiansky,et al.  Linking interleukin-6 receptor blockade with tocilizumab and its hematological effects using a modeling approach , 2011, Journal of Pharmacokinetics and Pharmacodynamics.

[13]  Rosario Garrido,et al.  Target-mediated drug disposition and prolonged liver accumulation of a novel humanized anti-CD81 monoclonal antibody in cynomolgus monkeys , 2013, mAbs.

[14]  J. Pérez-Ruixo,et al.  Pharmacokinetic and Pharmacodynamic Modeling of Pegylated Thrombopoietin Mimetic Peptide (PEG‐TPOm) After Single Intravenous Dose Administration in Healthy Subjects , 2009, Journal of clinical pharmacology.

[15]  Donald E Mager,et al.  Integrated Cellular Bone Homeostasis Model for Denosumab Pharmacodynamics in Multiple Myeloma Patients , 2008, Journal of Pharmacology and Experimental Therapeutics.

[16]  Yow-Ming C Wang,et al.  Pharmacodynamics-Mediated Drug Disposition (PDMDD) and Precursor Pool Lifespan Model for Single Dose of Romiplostim in Healthy Subjects , 2010, The AAPS Journal.

[17]  W. Huisinga,et al.  Predicting the F(ab)-mediated effect of monoclonal antibodies in vivo by combining cell-level kinetic and pharmacokinetic modelling , 2012, Journal of Pharmacokinetics and Pharmacodynamics.

[18]  G. Meno-Tetang,et al.  On the prediction of the human response: a recycled mechanistic pharmacokinetic/pharmacodynamic approach. , 2005, Basic & clinical pharmacology & toxicology.

[19]  H. Grimm Gaining insights into the consequences of target-mediated drug disposition of monoclonal antibodies using quasi-steady-state approximations , 2009, Journal of Pharmacokinetics and Pharmacodynamics.

[20]  Leonid Kagan,et al.  Interspecies Scaling of Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Type I Interferons , 2010, Pharmaceutical Research.

[21]  H. Gram,et al.  Pharmacokinetic and Pharmacodynamic Properties of Canakinumab, a Human Anti-Interleukin-1β Monoclonal Antibody , 2012, Clinical Pharmacokinetics.

[22]  W. Jusko,et al.  Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki Rats , 2011, Journal of Pharmacology and Experimental Therapeutics.

[23]  Yow-Ming C Wang,et al.  Pharmacokinetics of Anti-hepcidin Monoclonal Antibody Ab 12B9m and Hepcidin in Cynomolgus Monkeys , 2010, The AAPS Journal.

[24]  P. McNamara,et al.  Effect of plasma protein and tissue binding on the time course of drug concentration in plasma , 1979, Journal of Pharmacokinetics and Biopharmaceutics.

[25]  S. Ait-Oudhia,et al.  Simultaneous Pharmacokinetics/Pharmacodynamics Modeling of Recombinant Human Erythropoietin upon Multiple Intravenous Dosing in Rats , 2010, Journal of Pharmacology and Experimental Therapeutics.

[26]  J. P. Perez Ruixo,et al.  The Utility of Modeling and Simulation Approaches to Evaluate Immunogenicity Effect on the Therapeutic Protein Pharmacokinetics , 2012, The AAPS Journal.

[27]  A. Krause,et al.  Visualization and Communication of Pharmacometric Models With Berkeley Madonna , 2014, CPT: pharmacometrics & systems pharmacology.

[28]  B. Agoram,et al.  Use of pharmacokinetic/ pharmacodynamic modelling for starting dose selection in first-in-human trials of high-risk biologics. , 2009, British journal of clinical pharmacology.

[29]  PJ Lowe,et al.  Applying Physiological and Biochemical Concepts to Optimize Biological Drug Development , 2010, Clinical pharmacology and therapeutics.

[30]  Iain Gardner,et al.  Pharmacokinetics, Pharmacodynamics and Physiologically-Based Pharmacokinetic Modelling of Monoclonal Antibodies , 2013, Clinical Pharmacokinetics.

[31]  D. Mager,et al.  Simultaneous Modeling of Abciximab Plasma Concentrations and ex Vivo Pharmacodynamics in Patients Undergoing Coronary Angioplasty , 2003, Journal of Pharmacology and Experimental Therapeutics.

[32]  J. Sims,et al.  On setting the first dose in man: quantitating biotherapeutic drug-target binding through pharmacokinetic and pharmacodynamic models. , 2010, Basic & clinical pharmacology & toxicology.

[33]  W. Jusko,et al.  Target-mediated pharmacokinetic and pharmacodynamic model of recombinant human erythropoietin (rHuEPO) , 2007, Journal of Pharmacokinetics and Pharmacodynamics.

[34]  J. Pérez-Ruixo,et al.  Population Pharmacokinetic Analysis of Denosumab in Patients with Bone Metastases from Solid Tumours , 2012, Clinical Pharmacokinetics.

[35]  F. Mentré,et al.  A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects. , 2011, British journal of clinical pharmacology.

[36]  Donald E. Mager,et al.  Receptor-Mediated Pharmacokinetic/Pharmacodynamic Model of Interferon-β 1a in Humans , 2002, Pharmaceutical Research.

[37]  Steven W. Martin,et al.  The role of mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modelling in translational research of biologics. , 2007, Drug discovery today.

[38]  L. Gibiansky,et al.  Target-mediated drug disposition model for drugs that bind to more than one target , 2010, Journal of Pharmacokinetics and Pharmacodynamics.

[39]  Y. Vugmeyster,et al.  Agonistic TAM-163 antibody targeting tyrosine kinase receptor-B , 2013, mAbs.

[40]  M. Boedigheimer,et al.  Pharmacokinetic and Pharmacodynamic Relationship of AMG 811, An Anti-IFN-γ IgG1 Monoclonal Antibody, in Patients with Systemic Lupus Erythematosus , 2014, Pharmaceutical Research.

[41]  D. Mager,et al.  Selection between Michaelis–Menten and target-mediated drug disposition pharmacokinetic models , 2010, Journal of Pharmacokinetics and Pharmacodynamics.

[42]  G Levy,et al.  Pharmacologic target‐mediated drug disposition , 1994, Clinical pharmacology and therapeutics.

[43]  Philip J. Aston,et al.  A mathematical analysis of rebound in a target-mediated drug disposition model: I.Without feedback , 2014, Journal of mathematical biology.

[44]  W. Krzyzanski,et al.  Pharmacokinetic model of target-mediated disposition of thrombopoietin , 2004, AAPS PharmSci.

[45]  L. Peletier,et al.  Dynamics of target-mediated drug disposition. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[46]  Donald E Mager,et al.  Pharmacokinetics of Recombinant Human Leukemia Inhibitory Factor in Sheep , 2004, Journal of Pharmacology and Experimental Therapeutics.

[47]  Terrence P. Kenakin,et al.  A Pharmacology Primer: Theory, Application and Methods , 2004 .

[48]  P. H. van der Graaf,et al.  A mathematical analysis of rebound in a target-mediated drug disposition model: II. With feedback , 2014, Journal of mathematical biology.

[49]  P. Lowe,et al.  From Target Selection to the Minimum Acceptable Biological Effect Level for Human Study: Use of Mechanism-based PK/PD Modeling to Design Safe and Efficacious Biologics , 2011, The AAPS Journal.

[50]  Leonid Kagan,et al.  Subcutaneous Absorption of Monoclonal Antibodies: Role of Dose, Site of Injection, and Injection Volume on Rituximab Pharmacokinetics in Rats , 2011, Pharmaceutical Research.

[51]  J. Pérez-Ruixo,et al.  Population Pharmacokinetics Meta-Analysis of Recombinant Human Erythropoietin in Healthy Subjects , 2007, Clinical pharmacokinetics.

[52]  P. Marathe,et al.  Factors Influencing Magnitude and Duration of Target Inhibition Following Antibody Therapy: Implications in Drug Discovery and Development , 2013, The AAPS Journal.

[53]  W. Huisinga,et al.  Nonlinear pharmacokinetics of therapeutic proteins resulting from receptor mediated endocytosis , 2009, Journal of Pharmacokinetics and Pharmacodynamics.

[54]  Wojciech Krzyzanski,et al.  Partial derivative—Based sensitivity analysis of models describing target-mediated drug disposition , 2007, The AAPS Journal.

[55]  T. Tozer,et al.  Effect of saturable binding on the pharmacokinetics of drugs: a simulation , 1980, The Journal of pharmacy and pharmacology.

[56]  U. Jaehde,et al.  Impact of Target‐Mediated Drug Disposition on Linagliptin Pharmacokinetics and DPP‐4 Inhibition in Type 2 Diabetic Patients , 2010, Journal of clinical pharmacology.

[57]  T. Prueksaritanont,et al.  Theoretical Analysis of Interplay of Therapeutic Protein Drug and Circulating Soluble Target: Temporal Profiles of ‘Free’ and ‘Total’ Drug and Target , 2011, Pharmaceutical Research.

[58]  L. Vaickus,et al.  Pharmacokinetics/Pharmacodynamics of Nondepleting Anti-CD4 Monoclonal Antibody (TRX1) in Healthy Human Volunteers , 2006, Pharmaceutical Research.

[59]  L. Gibiansky,et al.  Population PK and IgE Pharmacodynamic Analysis of a Fully Human Monoclonal Antibody Against IL4 Receptor , 2011, Pharmaceutical Research.

[60]  Peiming Ma Theoretical Considerations of Target-Mediated Drug Disposition Models: Simplifications and Approximations , 2011, Pharmaceutical Research.

[61]  John G. Wagner,et al.  Biopharmaceutics and Relevant Pharmacokinetics , 1971 .

[62]  Brian H Annex,et al.  A target‐mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans , 2002, Clinical pharmacology and therapeutics.

[63]  Leonid Kagan,et al.  Pharmacokinetic Modeling of the Subcutaneous Absorption of Therapeutic Proteins , 2014, Drug Metabolism and Disposition.

[64]  Zvia Agur,et al.  Targeted Drug Delivery by Gemtuzumab Ozogamicin: Mechanism-Based Mathematical Model for Treatment Strategy Improvement and Therapy Individualization , 2011, PloS one.

[65]  W. Jusko,et al.  Mechanism-based population pharmacokinetic modelling in diabetes: vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV. , 2012, British journal of clinical pharmacology.

[66]  W. Krzyzanski,et al.  Methods of solving rapid binding target-mediated drug disposition model for two drugs competing for the same receptor , 2012, Journal of Pharmacokinetics and Pharmacodynamics.

[67]  L. Gibiansky,et al.  Target-mediated drug disposition model: relationships with indirect response models and application to population PK–PD analysis , 2009, Journal of Pharmacokinetics and Pharmacodynamics.

[68]  Johan Gabrielsson,et al.  Dynamics of target-mediated drug disposition: characteristic profiles and parameter identification , 2012, Journal of Pharmacokinetics and Pharmacodynamics.

[69]  W. Jusko,et al.  Target-Mediated Pharmacokinetic and Pharmacodynamic Model of Exendin-4 in Rats, Monkeys, and Humans , 2012, Drug Metabolism and Disposition.

[70]  W. Jusko,et al.  Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Interferon-β1a in Monkeys , 2003, Journal of Pharmacology and Experimental Therapeutics.

[71]  M. Fink,et al.  Population Pharmacokinetic and Pharmacodynamic Model‐Based Comparability Assessment of a Recombinant Human Epoetin Alfa and the Biosimilar HX575 , 2012, Journal of clinical pharmacology.

[72]  Y. Sugiyama,et al.  Receptor-Mediated Transport of Peptide Hormones and Its Importance in the Overall Hormone Disposition in the Body , 1989, Pharmaceutical Research.

[73]  Gianne Derks,et al.  Mathematical analysis of the pharmacokinetic-pharmacodynamic (PKPD) behaviour of monoclonal antibodies: predicting in vivo potency. , 2011, Journal of theoretical biology.

[74]  Donald E. Mager,et al.  General Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition , 2001, Journal of Pharmacokinetics and Pharmacodynamics.

[75]  D. Mager,et al.  Interspecies Modeling and Prediction of Human Exenatide Pharmacokinetics , 2013, Pharmaceutical Research.

[76]  Wojciech Krzyzanski,et al.  Pharmacokinetics and pharmacodynamics of erythropoietin receptor in healthy volunteers , 2008, Naunyn-Schmiedeberg's Archives of Pharmacology.

[77]  R. Hansen,et al.  Properties of a general PK/PD model of antibody-ligand interactions for therapeutic antibodies that bind to soluble endogenous targets , 2010, mAbs.

[78]  William J. Jusko,et al.  Survey of monoclonal antibody disposition in man utilizing a minimal physiologically-based pharmacokinetic model , 2014, Journal of Pharmacokinetics and Pharmacodynamics.

[79]  D. Mager Target-mediated drug disposition and dynamics. , 2006, Biochemical pharmacology.

[80]  I. Mahmood Pharmacokinetic allometric scaling of antibodies: application to the first-in-human dose estimation. , 2009, Journal of pharmaceutical sciences.