Pharmacodynamics-Mediated Drug Disposition (PDMDD) and Precursor Pool Lifespan Model for Single Dose of Romiplostim in Healthy Subjects

The objective of this study was to characterize the pharmacokinetics and pharmacodynamics (PK-PD) of romiplostim after single-dose administration in healthy subjects. The mean serum romiplostim concentrations (PK data) and mean platelet counts (PD data) collected from 32 subjects receiving a single intravenous (0.3, 1 and 10 μg/kg) or subcutaneous (0.1, 0.3, 1, and 2 μg/kg) dose were fitted simultaneously to a mechanistic PK-PD model based on pharmacodynamics-mediated drug disposition (PDMDD) and a precursor pool lifespan concept. The two-compartment PK model incorporated receptor-mediated endocytosis and linear mechanisms as parallel elimination pathways. The maximal concentration of receptors (assumed to be proportional to the platelet count), the equilibrium dissociation constant, and the first-order internalization rate constant for endocytosis of the drug-receptor complex were 0.022 fg/platelet, 0.131 ng/mL, and 0.173 h−1, respectively. Romiplostim concentration stimulates the production of platelet precursors via the Hill function, where the SC50 was 0.052 ng/mL and Smax was 11.2. The estimated precursor cell and platelet lifespans were 5.9 and 10.5 days, respectively. Model-based simulations revealed that the romiplostim exposure and the platelet response are both dependent on the dose administered and the baseline platelet counts. Also, weekly dosing produced a sustained PD response while dosing intervals ≥2 weeks resulted in fluctuating platelet counts. Thus, the mechanistic PK-PD model was suitable for describing the romiplostim PK-PD interplay (PDMDD), the dose-dependent platelet stimulation, and the lifespans of thrombopoietic cell populations.

[1]  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.

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

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

[4]  J. Pérez-Ruixo,et al.  Pharmacodynamic Analysis of Recombinant Human Erythropoietin Effect on Reticulocyte Production Rate and Age Distribution in Healthy Subjects , 2008, Clinical pharmacokinetics.

[5]  Gisela Schwab,et al.  Pharmacokinetic/Pharmacodynamic Modeling of Pegfilgrastim in Healthy Subjects , 2006, Journal of clinical pharmacology.

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

[7]  J. T. Sullivan,et al.  Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand , 2004, Clinical pharmacology and therapeutics.

[8]  Lewis B. Sheiner,et al.  Simultaneous vs. Sequential Analysis for Population PK/PD Data I: Best-Case Performance , 2003, Journal of Pharmacokinetics and Pharmacodynamics.

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

[10]  R. Ramakrishnan,et al.  Basic Pharmacodynamic Models for Agents That Alter Production of Natural Cells , 1999, Journal of Pharmacokinetics and Biopharmaceutics.

[11]  Hartmut Derendorf,et al.  Modeling of Pharmacokinetic/Pharmacodynamic (PK/PD) Relationships: Concepts and Perspectives , 1999, Pharmaceutical Research.

[12]  N. Holford Drug Concentration, Binding, and Effect In Vivo , 1984, Pharmaceutical Research.

[13]  Yong Ho Kim,et al.  Model Appropriateness and Population Pharmacokinetic Modeling , 2003, Journal of clinical pharmacology.

[14]  William J Jusko,et al.  Diversity of mechanism-based pharmacodynamic models. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[15]  C. Begley,et al.  Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. , 2002, Blood.

[16]  C. Begley,et al.  Development of pancytopenia with neutralizing antibodies to thrombopoietin after multicycle chemotherapy supported by megakaryocyte growth and development factor. , 2002, Blood.

[17]  Hannah M Linden,et al.  Thrombopoietin: a pan-hematopoietic cytokine. , 2002, Cytokine & growth factor reviews.

[18]  C. Yang,et al.  Thrombocytopenia caused by the development of antibodies to thrombopoietin. , 2001, Blood.

[19]  L. Harker,et al.  Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet function in healthy human volunteers. , 2000, Blood.

[20]  D. Kuter,et al.  Interaction of thrombopoietin with the platelet c‐mpl receptor in plasma: binding, internalization, stability and pharmacokinetics , 1999, British journal of haematology.

[21]  H. Avraham,et al.  Binding and regulation of thrombopoietin to human megakaryocytes , 1998, British journal of haematology.

[22]  J. Dempsey,et al.  Thrombopoietin and its receptor, c-mpl, are constitutively expressed by mouse liver endothelial cells: evidence of thrombopoietin as a growth factor for liver endothelial cells. , 1998, Blood.

[23]  P. Hass,et al.  Human platelets as a model for the binding and degradation of thrombopoietin. , 1997, Blood.

[24]  V. Broudy,et al.  Human platelets display high-affinity receptors for thrombopoietin. , 1997, Blood.

[25]  J. Erusalimsky,et al.  Megakaryocytopoiesis: The Megakaryocyte/Platelet Haemostatic Axis , 1997 .

[26]  W. Sheridan,et al.  Thrombopoiesis and Thrombopoietins Molecular, Cellular, Preclinical, and Clinical Biology , 1997 .

[27]  B. Chong,et al.  Localization and regulation of thrombopoietin mRNa expression in human kidney, liver, bone marrow, and spleen using in situ hybridization. , 1997, Blood.

[28]  K. Authi,et al.  Platelets and Their Factors , 1997, Handbook of Experimental Pharmacology.

[29]  R. Rosenberg,et al.  The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. , 1995, Blood.

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

[31]  R P STEPHENSON,et al.  A MODIFICATION OF RECEPTOR THEORY , 1997, British journal of pharmacology and chemotherapy.