DDMODEL00000076: Yan_2011_EPO_biosimilar_PKPD

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Short description:
A population model based on pharmacodynamics- mediated drug disposition and cell maturation processes was used to characterize the PK/PD data for epoetin alfa HEXAL/Binocrit (HX575) and a comparator epoetin alfa
Original code
  • Population pharmacokinetic and pharmacodynamic model-based comparability assessment of a recombinant human Epoetin Alfa and the Biosimilar HX575.
  • Lowe PJ, Berghout A, Balser S, Krzyzanski W, Yan X, Fink M
  • Journal of clinical pharmacology, 11/2012, Volume 52, Issue 11, pages: 1624-1644
  • (1) Department of Pharmaceutical Sciences, State University of New York at Buffalo, (2) Modeling and Simulation, Novartis Pharma AG (3) Sandoz Biopharmaceuticals
  • The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic (PK/PD) model and assess the comparability between epoetin alfa HEXAL/Binocrit (HX575) and a comparator epoetin alfa by a model-based approach. PK/PD data-including serum drug concentrations, reticulocyte counts, red blood cells, and hemoglobin levels-were obtained from 2 clinical studies. In sum, 149 healthy men received multiple intravenous or subcutaneous doses of HX575 (100 IU/kg) and the comparator 3 times a week for 4 weeks. A population model based on pharmacodynamics-mediated drug disposition and cell maturation processes was used to characterize the PK/PD data for the 2 drugs. Simulations showed that due to target amount changes, total clearance may increase up to 2.4-fold as compared with the baseline. Further simulations suggested that once-weekly and thrice-weekly subcutaneous dosing regimens would result in similar efficacy. The findings from the model-based analysis were consistent with previous results using the standard noncompartmental approach demonstrating PK/PD comparability between HX575 and comparator. However, due to complexity of the PK/PD model, control of random effects was not straightforward. Whereas population PK/PD model-based analyses are suited for studying complex biological systems, such models have their limitations (statistical), and their comparability results should be interpreted carefully.
Celine Sarr
Context of model development: Similarity Assessment (MVC, Biosimilar, Formulation);
Long technical model description: The absorption of the drug after SC administration was described by a sequential absorption model. The exogenous EPO was infused to a depot compartment (A1) during a period of time (D), then absorbed into the central compartment (A2) by a first-order absorption rate constant (ka) with bioavailability (F). The endogenous EPO was produced through a zero-order process (KEPO). The EPO in the central compartments can distribute into the peripheral compartment (A3) via distribution rate constants k23 and k32. A target-mediated drug disposition (TMDD) model was applied to describe the disposition of EPO in the central compartment (A2).EPO can also be removed from the central compartment by a first-order elimination process (CL). To characterize the time course of RETs, RBCs, and HGB, we applied a series of transit compartments mimicking the various developmental stages of erythroid cells. The Michaelis-Menten (M-M) approximation of the TMDD model was used in the final model, although the full TMDD model and the rapid binding approximation were also tested.;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Aims of this analysis was to develop an integrated pharmacokinetic and pharmacodynamic (PK/PD) model and assess the comparability between epoetin alfa HEXAL/Binocrit;
Modelling task in scope: estimation;
Nature of research: Life cycle management;
Therapeutic/disease area: Haematology;
Annotations are correct.
This model is not certified.
  • Model owner: Celine Sarr
  • Submitted: Dec 9, 2015 9:58:13 AM
  • Last Modified: May 20, 2016 5:40:57 PM
Revisions
  • Version: 19 public model Download this version
    • Submitted on: May 20, 2016 5:40:57 PM
    • Submitted by: Celine Sarr
    • With comment: Updated model annotations.
  • Version: 4 public model Download this version
    • Submitted on: Dec 9, 2015 9:58:13 AM
    • Submitted by: Celine Sarr
    • With comment: Edited model metadata online.
 
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