DDMODEL00000273: Kovalenko_2016 PK model for dupilumab in atopic dermatitis patients and normals

  public model
Short description:
The best structural model was a two-compartment model with parallel linear and Michaelis–Menten elimination from the central compartment. Body weight was a significant covariate of the central volume. No gender effect was observed when controlling for weight. No differences between healthy volunteers and patients with atopic dermatitis (AD) were found.
Original code
  • Exploratory Population PK Analysis of Dupilumab, a Fully Human Monoclonal Antibody Against IL-4R?, in Atopic Dermatitis Patients and Normal Volunteers.
  • Kovalenko P, DiCioccio AT, Davis JD, Li M, Ardeleanu M, Graham N, Soltys R
  • CPT: Pharmacometrics & Systems Pharmacology, 11/2016, Volume 5, Issue 11, pages: 617-624
  • Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA.
  • An exploratory population pharmacokinetic model for functional dupilumab was developed. Data from healthy volunteers and patients with atopic dermatitis (AD) receiving intravenous or subcutaneous doses were integrated. The data included 197 participants (2,518 measurements of dupilumab in serum) from six phase I and II studies. The data were analyzed using stochastic approximation expectation-maximization and importance sampling methods. The best structural model was a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment. Estimated parameters were: central volume 2.74 L, elimination rate 0.0459 d-1 , central-to-peripheral rate 0.0652 d-1 , peripheral-to-central rate 0.129 d-1 , bioavailability 60.7%, maximal target-mediated elimination rate 0.968 mg/L/d, and Michaelis-Menten constant 0.01 mg/L. Body weight was a significant covariate of the central volume. No gender effect was observed when controlling for weight. No differences between healthy volunteers and patients with AD were found. The model adequately described dupilumab pharmacokinetics for intravenous and subcutaneous routes of administration.
Andre Jackson
Context of model development: Clinical end-point;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: The PK models was based on human data can be used to predict concentrations of functional dupilumab in future human studies, support regulatory responses, compare PK parameters of dupilumab to PK parameters of other monoclonal antibodies, support dose selection, test for weight, gender and disease as covariates, conduct allometric scaling, and develop a population PD model.;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Immunology;
Annotations are correct.
This model is not certified.
  • Model owner: Andre Jackson
  • Submitted: Dec 21, 2017 2:46:04 PM
  • Last Modified: Dec 21, 2017 2:46:04 PM
Revisions
  • Version: 8 public model Download this version
    • Submitted on: Dec 21, 2017 2:46:04 PM
    • Submitted by: Andre Jackson
    • With comment: Updated model annotations.
 
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