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Population PK and IgE Pharmacodynamic Analysis of a Fully Human Monoclonal Antibody Against IL4 Receptor

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ABSTRACT

Purpose

For AMG 317, a fully human monoclonal antibody to interleukin receptor IL-4Rα, we developed a population pharmacokinetic (PK) model by fitting data from four early phase clinical trials of intravenous and subcutaneous (SC) routes simultaneously, investigated important PK covariates, and explored the relationship between exposure and IgE response.

Methods

Data for 294 subjects and 2183 AMG 317 plasma concentrations from three Phase 1 and 1 Phase 2 studies were analyzed by nonlinear mixed effects modeling using first-order conditional estimation with interaction. The relationship of IgE response with post hoc estimates of exposure generated from the final PK model was explored based on data from asthmatic patients.

Results

The best structural model was a two-compartment quasi-steady-state target-mediated drug disposition model with linear and non-linear clearances. For a typical 80-kg, 40-year subject, linear clearance was 35.0 mL/hr, central and peripheral volumes of distribution were 1.78 and 5.03 L, respectively, and SC bioavailability was 24.3%. Body weight was an important covariate on linear clearance and central volume; age influenced absorption rate. A significant treatment effect was observable between the cumulative AUC and IgE response measured.

Conclusion

The population PK model adequately described AMG 317 PK from IV and SC routes over a 60-fold range of doses with two dosing strengths across multiple studies covering healthy volunteers and patients with mild to severe asthma. IgE response across a range of doses and over the sampling time points was found to be related to cumulative AMG 317 exposure.

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Authors and Affiliations

  1. Department of Pharmacokinetics and Metabolism, Amgen Inc., Thousand Oaks, California, 91320, USA

    Tarundeep Kakkar, Thuy Vu, Adimoolam Narayanan, Alex Colbert & Peiming Ma

  2. Rainbow Pharma Consulting, Pte. Ltd., Singapore, Singapore

    Cynthia Sung

  3. QuantPharm LLC, North Potomac, Maryland, USA

    Leonid Gibiansky

  4. Department of General Medicine & Inflammation, Amgen Inc., Thousand Oaks, California, 91320, USA

    Shao-Lee Lin

  5. Department of Early Development, Amgen Inc., Thousand Oaks, California, 91320, USA

    Michael Vincent & Christopher Banfield

  6. Department of Clinical Immunology & BSM, Amgen Inc., Thousand Oaks, California, 91320, USA

    Sarah Hoofring & Marta Starcevic

Authors
  1. Tarundeep Kakkar
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  2. Cynthia Sung
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  4. Thuy Vu
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  10. Sarah Hoofring
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Corresponding author

Correspondence to Tarundeep Kakkar.

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Fig S1

Goodness of Fit Plots for PK model validation. Predictions for study D using model developed from other 3 studies. (left) Observed AMG 317 concentrations (ng/mL) vs. predicted concentrations; the solid grey line is the line of unity and the red solid and dotted lines are the lines of trend and linear regression, respectively. (right) Residuals vs. time; the grey line is the line of zero residuals, and the red line represents the trend of all points. (DOCX 202 kb)

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Kakkar, T., Sung, C., Gibiansky, L. et al. Population PK and IgE Pharmacodynamic Analysis of a Fully Human Monoclonal Antibody Against IL4 Receptor. Pharm Res 28, 2530–2542 (2011). https://doi.org/10.1007/s11095-011-0481-y

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  • DOI: https://doi.org/10.1007/s11095-011-0481-y

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