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Pharmacokinetic and Pharmacodynamic Relationship of AMG 811, An Anti-IFN-γ IgG1 Monoclonal Antibody, in Patients with Systemic Lupus Erythematosus

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Abstract

Purpose

To investigate the relationships between AMG 811 exposure, concentration changes in serum IFN-γ, and IFN-γ-induced protein 10 (CXCL10), and to identify important contributions of baseline covariates to these relationships.

Methods

A mechanism based pharmacokinetic (PK)-pharmacodynamic (PD) model was developed. A target mediated disposition model was used to describe AMG 811 and target IFN-γ interaction. CXCL10 was predicted to be driven by estimated free IFN-γ levels.

Results

For an average systemic lupus erythematosus (SLE) subject, the linear clearance (CL) of AMG 811 was 0.176 L/day, and the central (Vc) and peripheral (Vp) volumes of distribution were 1.48 and 2.12 L, respectively. Body weight was found to correlate with CL, Vc, Vp, and inter compartment clearance (Q); and age was found to correlate with Vc. The relationship between estimated free serum IFN-γ concentration levels and serum CXCL10 in logarithmic scales was best described by a linear model with slope and intercept estimated to be 0.197 and -0.3, respectively.

Conclusions

The largest observed reduction of serum CXCL10 concentration was achieved at the highest AMG 811 dose tested (180 mg SC). This model enables simulations of AMG 811 PK-PD profiles under various dosing regimens to support future clinical studies.

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank all the patients, the investigators, and their medical, nursing, and laboratory staff who participated in the clinical studies included in the present analysis. These studies were sponsored by Amgen Inc., which was involved in the study design, data collection, analysis, interpretation, writing the manuscript, and the decision to submit the manuscript for publication. Ping Chen, Thuy Vu, Adimoolam Narayanan, Winnie Sohn, Jin Wang, Michael Boedigheimer, Andrew Welcher, Barbara Sullivan, David Martin, and Juan Jose Perez Ruixo are employees of Amgen Inc. and own stock in Amgen Inc. at the time this analysis was conducted. Peiming Ma is a former employee of Amgen Inc. The authors have no other conflict of interest to declare.

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Authors and Affiliations

  1. Pharmacokinetics and Drug Metabolism, Thousand Oaks, California, USA

    Ping Chen, Thuy Vu, Adimoolam Narayanan, Winnie Sohn, Jin Wang, Juan Jose Perez Ruixo & Peiming Ma

  2. Medical Sciences, Amgen Inc, One Amgen Center Dr, 91320, Thousand Oaks, California, USA

    Michael Boedigheimer, Andrew A. Welcher & Barbara Sullivan

  3. Medical Sciences, Amgen Inc, 1201 Amgen Court West, 98119, Seattle, Washington, USA

    David A. Martin

  4. Amgen Inc., MS 28-3-B, One Amgen Center Dr, 91320, Thousand Oaks, California, USA

    Ping Chen

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  1. Ping Chen
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Correspondence to Ping Chen.

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Chen, P., Vu, T., Narayanan, A. et al. Pharmacokinetic and Pharmacodynamic Relationship of AMG 811, An Anti-IFN-γ IgG1 Monoclonal Antibody, in Patients with Systemic Lupus Erythematosus. Pharm Res 32, 640–653 (2015). https://doi.org/10.1007/s11095-014-1492-2

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  • DOI: https://doi.org/10.1007/s11095-014-1492-2

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