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Blockade of the High-Affinity Interleukin-2 Receptors with Daclizumab High-Yield Process: Pharmacokinetic/Pharmacodynamic Analysis of Single- and Multiple-Dose Phase I Trials

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Abstract

Background and Objective

Daclizumab high-yield process (DAC HYP) is a humanized monoclonal antibody that selectively blocks the α-subunit (CD25) of the high-affinity interleukin-2 receptors, and has shown robust efficacy as a treatment for multiple sclerosis (MS). This work quantitatively characterized the relationship between DAC HYP serum concentrations and saturation of CD25 expressed on antigen-rich target T cells in blood.

Methods

Serial pharmacokinetic and 968 CD25 measurements from three double-blind, randomized, placebo-controlled, phase I studies of DAC HYP (50–300 mg subcutaneous and 200–400 mg intravenous doses or placebo) in healthy volunteers (n = 95) were analyzed using nonlinear mixed-effects modeling. CD25 occupancy was determined using flow cytometry and a fluorescently-labeled DAC HYP-competing antibody.

Results

CD25 occupancy was described using a direct inhibitory sigmoidal maximum effect (E max) model (where DAC HYP fully inhibited CD25 labeling with competing antibody). Two IC50 (serum concentration corresponding to 50 % of maximal inhibition) parameters were used to describe rapid CD25 saturation at initiation of dosing and apparently slower desaturation during DAC HYP washout. Parameter estimates (95 % bootstrap confidence intervals) were: baseline CD25 labeling, 47 % (45–48); DAC HYP IC50(saturation), 0.023 µg/mL (0.005–0.073); IC50(desaturation) 0.86 µg/mL (0.74–0.98); Hill coefficient 5.6 (4.3–6.8).

Conclusions

Based on the developed model, the 150 mg monthly subcutaneous regimen of DAC HYP in subjects with MS is predicted to saturate CD25 on target effector T cells within a few hours of dosing and maintain CD25 saturation during the entire dosing interval. Free CD25 levels return to baseline within 4–6 months of the last DAC HYP dose.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, AbbVie, 1 North Waukegan Road, North Chicago, IL, USA

    Mukul Minocha & Ahmed A. Othman

  2. Clinical Pharmacology, Biogen, Cambridge, MA, USA

    Jonathan Q. Tran

  3. AbbVie Biotherapeutics, Redwood City, CA, USA

    James P. Sheridan

  4. Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Ahmed A. Othman

Authors
  1. Mukul Minocha
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  2. Jonathan Q. Tran
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  3. James P. Sheridan
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  4. Ahmed A. Othman
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Corresponding author

Correspondence to Ahmed A. Othman.

Ethics declarations

The studies that contributed data to this analysis were funded by Facet, which has been acquired by AbbVie. The authors were responsible for analysis and interpretation of the data, and writing and reviewing the manuscript. AbbVie and Biogen reviewed and approved the publication. Drs. Minocha, Sheridan, and Othman are employees and shareholders of AbbVie, and Dr. Tran is an employee and shareholder of Biogen. DAC HYP is currently under development by AbbVie and Biogen for the treatment of MS. The authors declare no other relationships or activities that could appear to have influenced the submitted work.

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Minocha, M., Tran, J.Q., Sheridan, J.P. et al. Blockade of the High-Affinity Interleukin-2 Receptors with Daclizumab High-Yield Process: Pharmacokinetic/Pharmacodynamic Analysis of Single- and Multiple-Dose Phase I Trials. Clin Pharmacokinet 55, 121–130 (2016). https://doi.org/10.1007/s40262-015-0305-z

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  • DOI: https://doi.org/10.1007/s40262-015-0305-z

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