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Population Pharmacokinetics of Daclizumab High-Yield Process in Healthy Volunteers and Subjects with Multiple Sclerosis: Analysis of Phase I–III Clinical Trials

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Abstract

Background and Objectives

Daclizumab high-yield process (HYP) is a humanized IgG1 monoclonal antibody that binds to the α-subunit (CD25) of the interleukin-2 receptor. The present work characterized the population pharmacokinetics of daclizumab HYP in healthy volunteers (HVs) and subjects with relapsing–remitting multiple sclerosis (RRMS) and evaluated the effects of covariates on daclizumab HYP exposure.

Methods

Measurable serum concentrations (n = 17,139) from 1670 subjects in seven clinical studies (three phase I, one immunogenicity, one phase II with extension, and one phase III) were included in this pharmacokinetic analysis using non-linear mixed–effects modeling. The three phase I studies evaluated single or multiple doses that ranged from 50 to 400 mg with either intravenous or subcutaneous (SC) administration in HVs (n = 71). The phase II with extension studies evaluated doses of 150 or 300 mg SC every 4 weeks (n = 567), and the immunogenicity (n = 113) and the phase III (n = 919) studies evaluated 150 mg SC every 4 weeks, all in RRMS patients.

Results

A two-compartment model with first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Clearance (CL) was 0.212 L/day and the central volume of distribution was 3.92 L, scaled by [body weight (kg)/68] with exponents of 0.87 and 1.12, respectively. The peripheral volume of distribution was 2.42 L. Absorption lag time, mean absorption time, and absolute bioavailability (100–300 mg SC) were 1.61 h, 7.2 days, and 88 %, respectively. The daclizumab HYP terminal half-life was 21 days. Baseline CD25, age, and sex did not influence daclizumab HYP pharmacokinetics. Body weight explained 37 and 27 % of the inter-individual variability for CL and central volume of distribution, respectively. Neutralizing antibody (NAb)-positive status (included as a time-varying covariate) increased daclizumab HYP CL by 19 %.

Conclusions

Consistent with previous findings in HVs, this analysis including extensive data from RRMS patients demonstrates that daclizumab HYP is characterized by slow CL, linear pharmacokinetics at doses above 100 mg, and high SC bioavailability. The pharmacokinetics of daclizumab HYP were not influenced by age (range 18–66 years), the sex of adult subjects, or the baseline CD4+CD25+ T cells (target level). The impact of covariates (body weight, NAb) on daclizumab HYP pharmacokinetics is unlikely to be clinically relevant.

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Acknowledgments

We would like to acknowledge Wei Liu and Vineeth Kurnala of Biogen for dataset preparation.

Author information

Author notes

  1. Lei Diao

    Present address: Janssen China R&D, Shanghai, China

  2. Jonathan Q. Tran

    Present address: Receptos, a wholly owned subsidiary of Celgene, San Diego, CA, USA

Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, Biogen, Cambridge, MA, USA

    Lei Diao, Yaming Hang, Ivan Nestorov & Jonathan Q. Tran

  2. Clinical Pharmacology and Pharmacometrics, Abbvie, North Chicago, IL, USA

    Ahmed A. Othman

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

    Ahmed A. Othman

Authors
  1. Lei Diao
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  2. Yaming Hang
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  4. Ivan Nestorov
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Corresponding author

Correspondence to Lei Diao.

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Disclosures

The phase I studies that contributed data to this analysis were funded by Facet, which was acquired by AbbVie. All other non-phase I studies presented in this manuscript were funded by Biogen and AbbVie. All authors contributed to the analysis and interpretation of the data, writing, reviewing and approving the manuscript. Dr. Hang and Dr. Nestorov are employees and shareholders of Biogen. Dr. Diao and Dr. Tran are previous employees of Biogen. Dr. Othman is an employee and shareholder of Abbvie. The authors declare no other conflict of interests.

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Diao, L., Hang, Y., Othman, A.A. et al. Population Pharmacokinetics of Daclizumab High-Yield Process in Healthy Volunteers and Subjects with Multiple Sclerosis: Analysis of Phase I–III Clinical Trials. Clin Pharmacokinet 55, 943–955 (2016). https://doi.org/10.1007/s40262-016-0366-7

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  • DOI: https://doi.org/10.1007/s40262-016-0366-7

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