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Pharmacokinetics of Subcutaneous IgPro20 in Patients with Primary Immunodeficiency

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Abstract

Background and Objectives: Immunoglobulin replacement is a standard therapy for patients with primary immunodeficiencies. Subcutaneous administration of immunoglobulin offers more constant IgG levels than intravenous administration and simplifies administration for some patients. Use of L-proline as an excipient contributes to the stability of highly concentrated IgG preparations. The aims of the present study were to evaluate the pharmacokinetics of IgPro20 (Hizentra®), a new 20% subcutaneous IgG solution, and compare the area under the serum concentration-time curve (AUC) with that of a similar intravenous 10% IgG solution (IgPro10; Privigen®). At the request of the US FDA, an algorithm for determining IgG trough level ratios (TLRs) was developed in order to provide physicians with a practical tool for monitoring doses during steady-state IgPro20 therapy.

Methods: This was a prospective, open-label, multicentre, single-arm, phase III clinical trial conducted in the US. The study was performed in a primary-care setting. Eligible patients were males or females aged 6–75 years with a primary immunodeficiency (common variable immunodeficiency or X-linked agamma-globulinaemia) who had received regular treatment with IgPro10 for at least 3 months prior to entering this study and had achieved serum trough concentration (Ctrough) values ≥5 g/L.

IgPro20 was administered subcutaneously once weekly at initial doses equivalent to 130% of patients’ previous doses, based on the results obtained in a Vivaglobin® study and due to an FDA request. After run-in, each patient’s dose was adjusted to achieve an AUC comparable to that achieved with IgPro10 administered intravenously.

Results: Eighteen patients completed the study. Mean IgPro20 : IgPro10 dose ratio (dose adjustment coefficient) was 1.53 (range 1.26–1.87). The resulting mean AUCs were 105.6g · day/L for IgPro20 versus 103.2g · day/L for IgPro10 (geometric mean ratio 1.002; lower one-sided 95% confidence limit [CL] 0.951). Thus, the primary endpoint of the study was met, as this result exceeded the pre-specified criterion of the lower one-sided 95% CL of ≥0.8 for non-inferiority. At these AUCs, which were considered equivalent, the mean IgPro20 : IgPro10 TLR, determined by the developed algorithm, was 1.29 (range 1.18–1.73). Titres of specific antibodies tested were well above respective product specifications, suggesting that protection against infection would be effective.

Conclusion: Steady-state AUCs with subcutaneous IgPro20 and intravenous IgPro10 were equivalent. Mean dose adjustment coefficient and mean TLR can be used for initial dose conversion without risk of under-protection but vary too widely to be considered measures of equivalence.

Trial registration number (clinicaltrials.gov): NCT00419341

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Acknowledgements

This study was supported by CSL Behring LLC (King of Prussia, PA, USA), including design and conduct of the study, and collection, management, analysis and interpretation of the data. The opinions expressed in this paper are those of the authors.

The authors thank Dr Christian Peters for his help during the conduct of the study, and Dr Andrea Sebald and Dr Martin Bexon for critical review of the manuscript. The assistance of Fritz Schindel, Corinna Miede and Cordula Massion (Accovion GmbH) for the statistical analyses is gratefully appreciated. We also acknowledge the editorial assistance of Phocus Services Ltd, supported by CSL Behring.

Richard L. Wasserman has received clinical trial support from CSL Behring, Baxter Healthcare, NABI and Talecris, and consultant fees from CSL Behring and Baxter Healthcare. Isaac Melamed has received honoraria from Baxter Healthcare. Robert P. Nelson Jr has no potential conflicts of interest that are directly relevant to the content of this study. Alan P. Knutsen has received clinical trial support from Genentech, Novartis and CSL Behring. Mary Beth Fasano has received clinical trial support from CSL Behring, Shire and Lev Pharmaceuticals. Mark R. Stein has received consultant fees from CSL Behring and Baxter and clinical trial support from CSL Behring, Baxter, Talecris, Merck, AstraZeneca, Novartis, Schering Plough and GlaxoSmithKline. Mikhail A. Rojavin is an employee of CSL Behring and has no other potential conflicts of interest that are directly relevant to the content of this study. Joseph A. Church has received research grants from Baxter Healthcare, CSL Behring and Pfizer, and has performed consultation services for Baxter Healthcare.

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Authors and Affiliations

  1. DallasAllergyImmunology and Medical City Children’s Hospital, 7777 Forest Lane Suite B-332, Dallas, Texas, 75230, USA

    Richard L. Wasserman

  2. IMMUNOe International Research Centers, Centennial, Colorado, USA

    Isaac Melamed

  3. Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA

    Robert P. Nelson Jr

  4. Pediatric Research Institute, St Louis University Health Sciences Center, St Louis, Missouri, USA

    Alan P. Knutsen

  5. University of Iowa Hospitals & Clinics, Iowa City, Iowa, USA

    Mary Beth Fasano

  6. Allergy Associates of the Palm Beaches, North Palm Beach, Florida, USA

    Mark R. Stein

  7. CSL Behring LLC, King of Prussia, Pennsylvania, USA

    Mikhail A. Rojavin

  8. Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

    Joseph A. Church

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  1. Richard L. Wasserman
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Correspondence to Richard L. Wasserman.

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Wasserman, R.L., Melamed, I., Nelson, R.P. et al. Pharmacokinetics of Subcutaneous IgPro20 in Patients with Primary Immunodeficiency. Clin Pharmacokinet 50, 405–414 (2011). https://doi.org/10.2165/11587030-000000000-00000

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