Pharmacokinetics of subcutaneous igpro20 in patients with primary immunodeficiency

Richard L. Wasserman, Isaac Melamed, Robert P. Nelson, Alan P. Knutsen, Mary Beth Fasano, Mark R. Stein, Mikhail A. Rojavin, Joseph A. Church

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 agammaglobulinaemia) 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 ‡5g/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 runin, 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 105.6 g®day/L for IgPro20 versus 103.2 ®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 underprotection but vary too widely to be considered measures of equivalence.

Original languageEnglish (US)
Pages (from-to)405-414
Number of pages10
JournalClinical Pharmacokinetics
Volume50
Issue number6
DOIs
StatePublished - May 16 2011

Fingerprint

Pharmacokinetics
Area Under Curve
Immunoglobulin G
Immunoglobulins
Common Variable Immunodeficiency
Phase III Clinical Trials
Hizentra
Excipients
Intravenous Immunoglobulins
Serum
Proline
Intravenous Administration
Primary Health Care
Therapeutics
Physicians
Antibodies
Infection

Keywords

  • Agammaglobulinaemia
  • Bioequivalence
  • Common-variable-immunodeficiency
  • Immunodeficiency-disorders
  • Immunoglobulin-G
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Wasserman, R. L., Melamed, I., Nelson, R. P., Knutsen, A. P., Fasano, M. B., Stein, M. R., ... Church, J. A. (2011). Pharmacokinetics of subcutaneous igpro20 in patients with primary immunodeficiency. Clinical Pharmacokinetics, 50(6), 405-414. https://doi.org/10.2165/11587030-000000000-00000

Pharmacokinetics of subcutaneous igpro20 in patients with primary immunodeficiency. / Wasserman, Richard L.; Melamed, Isaac; Nelson, Robert P.; Knutsen, Alan P.; Fasano, Mary Beth; Stein, Mark R.; Rojavin, Mikhail A.; Church, Joseph A.

In: Clinical Pharmacokinetics, Vol. 50, No. 6, 16.05.2011, p. 405-414.

Research output: Contribution to journalArticle

Wasserman, RL, Melamed, I, Nelson, RP, Knutsen, AP, Fasano, MB, Stein, MR, Rojavin, MA & Church, JA 2011, 'Pharmacokinetics of subcutaneous igpro20 in patients with primary immunodeficiency', Clinical Pharmacokinetics, vol. 50, no. 6, pp. 405-414. https://doi.org/10.2165/11587030-000000000-00000
Wasserman, Richard L. ; Melamed, Isaac ; Nelson, Robert P. ; Knutsen, Alan P. ; Fasano, Mary Beth ; Stein, Mark R. ; Rojavin, Mikhail A. ; Church, Joseph A. / Pharmacokinetics of subcutaneous igpro20 in patients with primary immunodeficiency. In: Clinical Pharmacokinetics. 2011 ; Vol. 50, No. 6. pp. 405-414.
@article{f84db79f2d7749ac9fc0b83938cde744,
title = "Pharmacokinetics of subcutaneous igpro20 in patients with primary immunodeficiency",
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{\circledR}), 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{\circledR}). 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 agammaglobulinaemia) 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 ‡5g/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{\circledR} study and due to an FDA request. After runin, 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 105.6 g{\circledR}day/L for IgPro20 versus 103.2 {\circledR}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 underprotection but vary too widely to be considered measures of equivalence.",
keywords = "Agammaglobulinaemia, Bioequivalence, Common-variable-immunodeficiency, Immunodeficiency-disorders, Immunoglobulin-G, Pharmacokinetics",
author = "Wasserman, {Richard L.} and Isaac Melamed and Nelson, {Robert P.} and Knutsen, {Alan P.} and Fasano, {Mary Beth} and Stein, {Mark R.} and Rojavin, {Mikhail A.} and Church, {Joseph A.}",
year = "2011",
month = "5",
day = "16",
doi = "10.2165/11587030-000000000-00000",
language = "English (US)",
volume = "50",
pages = "405--414",
journal = "Clinical Pharmacokinetics",
issn = "0312-5963",
publisher = "Adis International Ltd",
number = "6",

}

TY - JOUR

T1 - Pharmacokinetics of subcutaneous igpro20 in patients with primary immunodeficiency

AU - Wasserman, Richard L.

AU - Melamed, Isaac

AU - Nelson, Robert P.

AU - Knutsen, Alan P.

AU - Fasano, Mary Beth

AU - Stein, Mark R.

AU - Rojavin, Mikhail A.

AU - Church, Joseph A.

PY - 2011/5/16

Y1 - 2011/5/16

N2 - 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 agammaglobulinaemia) 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 ‡5g/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 runin, 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 105.6 g®day/L for IgPro20 versus 103.2 ®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 underprotection but vary too widely to be considered measures of equivalence.

AB - 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 agammaglobulinaemia) 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 ‡5g/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 runin, 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 105.6 g®day/L for IgPro20 versus 103.2 ®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 underprotection but vary too widely to be considered measures of equivalence.

KW - Agammaglobulinaemia

KW - Bioequivalence

KW - Common-variable-immunodeficiency

KW - Immunodeficiency-disorders

KW - Immunoglobulin-G

KW - Pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=79955837379&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955837379&partnerID=8YFLogxK

U2 - 10.2165/11587030-000000000-00000

DO - 10.2165/11587030-000000000-00000

M3 - Article

C2 - 21553933

AN - SCOPUS:79955837379

VL - 50

SP - 405

EP - 414

JO - Clinical Pharmacokinetics

JF - Clinical Pharmacokinetics

SN - 0312-5963

IS - 6

ER -