Pharmacokinetics and safety of subcutaneous immune globulin (human), 10% caprylate/chromatography purified in patients with primary immunodeficiency disease

Abstract

Subcutaneous administration of intravenous immunoglobulin G (IgG) preparations provides an additional level of patient convenience and more options for patients with poor venous access or a history of intravenous IgG reactions. An open-label, pharmacokinetic trial (n = 32) determined the non-inferiority of the subcutaneous versus intravenous route of 10% caprylate/chromatography purified human immune globulin intravenous (IGIV-C; Gamunex®) administration by comparing the steady-state area under the concentration-versus-time curve (AUC) of total plasma IgG in patients with primary immunodeficiency disease. Patients on stable IGIV-C received two intravenous infusions (administered 3 or 4 weeks apart). Seven to 10 days after the second intravenous infusion, all patients switched to a weekly infusion of subcutaneous IGIV-C, with the dose equal to 137% of the previous weekly equivalent intravenous dose, for up to 24 weeks. Samples for pharmacokinetic analysis were collected during steady state for intravenous and subcutaneous IGIV-C treatments. The AUC(0-) τ geometric least-squares mean ratio was 0·89 (90% confidence interval, 0·86-0·92) and met the criteria for non-inferiority. The overall mean steady-state trough concentration of plasma total IgG with subcutaneous IGIV-C was 11·4 mg/ml, 18·8% higher than intravenous IGIV-C (9·6 mg/ml). Subcutaneous IGIV-C was safe and well tolerated. Subcutaneous IGIV-C infusion-site reactions were generally mild/moderate and the incidence decreased over time. No serious bacterial infections were reported. Weekly subcutaneous IGIV-C infusion using 137% of the weekly equivalent intravenous immunoglobulin dose provides an AUC comparable to intravenous administration, thus allowing patients to maintain the same IgG preparation/formulation if switching between intravenous and subcutaneous infusions.

Fig. 1

Study design. In this open-label crossover study, patients were categorized into three groups depending on their most recent immunoglobulin G (IgG) treatment history. Patients in group 1 were receiving a stable (≥3 months) dose of immune globulin intravenous (human), 10% caprylate/chromatography purified (IGIV-C), 200–600 mg/kg, every 3 or 4 weeks. Group 1 directly entered the intravenous phase, with the first infusion coinciding with the patients’ next regularly scheduled administration. Patients in group 2 were receiving 200–600 mg/kg of intravenous immunoglobulin (IVIg), other than IGIV-C, every 3 or 4 weeks. Group 2 entered a 3-month run-in period and received intravenous IGIV-C at an equivalent dose and dosing interval as the patients’ previous IVIg therapy. Group 2 was then eligible to enter the intravenous phase. Group 3 included patients receiving IgG therapy via non-intravenous routes of administration (e.g. subcutaneous or intramuscular), patients not currently receiving IgG treatment but who had received it in the past, patients receiving any IVIg but not at a stable dose, patients receiving any IVIg but not in the dose range of 200–600 mg/kg, and patients receiving any IVIg but not at a scheduled interval of every 3 or 4 weeks. Group 3 entered a 4-month run-in period and received intravenous IGIV-C at a dose of 200–600 mg/kg every 3–4 weeks. Group 3 was then eligible to enter the intravenous phase.

Fig. 2

Steady-state plasma total immunoglobulin G (IgG) concentration-versus-time curves during intravenous or subcutaneous administration of immune globulin intravenous (human), 10% caprylate/chromatography purified (IGIV-C). Projected total IgG concentrations for subcutaneous IGIV-C (days 7–28) were based on measured concentrations over 0–7 days obtained during week 17 of the subcutaneous phase. Data are reported for the pharmacokinetic population and as mean ± standard error.

Fig. 3

Plasma total immunoglobulin G (IgG) trough concentrations during intravenous or subcutaneous administration of immune globulin intravenous (human), 10% caprylate/chromatography purified (IGIV-C), by visit. Data are reported for the IgG population and as mean ± standard error.

Fig. 4

Mean serum trough concentrations of antibodies against Haemophilus influenzae and six Streptococcus pneumoniae serotypes during intravenous or subcutaneous administration of immune globulin intravenous (human), 10% caprylate/chromatography purified. Data are reported for the immunoglobulin G population.