J Allergy Clin Immunol. 2012 Oct;130(4):951-7.e11.

Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency.

Wasserman RL, Melamed I, Stein MR, Gupta S, Puck J, Engl W, Leibl H, McCoy B, Empson VG, Gelmont D, Schiff RI; IGSC, 10% with rHuPH20 Study Group.

Allergy/Immunology Research Center of North Texas, Dallas, Tex., USA.

 

Abstract

BACKGROUND: Subcutaneous immunoglobulin (IGSC) replacement therapy for primary immunodeficiency (PI) is equally efficacious to intravenous immunoglobulin (IGIV), induces fewer systemic reactions, and may be self-infused. Limited SC infusion volumes and reduced bioavailability, however, necessitate multiple infusion sites, more frequent treatment, and dose adjustment to achieve pharmacokinetic equivalence. Recombinant human hyaluronidase (rHuPH20) increases SC tissue permeability and facilitates dispersion and absorption, enabling administration of monthly doses in one site.

OBJECTIVE: This study investigated the efficacy and tolerability of rHuPH20-facilitated IGSC (IGHy) in patients with PI.

METHODS: In this open-label, multicenter phase III study, 87 patients with PI aged ≥2 years received 10% IGIV for 3 months, then IGHy (n = 83) for approximately 14 to 18 months at 108% of the IGIV dose. IGHy infusions began weekly, increasing to 3- or 4-week intervals.

RESULTS: The majority (94.0%) of IGHy infusions were administered every 3 or 4 weeks, using one site (median, 1.09/month), with a mean volume of 292.2 mL. The bioavailability of IGHy measured by area under the concentration versus time curve was 93.3% of IGIV, which is pharmacokinetically equivalent. Systemic reactions were less frequent with IGHy than with IGIV (8.3% vs 25.0% of infusions). Local reactions to IGHy were generally mild to moderate, with a rate of 0.203 per infusion. The acute serious bacterial infection rate per subject-year for IGHy was low (0.025; upper 99% CI limit, 0.046). Overall infection rates per subject-year were 2.97 for IGHy and 4.51 for IGIV.

CONCLUSION: IGHy was effective, safe, and pharmacokinetically equivalent to IGIV at the same administration intervals, but it caused fewer systemic reactions. Tolerability was good despite high infusion volumes and rates.

Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc.

PMID: 22846381

 

Supplements:

Subcutaneous administration of immunoglobulin (IGSC) for the treatment of antibody deficiency has many advantages relative to intravenous administration (IGIV), including fewer systemic side effects and ease and safety of self-administration.  However, the amount of IgG that can be infused into a single site is limited, necessitating the use of several injection sites usually administered once a week.  The limitation is caused by poor diffusion of the infusate from the administration site which results in local induration.  This is due primarily to the presence of hyaluronan, a repeating copolymer of N-acetyl-glucosamine and glucuronic acid, a that soluble gel-like component of the extracellular matrix, that limits bulk fluid flow in the interstitial tissue restricting access to the lymphatic vessels that are the main conduit for absorption into the vascular space.  Hyaluronan normally has a very rapid turnover due to endogenous hyaluronidase and high rate of re-synthesis.  Exogenously administered recombinant human hyaluronidase (rHuPH20, Halozyme Therapeutics, Inc.) enzymatically cleaves hyaluronan, enabling bulk fluid flow of infused drugs and biologics (1).

The enhancing effect of rHuPH20 on infusions of gammaglobulin was shown in a porcine model by Kang, et al (2).  Human gammaglobulin preceded by either rHuPH20 or buffer control was infused subcutaneously in Yucatan Mini Pigs whose skin most closely approximates the structure of human skin.  Compared to the buffer, rHuPH20 significantly reduced the in-line pressure required for the infusion.  The area and volume of the local swelling also was reduced (P < 0.0001) as was the firmness determined in a blinded fashion.  RHuPH20 significantly improved cutaneous elasticity, a measure of the firmness, in an indirect assay that applied 270 mbar of negative pressure to the surface of the skin.   As a result of the reduced interstitial pressure, cutaneous blood flow at the site of the infusion, as determined by a laser Doppler imager, was improved.  The IgG was more rapidly absorbed as demonstrated by fluorescent staining of skin biopsies of the infusion site obtained at 1, 4, and 8 days post infusion.   Thus, the rHuPH20 enhanced diffusion in the subcutaneous tissue and reduced tissue distortion and pressure, thereby improving cutaneous blood flow at the end of the infusion, and enhancing absorption from the subcutaneous space into the vascular compartment.

As demonstrated in the study reported by Wasserman, et al (3), when rHuPH20 is administered prior to a 10% solution of gammaglobulin, infusions in excess of 600 mL can be administered in a single site at an IV-like infusion rate of 300 mL/hr.  This permits infusion of up to a full monthly therapeutic dose of gammaglobulin in a single subcutaneous infusion site.   The following series of photographs of a mild injection site reaction (courtesy of Dr. Richard Wasserman) show how the infusion of a large volume of 10% IgG is possible with good diffusion and minimal distortion of the skin.  In most cases the sites returned to normal within 24 to 48 hours.

Yeshi Mikyas-fig1

Images adapted from Immunotherapy, Volume 6, Issue 4, 2014 (Ahead of Print), with permission of Future Medicine Ltd

 

Reference:

1.      Bookbinder LH, Hofer A, Haller MF, Zepeda ML, Keller GA, Lim JE, et al. A recombinant human enzyme for enhanced interstitial transport of therapeutics. Journal of controlled release : official journal of the Controlled Release Society. 2006;114(2):230-41.

2.      Kang DW, Oh DA, Fu GY, Anderson JM, Zepeda ML. Porcine model to evaluate local tissue tolerability associated with subcutaneous delivery of protein. Journal of pharmacological and toxicological methods. 2013;67(3):140-7.

3.      Wasserman RL, Melamed I, Stein MR, Gupta S, Puck J, Engl W, et al. Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency. J Allergy Clin Immunol. 2012;130(4):951-7 e11.

 

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