The New Generation of Liquid Intravenous Immunoglobulin Formulations in Patient Care: A Comparison of Intravenous Immunoglobulins

Abstract

Intravenous immunoglobulin (IGIV) replacement therapy is the standard of care for primary immunodeficiencies with impaired humoral immunity. It is also the immunomodulatory therapy of choice for some types of neuroimmunologic and autoimmune hematologic disorders and for immunomodulation in bone marrow and some solid organ transplants. Currently available IGIV products include older lyophilized formulations, 5% liquid products, and newer, liquid, ready-to-use, 10% formulations. Differences in the formulations, manufacturing processes, excipients, pH, and other physicochemical properties of IGIV products may affect their clinical efficacy and tolerability. Among at-risk patients, the possibility of serious complications such as renal insufficiency, heart failure, thrombotic events, and immunological reactions may be increased if an IGIV formulation has sugar as a stabilizer, has high sodium or immunoglobulin A (IgA) content, or is hyperosmolar. The 10% liquid formulations may offer advantages because of their lower IgA concentrations, optimal pH, glycine or proline stabilizers, low sodium content, and lower osmolality. Liquid formulations are more convenient for patients and health care providers due to shorter infusion times and easier preparation and administration.

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“…Differences in the formulations, manufacturing processes, excipients, pH and other physicochemical properties of IVIG products may affect their safety [21][22][23]. For example, procoagulant substances in IVIG preparations, particularly FXIa, have been identified as a probable cause of IVIG-related TEEs [17,24,25].…”

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“…The final osmolality of IVIg at time of infusion ranges between physiological values of 280-296 mOsm to values greater then 1 Osm, which is primarily determined by the sugar (sucrose, maltose, mannitol and sorbitol) and sodium content of the preparation (Dantal, 2013;Hooper, 2008;Radosevich & Burnouf, 2010;Shah, 2005;Stein, 2010). This is an important consideration as hyperosmotic preparations of IVIg can increase osmotic pressure resulting in adverse compartmental fluid-shifts in the body (Ahsan et al, 1994).…”

“…This is an important consideration as hyperosmotic preparations of IVIg can increase osmotic pressure resulting in adverse compartmental fluid-shifts in the body (Ahsan et al, 1994). The sugar content contained in IVIg preparations is designed to prevent IgG dimer (1-10%) aggregate formation within individual IVIg preparations, although complications may occur such as acute renal failure where the patient has to undergo emergency renal haemodialysis with mortality occurring at 10-15% of cases (Dantal, 2013;Graumann & Zawada, 2010;Itkin & Trujillo, 2005;Renjen et al, 2004;Stein, 2010). The sodium content contained in IVIg preparations is approximately 0.9%, which similarly contributes to the final osmolality, tolerability and adverse effects of IVIg (Lemm, 2002;Stein, 2010;Vo et al, 2006).…”

“…IVIg preparations primarily contain IgG (>95%) with low amounts of IgA, and minor traces of IgM, in addition to stabilizers such as sucrose, maltose, mannitol and sorbitol (Lemieux et al, 2005;Negi et al, 2007;Prins et al, 2007;Stein, 2010). Commercial IVIg preparations come in two forms: a liquid and lypophilized form, whereby the latter is reconstituted with sterile water into a liquid at time of infusion.…”

“…Commercial IVIg preparations come in two forms: a liquid and lypophilized form, whereby the latter is reconstituted with sterile water into a liquid at time of infusion. Two important product parameters of IVIg are important at time of infusion -osmolality and pH (Shah, 2005;Stangel & Pul, 2006;Stein, 2010).…”