New Model Provides Insights Into Intravenous and Subcutaneous Immunoglobulin Pharmacokinetics in Patients With Primary Immunodeficiencies

KING OF PRUSSIA, Pa., March 19, 2011 /PRNewswire/ -- CSL Behring today announced the development of an innovative pharmacokinetic (PK) model that allows the absorption, distribution, metabolism, and elimination of subcutaneous (SC) immunoglobulin G (IgG) following administration to be simulated with a high degree of accuracy and precision. The new PK model provides a novel means of simulating the mechanism by which SC IgG is transported after it is injected into the subcutaneous tissue. Data from the model, which was developed by CSL Behring in collaboration with researchers at Cardiff University, Keele University, and Prism Ideas Ltd, were described in both a poster presentation and an oral presentation at the 2011 American Academy of Allergy, Asthma and Immunology annual meeting.

The current understanding of the clinical implications of SC versus intravenous (IV) dosing of IgG in primary immunodeficiency (PI) patients is limited. In addition, little is known about where SC IgG travels within the body after it is administered and how long it remains there. This information defines IgG's pharmacokinetic (PK) profile and could affect the volume and frequency of IgG dosing for PI patients.

"At CSL Behring we are continually searching for and identifying ways of improving treatment for patients with primary immunodeficiencies," said Martin Bexon, M.D., Program Director, Global Clinical Research and Development at CSL Behring. "This model increases our knowledge of how SC IgG is distributed throughout the body and has the potential to help us further optimize a dosing schedule that balances the convenience and therapeutic value of Hizentra for PI patients."

The new PK model, presented at this meeting in both a poster (Bexon et al; Poster 46; Session 2203) and an oral presentation (Jolles et al; Session 4602) describes a complex system of continuous interactions between extravascular (tissue) and intravascular (blood) compartments that help determine the location and level of SCIG in different parts of the body after injection. Unlike IVIG, which is injected directly into the intravascular compartment, SCIG is injected into the extravascular compartment. Fluctuations in serum IgG after IVIG dosing, which were lower in the first half of the 30-day dosing cycle and higher in the second half of the cycle than would be anticipated, led the study authors to hypothesize that IgG must be distributed to multiple compartments in the body. This strongly supports the theory that IgG distribution from the intravascular to the extravascular compartment occurs early in the dosing cycle, with the reverse occurring later in the dosing cycle.

After SC injection into the extravascular space, the model describes the interplay between IgG being broken down before reaching the circulation and also salvaged from this space to be returned to the bloodstream. The fate of IgG is similar between IVIG and SCIG after it reaches the intravascular compartment.

"Clearly a need exists to better understand the highly complex pharmacokinetic interactions that take place after an infusion of IgG, especially SCIG, in areas of the body that are not traditionally monitored by clinicians," said Stephen Jolles, M.D., University Hospital of Wales, Cardiff, U.K. "This new PK model represents a major step toward filling this need, especially for clinicians who measure serum IgG as a means of determining overall levels of IgG, and provides valuable insight into movement of IgG around the body with implications for improving PI patient dosing and treatment."

About Primary Immunodeficiencies

Primary immunodeficiency (PI) is a group of more than 150 diseases that affect the cells, tissues and proteins of the immune system.(1) In people with PI, the immune system is either absent or functioning inadequately, leaving them more susceptible to infection.(2) For individuals with PI – many of them children – infections may not improve with treatment as expected, and may keep returning. As a result, patients may face repeated rounds of antibiotics or be hospitalized for treatment. Repeated infections can lead to organ damage, which, over time, can become life-threatening. Collectively, PIs affect an estimated 10 million people worldwide, and the incidence is estimated to be 1 in 10,000.(3) For more information on PI, please visit www.cslbehring.com or contact the leading PI patient advocate groups in the United States the Immune Deficiency Foundation and the Jeffrey Modell Foundation.

About Hizentra®

Hizentra® (Immune Globulin Subcutaneous [Human]), the first and only 20 percent SCIg developed for subcutaneous use, is approved in the United States and in registration in the EU and Switzerland. It is stable at 25 degrees C for 30 months due to formulation with L-proline. In the United States, Hizentra is indicated for the treatment of patients with primary immunodeficiency (PI), and contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations or components of Hizentra, and in persons with selective immunoglobulin A deficiency who have known antibody against IgA and a history of hypersensitivity. The most common drug-related adverse reactions, observed in 5 percent or more of subjects in the U.S. clinical study, were local injection-site reactions, headache, vomiting, pain, and fatigue. For more information, including full U.S. prescribing information, visit www.hizentra.com.

Hizentra is part of the immunoglobulin (Ig) franchise for CSL Behring. This comprehensive Ig product portfolio also includes the first U.S. FDA-approved subcutaneous immunoglobulin and the first proline-stabilized intravenous immunoglobulin. CSL Behring manufactures Hizentra at its state-of-the art facility in Bern, Switzerland, where advanced technologies are applied to further ensure product safety and ample supply. This facility represents the long-term commitment of CSL Behring to global Ig markets.

Important Safety Information

Hizentra®, Immune Globulin Subcutaneous (Human), is indicated as replacement therapy for the treatment of patients with primary humoral immunodeficiency.

Hizentra is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations or components of Hizentra, and in persons with selective immunoglobulin A deficiency who have known antibody against IgA and a history of hypersensitivity. If anaphylactic reactions are suspected, administration should be discontinued immediately and the patient treated as medically appropriate. Because Hizentra contains the stabilizer L-proline, it is also contraindicated in patients with hyperprolinemia.

Hizentra should be administered subcutaneously only.

Hizentra is derived from human plasma. The risk of transmission of infectious agents including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be eliminated completely.

The most common drug-related adverse reactions, observed in 5 percent or more of subjects in the clinical study, were local injection-site reactions, headache, vomiting, pain, and fatigue.

Monitor patients for reactions associated with IVIg treatment that might occur with Hizentra, including renal dysfunction/failure, thrombotic events, aseptic meningitis syndrome (AMS), hemolysis and transfusion-related acute lung injury (TRALI).

For full prescribing information, visit www.hizentra.com/consumer/prescribing-information.aspx.

About CSL Behring

CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide. CSL Behring therapies are indicated for the treatment of coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies and inherited respiratory disease. The company's products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in newborns. CSL Behring operates one of the world's largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited (ASX:CSL), a biopharmaceutical company headquartered in Melbourne, Australia. For more information, visit www.cslbehring.com.

(1). Immune Deficiency Foundation. About primary immunodeficiencies: What is a primary immunodeficiency? http://www.primaryimmune.org/about_pi/about_pi.htm. Accessed February 2011.

(2). National Institute of Child Health & Human Development. Primary Immunodeficiency: What is primary immunodeficiency? http://www.nichd.nih.gov/health/topics/Primary_Immunodeficiency.cfm. Accessed February 2011.

(3). Jeffrey Modell Foundation. Primary Immunodeficiency Resource Center. About PI. http://www.info4pi.org/aboutPI/index.cfm?section=aboutPI&CFID=36419223&CFTOKEN=3244. Accessed February 2011.

SOURCE CSL Behring