IGIV Therapy: The Process, The Product, The Patient, and The Pocketbook

At a symposium moderated by R. Donald Harvey, III, PharmD, BCPS, BCOP, and held in conjunction with the American College of Clinical Pharmacy’s 2003 Annual Meeting, four specialists in pharmacy and hematology/oncology discussed the considerations in the use of IGIV therapy. Topics included IGIV manufacturing and purification processes, efficacy and safety of IGIV agents, and current approved and experimental uses of IGIV therapy.

This program was supported by an unrestricted educational grant from Bayer.

The Process: New Methods of Purification and Viral Safety

The intravenous use of immunoglobulin G (IGIV) therapy has afforded a significant therapeutic benefit, but also the need to address issues of purification and safety, said Thomas G. Schleis, MS, RPh, Director of Pharmacy Services, Northwest Medical Specialties, Tacoma, Washington. According to Dr. Schleis, “Newer IGIV agents not only provide superior antiviral safety, but also show advances in product purity and manufacturing processes.” The sum of these processes, he said, is what will optimize IGIV product safety.

Potential Pathogen Transmission
IGIV therapy is currently used for a number of US Food and Drug Administration-approved and off-label indications, including primary immune deficiency,
idiopathic thrombocytopenic purpura (ITP), B-cell chronic lymphocytic leukemia (CLL), Kawasaki syndrome, and immunodeficiency associated with pediatric HIV and bone marrow transplantation and various neurological, dermatological and other conditions. A safety issue with IGIV emerged when hepatitis C was transmitted with IGIV products in the 1990s. Later, concern arose over the potential transmission of Creutzfeldt-Jakob disease (vCJD), although this has not been observed. Today, a number of viruses, prions, and other pathogens represent potential safety issues (Table 1). Due to such concerns, solvent/ detergent or pasteurization was added to some IGIV manufacturing processes in the late 1990s, and additional purification processes to newer products (Carimune, Gamunex) that are also able to remove prions, the agents responsible for Creutzfeldt-Jakob disease (CJD).

Pathogen Reduction Methods
According to Dr. Schleis, steps to help reduce the risk of pathogen transmission with IGIV therapy include vigilant screening of donors as well as a number of product purification methods (Table 2). Three main methods of virus reduction include partitioning in which the virus remains in a partition of phase (fractionation, depth filtration, caprylate, PEG + bentonite, DEAE, chromatography), inactivation in which the virus is disrupted (solvent/detergent, caprylate, low pH, hydrolase incubation, pasteurization), and filtration in which virus is removed based on size (nanofiltration). “However, challenges
exist in eliminating viruses. First, viruses differ greatly in size, RNA/DNA, lipid versus non-lipid envelope, and chemical sensitivity or resistance. In addition, new pathogens, such as west nile virus and SARS, are always emerging,” Dr. Schleis pointed out. For this reason, he said, validation of virus elimination is essential.

Another pathogen causing concern is the prion associated with CJD, a rare and fatal nervous system disease, which has been shown to be transmitted with corneal or dura mater transplantation and human pituitary growth hormone. Even though current studies have not shown transmission of classical CJD with blood or plasma, FDA guidelines with regard to blood/ plasma donation include screening donors for CJD and excluding those with known risk factors. With regard to variant CJD, this disease appears to have greater lymphoid involvement than classical CJD, raising the potential of blood infectivity. Thus, the FDA guidelines mandate precautionary withdrawal of plasma derivative batches if a pool donor is subsequently diagnosed with variant CJD.

According to Dr. Schleis, different IGIV agents utilize different methods to eliminate viruses and prions (responsible for CJD), with the most recent FDA-
approved IGIV agent, Gamunex; incorporating multiple purification mechanisms. “Because of the varied pathogens potentially involved, the use of multiple, independent, and preferably complementary inactivation and removal mechanisms ensures the greatest reduction in risk of transmission,” Dr. Schleis noted. In closing, Dr. Schleis noted that future study and clinical use will serve to define the efficacy, safety, and tolerability of newer IGIV therapies.

The Product: All IGIVs Are Not Equivalent

Intravenous immunoglobulin G (IGIV) therapies differ according to manufacturing, efficacy, and safety factors. “In addition to issues of manufacturer reputation and stability, method of preparation, safety, and individual patient factors must also be considered when selecting an IGIV agent,” said Jerry Siegel, PharmD, FASHP, Senior Director, Pharmaceutical Services, Ohio State University Medical Center, and Clinical Associate Professor & Assistant Dean, Ohio State University College of Pharmacy, Columbus, Ohio.

History of IGIV Use
According to Dr. Siegel, IGIV therapies have improved greatly in the last two decades, and most recent advances have allowed for even greater purification and clinical safety. Current US Food and Drug Administration (FDA)-approved use of IGIV therapies include primary immune deficiency (PID), idiopathic thrombocytopenic purpura, Kawasaki disease, pediatric HIV and bone marrow transplantation. The original formulation of IGIV was not intact and only indicated for PID. The year 1981 saw the availability of the first intact IGIV indicated for ITP. In the mid 1980s, low IgA products were developed, and in 1990 a National Institutes of Health consensus conference agreed that for FDA-approved indications the IVIG products available on the US market should have the same clinical efficacy. Despite these advances, safety concerns arose in the mid-1990s regarding hepatitis C virus transmission, which led to new antiviral manufacturing steps in some products. Subsequently, sucrose nephropathy and thrombosis warnings also emerged. In 2003, a new combination of manufacturing processes was developed, to improve the safety profile of the products.

Manufacturing Considerations
“A manufacturer’s reputation and stability are key considerations, as are blood source and purification processes used, when choosing an IGIV therapy,” said Dr. Siegel. Methods of preparation and viral inactivation employed in the different IGIV agents are widely varied (Table 1). “Solvent/detergent and pasteurization methods have been used for many years, while nanofiltration and caprylate are newer mechanisms of purification,” Dr. Siegel explained. According to Dr. Siegel, each of these methods has its advantages.

Nanofiltration, first implemented with Carimune NF, entails the removal of patho-gens by size. Any particle greater then 50 nanometers is removed during this process. Thus, nanofiltration causes no structural risk to immunoglobulin (< 50 nanometers) and leaves no detergent residue. This process allows for the removal of lipids, as well as non-lipid viruses and transmissible spongiform encephalopathy agents. “Essentially, Carimune NF is purified through nanofiltration, followed by low pH exposure to inactivate any possibly re- maining patho-gens,” Dr. Siegel said.

Caprylate treatment, first utilized with the newly approved Gamunex, serves to reduce viral load as part of a new integrated manufacturing process. Caprylate itself is a saturated medium-chained fatty acid. Unlike solvent/detergent methods, caprylate treatment is non-toxic. The caprylate process is also more efficient in providing a safe product without significant loss of the product.

Clinical Considerations
“When selecting an IGIV agent, finding the right match for the individual patient is a critical clinical concern,” Dr. Siegel noted. Issues to consider include agent volume load; osmolality; sodium, sugar, and IgA content; and pH.

First, sodium content can be a concern for patients with cardiac or renal disease. Among the IGIV agents, Gammagard/ Polygam have a 1.8% sodium content at 10% (increased osmolality), while Venoglobulin-S is low in sodium content. Gamimune N and Gamunex contain no sodium, but are also incompatible in saline. Second, sucrose levels also may be a concern for nephrotoxicity in some patients. All IGIV agents contain sugar, with the exception of Gamimune N S/D 10% and Gamunex, which are glycine based. Sodium and sugar content can also have an impact on osmolality, which ranges among IGIV agents from 192 mOsm/L to 1250 mOsm/L (Table 2).

IGIV agent pH may also raise certain clinical issues, said Dr. Siegel. While liquid products require acidic pH for stability, there has been some evidence of phlebitis in patients receiving an acidic solution through a small peripheral vein. In addition, caution is indicated in neonate patients due to the risk for metabolic acidosis. “The total blood volume of the neonate is so small that, even though the solution is not buffered, the total volume of the solution is significant in the capacity of the neonate to immediately buffer and adjust. The risk is to the most extent theoretical,” Dr. Siegel explained.

In terms of IgA levels, all IGIV agents are contraindicated in patients who have IgE- or IgG-mediated anti-IgA antibodies present.

In addition, efficacy is an important consideration in the clinical setting. In one study, Roifman and colleagues compared the efficacy of Gamimune N and Gamunex in persons with PID and ITP. The results appeared to show a trend toward greater efficaciousness with Gamunex, but further research is needed.

Finally, product stability can also be a clinical consideration with IGIV agents. Pfeifer and Siegel studied 11 formulations of seven products, tested with three bacteria and two fungi at three temperatures over 7 days. The results showed no growth at 7 days at 3Þ C, with stability extending to 72 hours with refrigeration.

Future Directions
In closing, Dr. Siegel noted that head-to-head comparison studies of IGIV agents are limited, and further research is needed to compare efficacy, stability, and effects of different manufacturing processes. He emphasized the importance of understanding the differences between IGIV agents, and of passing this knowledge on to clinicians, ultimately allowing them to provide optimal care to their patients.

The Patient: Emerging Clinical Applications

According to a 1990 National Insti-tutes of Health consensus conference, intravenous immunoglobulin G (IGIV) therapies are predominately used for off-label indications. “When clinicians are considering the use of IGIV therapies for off-label indications, it is essential to assess the goals of therapy as well as the efficacy and safety issues of both IGIV agents and alternative treatments,” said R. Donald Harvey, III, PharmD, BCPS, BCOP, Program Chair Senior Clinical Specialist, Hematology/Oncology, University of North Carolina Health Care; and Clinical Assistant Professor, University of North Carolina, Chapel Hill, North Carolina.

IGIV Applications
IGIV therapy is used for two main clinical purposes: 1) replacement of a deficient immune component and 2) modulation of the immune system. Immune replacement consists of repletion of the missing antibody, with lower doses often being sufficient for therapeutic benefit. Autoimmune modulation is more complex, with multiple purported mechanisms of action and higher doses being required for therapeutic benefit. Clinical applications of IGIV therapies include both US Food and Drug Administration-approved indications and off-label uses (Table 1). “Unfortunately, in many cases of emerging off-label uses, the diseases are unpredictable and rare, making large clinical trials difficult,” Dr. Harvey noted.

While IGIV offers a therapeutic benefit in a variety of diseases, the mechanisms of action are not completely understood. An increased understanding of several factors—including immune homeostasis mechanisms, lack of specificity/information at the molecular level, and immunologic source of disease (self vs non-self) —will be important in further defining the numerous purported IGIV mechanisms of action (Table 2). “In summary, IGIV inhibits the activation and proliferation of T cells; may promote apoptosis; may modulate B-cell repertoire through antibody production and neutralization of antibody production; may indirectly inhibit neutralization of microbial toxins, and may lead to a reduction in complement-mediated damage,” Dr. Harvey explained. “In addition, anti-inflammatory cytokines may be produced, but another important mechanism is likely a reduction in IL-1, IL-2, and beta interferon gamma in those stimulatory cytokines,” he added.

Novel New Applications
In considering IGIV therapy for patients, efficacy considerations include proven efficacy with approved indications, possible/probable efficacy based on
well-designed small studies, and an experi-mental or theoretical basis for efficacy for novel application.

By 2006, it is expected that more than 100,000 people will be on the waiting list for a renal transplantation. Approximately 30% of these have exogenously obtained preformed antibodies to human leukocyte antigens. Historically, any positive T-cell crossmatch would exclude a patient from transplant. “The question is, can patients’ allosensitization be reduced to allow for transplantation,” Dr. Harvey noted. The Cedars-Sinai desensitization protocol involves incubation of panel reactive antibody (PRA)-positive patient sera with IGIV. Donor plasma is added, and donor cell toxicity is measured after addition of complement. “The protocol has shown that complete protection in vitro is predictive of an in vivo response,” Dr. Harvey said. Similarly, Jordan and colleagues treated 101 patients with PRA > 50% with either IGIV monthly or placebo. Those receiving the IGIV demonstrated a 35% reduction in PRA/anti-HLA antibodies and significantly decreased time to transplant (4.8 vs 10.3 yrs). “Future study is needed in patients awaiting renal transplant to determine the possible roles of IGIV, plasmapheresis, and combination therapy approaches,” Dr. Harvey said.

Other novel applications of IGIV include the treatment of persons with certain dermatologic disorders, infectious diseases, hematologic disorders, asthma, late-stage or refractory systemic lupus erythematosus, and several neurologic disorders (Table 1).

In closing, Dr. Harvey emphasized that “when considering clinical use of IGIV therapies for off-label purposes, it is critical to assess the goals of therapy; efficacy, toxicity, and availability of IGIV versus other treatments; patient quality of life issues; and cost.”

The Pocketbook: Pharmacoeconomic Issues with IGIV

In addition to issues of pharmacokinetics, efficacy, and safety, pharmaco-economics is also a significant factor in considering intravenous immunoglobulin G (IGIV) therapies, said Parthiv J. Mahadevia, MD, MPH, Research Scientist, MEDTAP International, Inc., Bethesda, Maryland. According to Dr. Mahadevia, a recent pharmacoeconomic analysis study shows a cost savings with a new fourth-generation IGIV agent, Gamunex compared to Gamimune N in persons with primary immune deficiency (PID) and idiopathic thrombocytopenic purpura (ITP).

IGIV and Pharmacoeconomics
In today’s healthcare environment, healthcare costs are rising, resulting in an increase in demand for product value. Thus, polyvalent IGIV agents may be considered commodity products, leading to product selection by acquisition costs alone. According to Dr. Mahadevia, it is critical that efficacy and safety profiles be considered not only as independent factors, but also as part of an agent’s pharmacoeconomic profile. One randomized, double-blind, controlled trial showed a fourth- generation IGIV agent, Gamunex, to be associated with some efficacy advantages in persons with PID and ITP. “Such
clinical differences may impact resource use among patients, leading to cost differences, and should be considered in IGIV selection,” Dr. Mahadevia noted. Indeed, the analysis also showed associated cost savings with Gamunex in both patient groups.

Future Directions
It is hoped that these and other study data will be helpful in considering the use of an IGIV agent. In closing, Dr. Mahadevia noted that publication of the study results is expected in 2004.