Pharmacokinetics of Intravenous Immunoglobulin: A Systematic Review

Tamar Koleba, PharmD; Mary H. H. Ensom, PharmD, FASHP, FCCP, FCSHP

Disclosures

Pharmacotherapy. 2006;26(6):813-827. 

In This Article

Abstract and Introduction

Abstract

Background: Intravenous immunoglobulin (IGIV) is used in the treatment of a wide variety of immune disorders. To our knowledge, no comprehensive or systematic review on the pharmacokinetics of IGIV has been published despite the availability of many published individual studies.
Objective: To systematically review published studies of the pharmacokinetics of IGIV.
Methodology: We conducted a search of PubMed/MEDLINE from January 1966-September 2005 and EMBASE from January 1980-September 2005 for English-language articles on the pharmacokinetics of IGIV. This search was supplemented by a bibliographic review of all relevant articles.
Results: Data elements extracted from these articles included study design, number of study subjects, indication for IGIV therapy, IGIV treatment regimen (formulation, dosage, and duration), pharmacokinetic parameters (clearance, volume of distribution, elimination rate constant, and half-life), analytic methodology, pharmacokinetic model, and blood sampling times. The United States Preventive Services Task Force rating scale was used to categorize the 50 pertinent citations identified in our literature search. According to the rating scale, 12 studies were level I (prospective, randomized, controlled studies), 3 were level II-1 (prospective, nonrandomized, controlled studies), 30 were level II-2 (prospective, nonrandomized, uncontrolled [cohort] studies), and 5 were level III (case reports or descriptive studies).
Conclusion: The pharmacokinetics of IGIV shows considerable intra- and interpopulation variability among patients with normal immunoglobulin levels, patients with primary immunodeficiency diseases, bone marrow transplant recipients, patients with immune deficiency due to chronic lymphocytic leukemia or multiple myeloma, very low birth weight neonates, neonates with suspected sepsis, high-risk infants in the neonatal intensive care unit, high-risk infants with cardiopulmonary disease, children with cryptogenic West or Lennox-Gastaut syndrome, women and infants with fetal alloimmune thrombocytopenia, and women with recurrent spontaneous abortions. Despite the large number of studies characterizing the pharmacokinetics of IGIV, major literature gaps include lack of information on IGIV clearance or area under the curve parameters and target serum immunoglobulin G concentrations. Further study is needed to rigorously characterize the pharmacokinetic properties of IGIV in a range of patient populations.

Introduction

Immunoglobulins are endogenous proteins produced by B lymphocyte cells. As an essential component of humoral-mediated immunity, the major roles of immunoglobulins in host defense include antigen binding and various effector functions. These include complement activation, complement binding, and binding to various Fc receptors.[1] Intravenous immunoglobulin (IGIV) is a fractionated blood product made from pooled human plasma, 90-100% of which is composed of immunoglobulin G (IgG) molecules for intravenous administration. The first clinically successful use of IGIV was reported in 1979.[2] Numerous commercially manufactured products are now available in a variety of forms and concentrations. Intravenous immunoglobulin is used in the treatment of a variety of hyperreactive and hyporeactive immune disorders.[1] Clinical conditions commonly treated with IGIV include primary and secondary immunodeficiency diseases, Kawasaki's disease, Guillain-Barré syndrome, and idiopathic thrombocytopenia purpura.[3]

Early analysis of the pharmacokinetics of IGIV was performed by means of tracer studies with use of radioiodinated immunoglobulins. In 1969, a seminal review of the metabolism of immunoglobulins reported a mean half-life of IgG of 21 days in healthy humans, with 48% distributed intravascularly.[4] Analysis of radio signal-time curves indicated that immunoglobulins followed multicompartmental first-order kinetics. The rate of catabolism of the intravascular IgG pool, or fractional catabolic rate ([FCR] the amount of protein broken down daily as a fraction of the total present in the plasma or serum), was 6.3%/day. Plasma proteins appear to distribute in the intravascular space and into one or more extravascular spaces.[5] After intravenous administration, serum concentrations of IGIV exhibit initial rapid decline for 1-7 days, followed by a more gradual rate of decline.[6] Whereas low-molecular-weight antibody fragments such as Fab and Fv are eliminated through renal filtration, almost all intact immunoglobulin is eliminated through concentration-dependent catabolism, with increasing immunoglobulin concentrations being catabolized faster.[7] The initial elimination phase, sometimes called the α phase, is thought to be due to a combination of immunoglobulin catabolism and distribution to extravascular spaces, whereas the terminal or β phase is primarily thought to represent further immunoglobulin catabolism.[6,8]

Knowledge of IGIV pharmacokinetic parameters is desirable for several important reasons. First, knowledge of population and patient-specific pharmacokinetic parameters equips clinicians with the tools to rationally design IGIV therapeutic regimens in order to maximize clinical benefit.[9] Second, IGIV is not an innocuous therapeutic agent, and serious adverse effects are increasingly being reported.[10] Pharmacokinetic information may aid in reducing the rate and severity of adverse effects. Third, information on IGIV pharmacokinetics may enable more efficient use of an increasingly scarce resource. Since 1984, annual worldwide consumption of IGIV has increased from 7.4 to 55.0 metric tons.[11] The United States supplies approximately 60% of the world IGIV market.[12] Finally, knowledge of IGIV pharmacokinetics is essential for timely and rational development of future immunoglobulin products.[13]

Although many individual studies on the pharmacokinetics of IGIV have been published, we are not aware of any recent, comprehensive pharmacokinetic review. Thus, our objective was to systematically review published studies of the pharmacokinetics of IGIV.

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