Ask the Expert : Phillip Lieberman, MD Intramuscular Versus Intravenous Immunoglobulin Replacement Therapy and Measurement of Immunoglobulin Levels During Immunoglobulin Replacement Therapy Phillip Lieberman, MDa, and Melvin Berger, MD, PhD, FAAAAIb For more Ask the Expert questions and answers, visit www.aaaai.org/ask-the-expert.aspx.

Questions: (1) Why exactly was weekly intramuscular (IM) administered IgG condemned as a poor therapeutic choice compared with intravenous IG (IVIG) or subcutaneous IG (SCIG)? It has been hammered into us that IMIG is a poor choice, but I never read or heard why. (2) When making a change in the weekly dose or starting a patient on SCIG, when do you check the IgG level to assess how the change you made has affected the IgG level? (I realize there is probably not a hard-and-fast answer, but I am sure that some immunologist has an opinion on this.)

Response: Thank you for your inquiry. I am asking Mel Berger, MD, who is a nationally recognized expert in immunoglobulin replacement therapy to respond to your question. (1) Current doses of IgG replacement therapy for primary immune deficiencies are in the range of 600-800 mg/kg per month (6-8 mL/kg of 10% IgG or 3-4 mL/kg of 20% IgG per month). For a patient who weighs 70 kg, the volume needed would be more than 100 mL/wk IM of a 10% IgG product, >50 mL/wk of 20% product, and >65 mL/wk of a 16% IgG product (characteristic of the old IM immune serum globulin preparations). Administration of such large volumes IM would not be tolerated by most patients. Moreover, these large

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Department of Allergy/Immunology University of Tennessee College of Medicine, Germantown, Tenn b Immunology R&D, CSL Behring, LLC, King of Prussia, Pa No funding was received for this work. Conflicts of interest: M. Berger is a salaried employee of CSL Behring with equity interests. Received for publication August 22, 2013; accepted for publication August 23, 2013. Cite this article as: Lieberman P, Berger M. Intramuscular versus intravenous immunoglobulin replacement therapy and measurement of immunoglobulin levels during immunoglobulin replacement therapy. J Allergy Clin Immunol Pract 2013;1:705-6. http://dx.doi.org/10.1016/j.jaip.2013.08.007. Corresponding author: Phillip Lieberman, MD, Department of Allergy/Immunology, University of Tennessee College of Medicine, 7205 Wolf River Blvd, Suite 200, Germantown, TN 38138-1777. E-mail: [email protected]. J Allergy Clin Immunol Pract 2013;1:705-6. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.08.007

IM volumes risk nerve injury if given in gluteal sites. In the benchmark 1969 study in the United Kingdom, the discomfort of IM injections limited the dose to 25 mg/kg per week. The higher dose of 50 mg/kg per week (maximum of 200 mg/kg per month) was continued in only a few hearty individuals because of severe infections.1 A crossover study of 100 mg/kg per month given IM or IV showed a significant decrease in nonsevere upper respiratory tract infections during the IM treatment phase, which was thought to be due to better reporting during the IV treatment phase, when the subjects were seen monthly.2,3 There was no difference in overall efficacy.2 Once IVIG became available, however, doses started increasing as patients and physicians saw that higher doses resulted in greater increments in the serum IgG levels and much better freedom from acute infections and other symptoms,3,4 so IM treatment became unpopular. There also was the sense that IM injections resulted in some degradation of IgG in the tissues. I do not believe that this was ever studied with rigorous pharmacokinetic evaluations, but it is clear that there is a decrease in the bioavailability of IgG given subcutaneously compared with intravenously, and we assume the same would be true for IM injections.5 (2) When a patient is started on weekly SCIG at 25% of the previous monthly IVIG dose and the first SC infusion is given 1 week after the last IV infusion (as has been done in most US licensing studies), the serum level will initially remain higher than the trough on the previous IgG regimen because the SCIG is started before the serum level from the IV dose has reached its nadir. Results of different studies suggest that, after switching from IVIG to SCIG, it takes 8 weeks,6 5 weeks,7 or 7 to 12 weeks8 to achieve a “steady state.” Most US licensing studies, therefore, allow 12 weeks as a “wash-in/wash-out” period before measuring the new IgG level. If the weekly SCIG dose is 25% of the previously monthly IV dose (in other words, the same total monthly dose), then the steady-state level is likely to be 12% to 15% higher than the trough on IVIG.9 If the dose of SCIG is adjusted upward to compensate for the decreased bioavailability of SCIG, then you can expect a fairly linear dose response. Thus, if the weekly SCIG dose is 35% to 40% of the previous monthly IVIG dose, then the total monthly SCIG dose will be 1.5 to 1.6 times the previous monthly IVIG dose and the steady-state level should be 30% to 40% higher than the previous trough on every 4-weekly IVIG.9 Regardless of the route of therapy, the dose should be 705

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adjusted according to the individual patient’s clinical condition rather than a “target” serum IgG level. REFERENCES 1. Medical Research Council Working Party. Hypogammaglobulinemia in the UK. Lancet 1969;1:163-8. 2. Amman AJ, Ashman RF, Buckley RH, Hardie WR, Krantmann HJ, Nelson J, et al. Use of Intravenous g-globulin in antibody immunodeficiency: results of a multicenter controlled trial. Clin Immunol Immunopathol 1982;22:60-7. 3. Buckley RH. Long term use of intravenous immune globulin in patients with primary immunodeficiency diseases: inadequacy of current dosage practices and approaches to the problem. J Clin Immunol 1982;2(Suppl):15S-21S. 4. Pirofsky B. Intravenous immune globulin therapy in hypogammaglobulinemia. Am J Med 1984;76:78-82.

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5. Berger M, Jolles S, Orange JS, Sleasman JW. Bioavailability of IgG administered by the subcutaneous route. J Clin Immunol 2013;33:984-90. 6. Ochs H, Gupta S, Kiessling P, Nicolay U, Berger M. Safety and efficacy of selfadministered immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol 2006;26:265-73. 7. Wasserman RL, Irani AM, Tracy J, Tsoukas C, Stark D, Levy R, et al. Pharmacokinetics and safety of subcutaneous immune globulin (human) 10% caprylate/chromatography purified in patients with primary immunodeficiency disease. Clin Exp Immunol 2010;161:518-26. 8. Wasserman RL, Melamed I, Nelson RP Jr, Knutsen AP, Fasano MB, Stein MR, et al. Pharmacokinetics of subcutaneous IgPro20 in patients with primary immunodeficiency. Clin Pharmacokinet 2011;50:405-14. 9. Berger M, Rojavin M, Kiessling P, Zenker O. Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies. Clin Immunol 2011;139:133-41.

Intramuscular versus intravenous immunoglobulin replacement therapy and measurement of immunoglobulin levels during immunoglobulin replacement therapy.

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