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Francisco A. Bonilla, MD, PhD Boston Children’s Hospital Harvard Medical School

Intravenous and Subcutaneous IgG Replacement Therapy. Francisco A. Bonilla, MD, PhD Boston Children’s Hospital Harvard Medical School. Disclosures. Albany Medical College Honorarium Baxter, Inc. Consultant The Cowen Group, Inc. Consultant CSL Behring, Inc.

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Francisco A. Bonilla, MD, PhD Boston Children’s Hospital Harvard Medical School

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  1. Intravenous and Subcutaneous IgG Replacement Therapy Francisco A. Bonilla, MD, PhD Boston Children’s Hospital Harvard Medical School

  2. Disclosures • Albany Medical College • Honorarium • Baxter, Inc. • Consultant • The Cowen Group, Inc. • Consultant • CSL Behring, Inc. • Consultant, research support • Gerson-Lehrman Group, Inc. • Consultant • Grand Rounds Health • Consultant • Green Cross / American Research Group, Inc. • Data safety monitor • Immune Deficiency Foundation • Medical Advisory Board • Consultant Immunologist Program • Octapharma, Inc. • Data safety monitor • UpToDatein Medicine • Royalties

  3. Ig half-lives From Waldmann TA, et al., In: Merler E, ed. Immunoglobulins. Wash., DC: Natl. Acad. Sci.; 1970, and Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin Invest 1970; 49:673–80.

  4. IgG • Has the highest concentration of any serum Ig • The total body content of IgG is approximately 1 g/kg • About ½ is in the intravascular compartment

  5. Catabolism of IgG 100 • The rate of catabolism of IgG is proportional to the concentration • The half-life of IgG is inversely proportional to the concentration • Only true for IgG 90 80 70 60 50 Serum IgG concentration (mg/mL) 40 30 20 10 0 0 20 40 60 80 IgG survival t1/2 (days) From Waldmann TA, et al., In: Merler E, ed. Immunoglobulins. Washington, DC: National Academy of Sciences; 1970

  6. FcRn in IgG catabolism From Bonilla, FA, Immunol Allergy Clin N Am 2008; 28:803.

  7. IgG distribution in the body Synthesis SCIG IVIG Intravascular compartment Extravascular compartment(s) Catabolism Loss

  8. IgG administration • Intramuscular injection (IMIG) • Painful, can only administer small amounts, rarely used today • Intravenous infusion (IVIG) • Most widely applied, 90% of replacement therapy, all immunomodulatory therapy • Subcutaneous (SCIG) • Gaining popularity

  9. IVIG dosing • Loading dose 1 g/kg IV, if necessary • 300-400 mg/kg q 3 weeks (max. 600) • 400-600 mg/kg monthly (max. 800) • In general, interval not <2 weeks, not >4

  10. SCIG dosing • Loading dose 1 g/kg IV, if necessary • 100 mg/kg weekly (max. 200) • 50 mg/kg twice weekly (max. 100) • In general, not >twice weekly, or < q 2 weeks

  11. SCIG dosing • Each site may receive 20-40 cc • Max. infusion rate per site approx. 20-40 cc • Amount and rate for each site may depend on BMI (more subQ space can be a good thing) • For most pts., 3-4 sites necessary for each infusion

  12. Rapid push SCIG • One site • With or without pump • Usually more often than once/week (often daily)

  13. Rapid push SCIG • Retrospective review, one center, 104 pts, 2006-2008 • Average 3.1 infusions/week, usually one site, 3-20 mL over 5-20 minutes • Preferred by 71% of patients • IgG levels and rate of local symptoms (1/3 of pts.) same with push or pump Shapiro J ClinImmunol2010; 30:301

  14. IVIG vs SCIG dosing

  15. IVIG pharmacokinetics AUC From Bonilla, FA, Immunol Allergy Clin N Am 2008; 28:803.

  16. SCIG pharmacokinetics AUC From Berger M. Subcutaneous IgG therapy in immune deficiency diseases. In: Clinical focus on primary immune deficiencies, issue 13. Towson (MD): Immune Deficiency Foundation; 2008. p. 2.

  17. SCIG pharmacokinetics From Gustafson R, et al. Clin Exp Immunol 2008;152:277.

  18. IVIG half lives Sources: product prescribing literature and published clinical trials. Also see Bonilla, FA, Immunol Allergy Clin N Am 2008; 28:803.

  19. “Biological” IgG level From Bonagura VR et al., J Allergy Clin Immunol 2008; 122:210.

  20. IgG dosing meta analysis Orange et al. ClinImmunol 2010; 137:21

  21. IgG dosing meta analysis Orange et al. ClinImmunol 2010; 137:21

  22. SCIG dosing meta-analysis Slope=84.4 Orange et al. ClinExpImmunol 2012; 169:172

  23. SCIG dosing meta-analysis Orange et al. ClinExpImmunol 2012; 169:172

  24. IVIG-SCIG dose conversion Berger et al. ClinImmunol 2011; 139:133.

  25. IVIG vs SCIG (r) was 0.8938; P=0.0002 Berger et al. ClinImmunol 2011; 139:133.

  26. IVIG vs SCIG • Meta-analysis of published comparisons • 47 articles (10 clinical trials, 17 prospective cohorts and 20 retrospective cohorts) total number of evaluable patients was 1,028 of which 67.7 % were adults and 56.3 % carried the diagnosis of CVID • Similar IgG levels • Slightly lower serious bacterial infections with SCIG • Much lower systemic AE’s with SCIG • Improved QOL with SCIG • Reduced cost with SCIG Abolhassani et al. J ClinImmunol 2012 epub.

  27. SCIG DOSE Orange et al. ClinExpImmunol 2012; 169:172

  28. SCIG 2 doses Haddad et al. J ClinImmunol 2012; 32:281.

  29. IgG Bioavailability Berger et al. J ClinImmunol 2013;33:984.

  30. Bioavailability IV vs SC Bioavailability of SCIG = 69% IVIG Berger et al. J ClinImmunol 2013;33:984.

  31. Home care IgG • Healthcare database survey: 3,187 patients with PIDD on IgG replacement at home • 54% SCIG / 46% IVIG • SCIG use increases with age • Mean monthly dose: • SCIG – 409 mg/kg/month • IVIG – 568 mg/kg/month • Dose decreases with age Huang et al. J ClinImmunol 2013: 33:49

  32. Dose vs Age Literature review, 25 randomized and non-randomized studies Huang et al. J ClinImmunol 2013: 33:49

  33. IVIG vs SCIG Literature review, 25 randomized and non-randomized studies IV SC N IV SC N Lingman-Framme et al. Drugs 2013; 73:1307

  34. IVIG vs SCIG Literature review, 25 randomized and non-randomized studies HQOL superior with SCIG in 7 studies Global/general health Bodily pain Role social/emotional, physical Parental impact/emotional, time Family activities Vitality Mental health Social functioning Lingman-Framme et al. Drugs 2013; 73:1307

  35. IVIG vs SCIG Literature review, 25 randomized and non-randomized studies Lingman-Framme et al. Drugs 2013; 73:1307

  36. IVIG vs SCIG cost • Canadian study, single institution, home therapy • Switch from IVIG to SCIG • IgG product cost not included • Projected cost savings $1,912/pt/yr, 74% reduction • Lower personnel cost Martin et al. Transfus Med 2013; 23:55

  37. IVIG vs SCIGand BMI Shapiro, ClinExpImmunol 2013; 173:365

  38. IVIG vs SCIG and BMI Shapiro, ClinExpImmunol 2013; 173:365

  39. 20% SCIG: long-term efficacy/safety • Subjects 4-69 years old • EU – n=40, 148 weeks, 5,405 infusions • USA – n=21, 87 weeks, 1,735 infusions Jolles et al. ClinImmunol 2014; 150:161

  40. SCIG 10% IgG + hyaluronidase N=81 N=87 Wasserman J Allergy ClinImmunol 2012; 130:951

  41. SCIG 10% IgG + hyaluronidase Wasserman J Allergy ClinImmunol 2012; 130:951

  42. SCIG 10% IgG + hyaluronidase Wasserman J Allergy ClinImmunol 2012; 130:951

  43. SCIG 10% IgG + hyaluronidase Wasserman. Immunotherapy 6:553

  44. IgGregimens

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