a webcast immunology and allergy clinics of north america
TRANSCRIPT
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A Webcast
IMMUNOLOGY ANDALLERGY CLINICSOF NORTH AMERICA
IMMUNOLOGY ANDALLERGY CLINICSOF NORTH AMERICA
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
The Art of IgG Replacement in Treating Primary Immunodeficiency Patients
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
HISTORICAL PERSPECTIVE ON THE THERAPEUTIC USE OF GAMMAGLOBULIN
• 1952 - Treatment of agammaglobulinemia with IM immunoglobulin G (IgG)
• 1966 - Plasma therapy using a “buddy” system
• 1969 - Pepsin-digested Ig for IV use
• 1975 - Initial studies of Ig for use by IV route
• 1981 – Approval of IGIV for use in primary immune deficiencies
• 1994 – Transmission of hepatitis C by IGIV• FDA and GMP introduce solvent/detergent, pasteurization, caprylate to
prevent transmission of lipid envelope viruses
• 1999 – Renal failure by sucrose-containing IGIV products
• 2000 – CJD/new-variant prion disease• Quarantine of IGIV product produces a shortage• Nanofiltration introduced to remove prions
• 2002 – MedWatch for thrombotic events
CJD = Creutzfeldt-Jakob disease; FDA = Food and Drug AdministratIon; GMP = good manufacturing practices; IGIV = intravenous immunoglobulin G; IV = intravenous.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
IGIV COMPOSITION
• Donor pool– Derived from 2,000-10,000 donors
• may be as much as 60,000 donors
• Composition– Monomeric IgG (>95%) with small amounts of dimeric and
polymeric IgG1
– Small amounts of IgM and IgA present; varies with product
• Antibody content– One gram of IGIV contains 4x1018 molecules of antibody– >107 specificities to a broad range of bacterial and viral
pathogens
• Stabilized with sugars or amino acids; differs for each product
1. Rütter A, Luger TA. J Am Acad Dermatol 2001;44(6):1010-24.IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; IGIV = intravenous immunoglobulin G.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
DOSES OF IGIV FOR PIDD
• Early studies compared IGIV with IGIM
– IM dose: 0.6 cc/kg (~100 mg/kg/mo)
– Initial recommendation for IGIV was 200 mg/kg/mo for first IGIV products
• Late 1980s (Roifman): IgG trough serum levels ≥500 mg/dL reduced frequency of infection and improved pulmonary function1,2
• Recommendation modified in early 1990 to 400 mg/kg to achieve a trough level of ≥500 mg/dl
1. Roifman CM, Gelfand EW. Pediatr Infect Dis J 1988;7(5, suppl):S92-6. 2. Roifman CM, et al. Lancet 1987;i(8541):1075-7.IgG = immunoglobulin G; IGIM = intramuscular immunoglobulin G; IGIV = intravenous immunoglobulin G; IM = intramuscular; PIDD = primary immunodeficiency disease.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
DOSES OF IGIV FOR PIDD (cont)
• Quartier et al (Fisher et al)1
– Retrospective study of patients with x-linked agammaglobulinemia (Bruton’s disease)
– Incidence of bacterial infections requiring hospitalization fell from 0.4 to 0.06 per patient per year
• Serum IgG trough levels >500 mg/dL were effective in preventing severe acute bacterial infections
– Patients still developed enteroviral meningoencephalitis and chronic pulmonary disease
• Authors recommended a higher dose to maintain a higher serum IgG trough level (eg, >750 mg/dL to prevent enteroviral disease)
1. Quartier P, et al. J Pediatr 1999;134(5):589-96.IgG = immunoglobulin G; IGIV = intravenous immunoglobulin G; PIDD = primary immunodeficiency disease.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
IGIV TherapyBeforeDuring
IgG TROUGH LEVELS AND PNEUMONIA
IRR = 0.726 (CI, 0.658–0.801)
IgG (mg/dL) Incidence (CI)500 0.113 (0.042-0.300)600 0.082 (0.030-0.219)700 0.059 (0.022-0.162)800 0.043 (0.015-0.120)900 0.031 (0.011-0.090)
1000 0.023 (0.008-0.068)
2
1
0.5
0.2
0.1
0.05
0.02
0.01
0.0
Pneu
mon
ia In
cide
nce
per P
atien
t-Ye
ar
Trough IgG (mg/dL)0 200 400 600 800 1000
Orange JS, et al. Clin Immunol 2010;137:21-30.CI = confidence interval; IRR = incidence rate ratio; IgG = immunoglobulin G; IGIV = intravenous immunoglobulin G; IRR = incidence rate ratio.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
“BIOLOGIC TROUGH LEVELS”
Titrate IgG trough level to clinical efficacy for an individual patient
Bonagura VR, et al. J Allergy Clin Immunol 2008;122(1)210-2.*Time at which authors assumed care of this patient.IgG = immunoglobulin G; IGIV = intravenous immunoglobulin G; P = pneumonia; S = acute sinusitis.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
SUMMARY: DOSE OF IGIV FOR PATIENTS WITH ANTIBODY DEFICIENCY• 400-600 mg/kg/infusion every 4 weeks1
– Adjust dose and/or interval (q 2-3 weeks) depending on clinical response
– In patients starting with higher serum IgG levels, a rough goal is a serum trough level equal to pretreatment levels plus 300 mg/dL
• Follow clinical response; don’t treat the “numbers”– “Biologic trough levels” for better clinical efficacy– Patients with bronchiectasis require higher dosing2
• When changing the dose, it may take several (3) infusions to equilibrate to a new trough3
• Consider the SC route to eliminate trough levels1. Orange JS, et al. J Allergy Clin Immunol 2006;117(suppl):S525-3. 2. Lucas M, et al. J Allergy Clin Immunol 2010;125(6):1345-60. 3. Lehman HK, Ballow M. In: Leung DYM, et al, eds. Pediatric allergy: principles & practice, 2nd edition. St. Louis: Mosby; 2010. Chap 17.IgG = immunoglobulin G; IGIV = intravenous immunoglobulin G; SC = subcutaneous.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
IgG LEVELS: IGIV vs IGSC
Bonilla FA. Immunol Allergy Clin North Am 2008;28(4):803-19.IgG = immunoglobulin G; IGIV = intravenous immunoglobulin G; IGSC = subcutaneous immunoglobulin G.
IGIV IGSC
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
IgG DOSING: IGSC vs IGIV
• US FDA– To achieve AUC bioequivalence, IGSC must be
dosed higher than IGIV1-3
• 10% and 16% products – 137% of IV dose• 20% product – 153% of IV dose
• European Medicines Agency4 – IGSC is to be dosed at 100% of the IGIV dose
1. Wasserman RL, et al. Clin Exp Immunol 2010;161(3):518-26. 2. Ochs HD, et al. J Clin Immunol 2006;26:265-73. 3. Berger M, et al. Clin Immunol 2011;139:133-41. 4. European Agency for the Evaluation of Medical Products Human Medicines Evaluation Unit. Note for guidance on the clinical investigation of human normal immunoglobulin for subcutaneous and intramuscule use (CPMP.BPWG/283/00). 2002.AUC = area under the curve; IgG = immunoglobulin G; IGSC = subcutaneous immunoglobulin G; IGIV = intravenous immunoglobulin G; US FDA = US Food and Drug Administration.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
MECHANISM OF ACTION OF rHuPH201,2
• Hyaluronan forms a barrier to bulk movement of molecules in the interstitial space
• Focal depolymerization of hyaluronan increases hydraulic conductivity in the interstitium and rates of infusion/injection
• Reversible change by virtue of short enzyme half-life and rapid endogenous substrate turnover in the skin
• Increased dispersion decreases residence time in the interstitium
• More rapid uptake leads to better pharmacokinetics resulting in increased bioavailability
1. Day TD. J Physiol 1952;117:1-8. 2. Bookbinder LH, et al. J Controlled Release 2006;114:230-41.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
IGSC VS IgHY INFUSIONIGSC Site 15 mL
IGSC + rHuPH20 (IGHy) (approx. 300 mL IgG liquid 10% + rHuPH20)
IGHy IGHy
IGSC = subcutaneous immunoglobulin G.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
PHARMACOKINETICS OF ENZYME-FACILITATED IGSC INFUSION (ANIMAL MODEL)
• rHuPH20 increases Cmax and decreases Tmax for large-molecule therapeutics • More rapid absorption (Ka) results in shorter residence time and increased systemic bioavailability
Concentrations of radiolabeled IgG1 (10 mg/kg) administered via IV, SC, or SC + rHuPH20 in rodent model. Gamma counting expressed as counts per minute per mL of blood.
IgG
Ser
um L
evel
s (C
ount
s/m
L)
Time (h)0 10 20 50 604030 80 90 120110100 130
1.81 E+06
1.61 E+06
1.41 E+06
1.21 E+06
1.01 E+06
8.10 E+05
6.10 E+05
4.10 E+05
2.10 E+05
1.00 E+04
IgG 10 mg/kg SC + rHuPH20 IgG 10 mg/kg SC
IgG 10 mg/kg IV
70
IgG = immunoglobulin G; IGSC = subcutaneous immunoglobulin G; SC = subcutaneous; IV = intravenous.Bookbinder LH, et al. J Controlled Release 2006;114:230-241.
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IMMUNOLOGY AND ALLERGY CLINICS WEBCASTIMMUNOLOGY AND ALLERGY CLINICS WEBCAST
AUCs AFTER IGIV AND IGSC + rHUPH20 (IGHy)
--- IGIV― IGSC + rHuPH20 (IgHy)
Misbah S, et al. Clin Exp Immunol 2009;158(suppl 1):51-9.AUC = area under the curve; IgG = immunoglobulin G; IGIV = intravenous immunoglobulin G; IGSC = subcutaneous immunoglobulin G.