Bioavailability of IgG Administered by the Subcutaneous Route

Abstract

PurposeUS licensing studies of subcutaneous IgG (SCIG) calculate dose adjustments necessary to achieve area under the curve (AUC) of serum IgG vs. time on SCIG that is non-inferior to that on intravenous IgG (IVIG), within the FDA-set limit of ±20 %. The results are interpreted as showing that different SCIGs differ in bioavailability. We used three approaches to determine if the bioavailabilities were actually different.MethodsDose adjustments and AUCs from published licensing studies were used to calculate bioavailabilities using the formula: Bioavailability (% of IVIG) = AUC(SCIG) ÷ AUC(IVIG) x 1/Dose Adjustment. We also compared the increment in serum IgG concentration achieved with varying doses of SCIG in recent meta-analyses with the increment with different doses of IVIG, and determined the serum IgG concentrations when patients switched SCIG products at the same dose.ResultsThe actual bioavailabilities were: Gamunex® 65.0 %, Hizentra® 65.5 %, Gammagard® 67.2 %, Vivaglobin® 69.0 %. Regression analyses of serum IgG vs. dose showed that the mean increase in serum IgG resulting from a 100 mg/kg/month increment in SCIG dosing was 69.4 % of the increase with the same increment in IVIG dosing (84 mg/dL vs. 121 mg/dL). Patients switching SCIG preparations at the same dose had no change in serum IgG levels, confirming that bioavailabilities of the SCIG preparations did not differ.ConclusionsDecreased bioavailability appears to be a basic property of SCIG and not a result of any manufacturing process or concentration. Because serum IgG levels do not vary with different SCIG products at the same dose, adjustments are not necessary when switching products.

Efficacy and tolerability of 16% subcutaneous immunoglobulin compared with 20% subcutaneous immunoglobulin in primary antibody deficiency

“…SCIG has reduced bioavailability compared with IVIG, presumably because of decreased absorption in the subcutaneous tissues and increased local IgG catabolism [24]. However, bioavailability does not appear to be determined specifically by the concentration or formulation of the SCIG product [25]. The dosing used in this study achieved steady-state IgG levels that were similar between the two products; only two subjects required dose increases to maintain equivalent IgG levels during treatment with Hizentra.…”

“…Following screening, eligible subjects received Vivaglobin weekly for 8 weeks followed by Hizentra weekly for 24 weeks, with weeks 9-20 as a transition period and a final 12-week period (weeks [21][22][23][24][25][26][27][28][29][30][31][32]. Study visits took place at screening, entry and at 8, 12, 20 and 32 weeks.…”

“…0Á05). ‡ Protective titer for tetanus is !0Á1 IU/ml [25]. § Protective titer for positive predictive value (PPV) !0Á35 mg/ml [18][19][20].…”

International Consensus Document (ICON): Common Variable Immunodeficiency Disorders

“…187 If there is preexisting bronchiectasis, there is evidence for using 0.6 g/kg/month. 188 Some practitioners also recommend higher doses (0.6–0.8 g/kg/month) for patients with enteropathy or splenomegaly.…”

Immunoglobulin Therapy

“…37 Higher and more stable trough levels have been seen with the subcutaneous administration of immunoglobulin, alleviating the fatigue and general constitutional symptoms patients have on IVIG toward the end of their 3-4 weeks dosing interval. 25,26,41 However, Berger et al 42 have recently shown that all US-licensed SCIG products have a similar bioavailability: 66.7% ± 1.8% of IVIG. When immunoglobulin is administered via the SC route, the dose is absorbed into the circulation and redistributed to the peripheral tissues more slowly than when given via the IV route.…”