Steady-State Serum IgG Trough Levels Are Adequate for Pharmacokinetic Assessment in Patients with Immunodeficiencies Receiving Subcutaneous Immune Globulin

Abstract

Patients with primary immunodeficiency diseases often require lifelong immunoglobulin (IG) therapy. Most clinical trials investigating IG therapies characterize serum immunoglobulin G (IgG) pharmacokinetic (PK) profiles by serially assessing serum IgG levels. This retrospective analysis evaluated whether steady-state serum IgG trough level measurement alone is adequate for PK assessment. Based on individual patient serum IgG trough levels from two pivotal trials (phase 2/3 European [NCT01412385] and North American [NCT01218438]) of weekly 20% subcutaneous IG (SCIG; Cuvitru, Ig20Gly), trough level-predicted IgG AUC (AUCτ,tp) were calculated and compared with the reported AUC calculated from serum IgG concentration-time profiles (AUCτ). In both studies, mean AUCτ,tp values for Ig20Gly were essentially equivalent to AUCτ with point estimates of geometric mean ratio (GMR) of AUCτ,tp/AUCτ near 1.0 and 90% CIs within 0.80-1.25. In contrast, for IVIG, 10%, mean AUCτ,tp values were lower than AUCτ by >20%, (GMR [90% CI]: 0.74 [0.70-0.78] and 0.77 [0.73-0.81] for the two studies, respectively). Mean AUCτ,tp values calculated for 4 other SCIG products (based on mean IgG trough levels reported in the literature/labels) were also essentially equivalent to the reported AUCτ (differences <10% for all except HyQvia, a facilitated SCIG product), while differences for IVIG products were >20%. In conclusion, steady-state serum IgG levels following weekly SCIG remain stable, allowing for reliable prediction of AUC over the dosing interval using trough IgG levels. These findings indicate that measuring steady-state serum IgG trough levels alone may be adequate for PK assessment of weekly SCIG.

Keywords: Cuvitru; Pharmacokinetics; intravenous immunoglobulin; primary immunodeficiency diseases; subcutaneous immunoglobulin.

Conflict of interest statement

Zhaoyang Li, Barbara McCoy, Werner Engl, and Leman Yel are employees and shareholders of the Takeda group of companies.

© 2021. Ownership of copyright in the Article shall vest in the Rights Holder. When reproducing the Article or extracts from it, the Rights Holder shall acknowledge and reference first publication in the Journal.

Figures

Fig. 1

Trough-predicted AUCτ,tp versus reported AUCτ (90% CIs) for IVIG and SCIG in two phase 2/3 licensing studies of Ig20Gly (Cuvitru), calculated using individual patient data. Error bars represent 90% CIs. Horizontal reference line = GMR of 1.0. AUCτ, area under the curve calculated from serum IgG concentration-time profiles over a dosing interval; AUCτ,tp, trough level-predicted area under the curve over a dosing interval; CI, confidence interval; GMR, geometric mean ratio; Ig20Gly, Immune Globulin Subcutaneous (Human) 20% Solution; IVIG, intravenous immunoglobulin; SCIG, subcutaneous immunoglobulin; τ, dosing interval (3–4 weeks for IVIG [Kiovig/GammaGard and Gamunex] and facilitated SCIG [HyQvia/HYQVIA], and 1 week for SCIG [Cuvitru, Kiovig/GammaGard, Gamunex, and Hizentra])

Fig. 2

Agreement between trough-predicted AUCτ,tp versus reported AUCτ for IVIG (a) and SCIG (b) in two phase 2/3 licensing studies of Ig20Gly. To facilitate the interpretation, back-transformed values are shown. The central (upper/lower) line represents the mean (± 1.96 standard deviations) of the log-transformed difference of predicted vs reported values to account for the approximately Gaussian distribution of the AUCs. AUCτ, area under the curve calculated from serum IgG concentration-time profiles over a dosing interval. AUCτ,tp, trough level-predicted area under the curve over a dosing interval; Ig20Gly, Immune Globulin Subcutaneous (Human) 20% Solution; IVIG, intravenous immunoglobulin; SCIG, subcutaneous immunoglobulin; τ, dosing interval (3–4 weeks for IVIG, 10%, and 1 week for SCIG, 16% and SCIG, 20%)