Sungpil Han (1), Hyungsub Kim (1), Hyeong-Seok Lim (1)
(1) Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Korea
Objectives: Immune thrombocytopenia (ITP) is acquired thrombocytopenia by platelet destruction caused by autoantibodies. [1] Intravenous immunoglobulin (IVIg) can elevate the platelet count by blocking macrophage uptake of autoantibody-surrounded platelets. [2] Glucocorticoid administration is beneficial for ITP patients by enhancing apoptotic death of autoantibody-producing lymphocytes and downregulation of macrophage activity. [3] The objectives of this study is to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of IVIg-SN 10% in adult ITP patients in conjunction with glucocorticoid co-administration.
Methods: PK/PD data used for this analysis were from a prospective, non-randomized, open-label, single-arm, multi-center phase III clinical trial where 81 subjects intravenously received IVIg-SN 10% at a dose of 1g/kg/day for two consecutive days and 69 subjects completed the study. The response was defined as the achievement of the platelet count (PD marker) of > 50 × 10^9^/L at day 8, and 75.7% achieved the response satisfying the pre-defined non-inferiority condition (70%). PK analysis (25 subjects) was conducted by nonlinear mixed effect modeling implemented in NONMEM using first-order conditional estimation with INTERACTION method. PD analysis was performed using the indirect response model with a precursor pool and for those who received both IVIg-SN 10% and glucocorticoid (prednisolone, methylprednisone, or dexamethasone) the response-surface model for the platelet count was applied.
Results: The PK modeling was conducted, and covariate analysis revealed that sex (male) and body surface area affect PK of IVIg-SN 10% by increasing volume of distribution. Data showed the sharp increase in the IVIg-SN 10% concentration after intravenous administration and gradual decrease (t1/2β = 28.9 days). Median time to response was 2 days and mean duration of maintaining response was 9.13 days. Concomitant systemic glucocorticoid administration can increase and maintain the platelet count. The final plasma PK model and response-surface PD model describe the data reasonably well.
Conclusions: The current modeling and simulation analysis characterized the PK/PD of IVIg-SN 10% using the response-surface model of glucocorticoids, which will be useful in identifying the optimal dosing regimens of IVIg-SN 10% and glucocorticoids.
References:
[1] Neunert C, Lim W, Crowther M, Cohen A, Solberg L, Jr, Crowther MA. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190–4207.
[2] Neunert CE. Current management of immune thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2013;2013:276–282.
[3] Mizutani H, Furubayashi T, Imai Y, Kashiwagi H, Honda S, Take H, Kurata Y, Yonezawa T, Tarui S, Ikehara S. Mechanisms of corticosteroid action in immune thrombocytopenic purpura (ITP): experimental studies using ITP-prone mice, (NZW x BXSB) F1. Blood. 1992 Feb;79(4):942-7.
Reference: PAGE 27 (2018) Abstr 8587 [www.page-meeting.org/?abstract=8587]
Poster: Drug/Disease Modelling - Other Topics