Research ArticlesPharmacokinetic/Pharmacodynamic Modeling of the Effects of Intravenous Immunoglobulin on the Disposition of Antiplatelet Antibodies in a Rat Model of Immune Thrombocytopenia
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INTRODUCTION
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by decreased platelet counts and increased platelet destruction.1,2 This increased platelet destruction is believed to be due to the interaction of antiplatelet antibodies with proteins on the surface of the platelet, eventually leading to the destruction of the platelet.2,3 Imbach et al. first showed that intravenous (iv) administration of high‐doses of pooled immunoglobulin leads to increases in platelet counts in many
IgG Pharmacokinetic Model
To develop a quantitative model of ITP, antiplatelet antibody (7E3) pharmacokinetics (0.8–8 mg/kg) were studied in the presence or absence of IVIG (0–2 g/kg), in jugular vein‐cannulated Sprague‐Dawley rats. Additional 7E3 (8 mg/kg) PK studies were then performed in mice lacking FcRn receptor expression and in control mice, again in the presence or absence of IVIG (1 g/kg), to gain a better understanding of the role of FcRn in the observed effects of IVIG on 7E3 elimination. The methodology for
RESULTS
Best‐fit lines characterizing the effect of IVIG on 7E3 pharmacokinetics in control mice and in mice lacking FcRn expression are shown in Figure 1. The 7E3 concentrations decline monoexponentially in mice lacking expression of FcRn, but show polyexponential decline in control animals. The parameter values obtained from the fit are listed in Table 1.
Characterizations of 7E3 pharmacokinetics in the rat, in the absence or presence of IVIG, are shown in Figures 2 and 3, respectively.The 7E3
DISCUSSION
For the last two decades, researchers have been investigating the mechanisms by which IVIG increases platelet counts in patients with ITP. Although many different effects of IVIG have been identified, the relative importance of these effects has been difficult to determine. This study reports the mathematical characterization of antiplatelet antibody induced thrombocytopenia in an animal model of ITP, and demonstrates the application of modeling for the quantitative assessment of the
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