Research Articles
Pharmacokinetic/Pharmacodynamic Modeling of the Effects of Intravenous Immunoglobulin on the Disposition of Antiplatelet Antibodies in a Rat Model of Immune Thrombocytopenia

https://doi.org/10.1002/jps.10364Get rights and content

Abstract

Recently, our laboratory reported that intravenous immunoglobulin (IVIG) treatment increased antiplatelet antibody (7E3) clearance in a rat model of immune thrombocytopenic purpura (ITP). However, due to the multifaceted nature of IVIG therapy, the contribution of this increase in antiplatelet antibody clearance to the total therapeutic effect of IVIG was unclear. The purposes of the present study were to (1) develop a new, mechanistic model of immune gamma globulin (IgG) pharmacokinetics, (2) develop a pharmacokinetic/pharmacodynamic (PK/PD) model relating 7E3 concentrations to the platelet count time course observed following 7E3 treatment, and (3) use these mathematical models to gain insight into the significance of increased 7E3 clearance relative to the total effect of IVIG on 7E3‐induced thrombocytopenia. A mechanism‐based PK model was developed that adequately characterized IVIG effects on 7E3 pharmacokinetics. The structure of this model is based on competition between IgG molecules for occupancy of the protective FcRn receptor. The model accurately captured antiplatelet antibody concentration versus time data in the presence and absence of IVIG therapy, in the rat, in ‘wild‐type’ mice, and in ‘knockout’ mice lacking expression of the FcRn receptor. An indirect response PK/PD model was also developed, which accurately characterized 7E3 effects on platelet counts. Using these models, it was estimated that 50 ± 11% of the total protective effect of IVIG in this acute model of ITP can be accounted for by IVIG effects on 7E3 disposition. © 2003 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:1206–1215, 2003

Section snippets

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

REFERENCES (23)

  • Y.S. Mehta et al.

    In‐vitro inhibition of antiplatelet autoantibodies by intravenous immunoglobulins and Rh immunoglobulins

    J Postgrad Med

    (1996)
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