Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patients with severe persistent allergic (IgE‐mediated) asthma
- 16 July 2009
- journal article
- research article
- Published by Wiley in British Journal of Clinical Pharmacology
- Vol. 68 (1), 61-76
- https://doi.org/10.1111/j.1365-2125.2009.03401.x
Abstract
Omalizumab, a subcutaneously administered anti-IgE antibody, is effective for moderate-to-severe persistent allergic asthma. The aims were to (i) describe the population pharmacodynamics of free IgE with a mechanism-based, nonlinear, omalizumab-IgE binding model; (ii) deduce a target-free IgE suppression level by correlation with clinical outcomes; and (iii) check the adequacy of current approved dosing tables and explore potential doses and regimens beyond. Concentration data (omalizumab, free and total IgE) were obtained from 1781 patients aged 12-79 years, in four sparsely sampled randomized, placebo-controlled studies and 152 subjects in a richly sampled single-dose study. NONMEM predictive performance across the range of bodyweights (39-150 kg) and baseline IgE (19-1055 IU ml(-1)) was checked by simulation. Predicted free IgE levels were correlated with time-averaged patient diary clinical outcomes. The model accurately predicted observed omalizumab, free and total IgE concentrations. Free IgE concentrations correlated well with clinical signs and symptoms, allowing a target concentration of 14 ng ml(-1), at the midpoint of 4-week clinical observation periods, to be set for determining the dose and regimen for omalizumab. The omalizumab-IgE binding model is predictive for free IgE and demonstrates a nonlinear time-dependent relationship between free IgE suppression and clinical outcomes in asthma. Although currently approved dosing tables are close to optimal, it should be possible to treat patients with higher levels of baseline IgE if higher doses can be administered.This publication has 35 references indexed in Scilit:
- A mechanism‐based binding model for the population pharmacokinetics and pharmacodynamics of omalizumabBritish Journal of Clinical Pharmacology, 2007
- The anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammationJournal of Allergy and Clinical Immunology, 2005
- On the Prediction of the Human Response: A Recycled Mechanistic Pharmacokinetic/Pharmacodynamic ApproachBasic & Clinical Pharmacology & Toxicology, 2005
- The effect of treatment with omalizumab, an anti‐IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthmaAllergy, 2004
- Efficacy and safety of a recombinant anti‐immunoglobulin E antibody (omalizumab) in severe allergic asthmaClinical & Experimental Allergy, 2004
- The global burden of asthma: executive summary of the GINA Dissemination Committee ReportAllergy, 2004
- Omalizumab rapidly decreases nasal allergic response and FcεRI on basophilsJournal of Allergy and Clinical Immunology, 2004
- Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthmaJournal of Allergy and Clinical Immunology, 2001
- Characterization of Complex Formation by Humanized Anti-IgE Monoclonal Antibody and Monoclonal Human IgEBiochemistry, 1995
- Association of Asthma with Serum IgE Levels and Skin-Test Reactivity to AllergensThe New England Journal of Medicine, 1989