Omalizumab decreases IgE production in patients with allergic (IgE-mediated) asthma; PKPD analysis of a biomarker, total IgE
Version of Record online: 11 JUL 2011
© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society
British Journal of Clinical Pharmacology
Special Issue: Uropharmacology Themed Section
Volume 72, Issue 2, pages 306–320, August 2011
How to Cite
Lowe, P. J. and Renard, D. (2011), Omalizumab decreases IgE production in patients with allergic (IgE-mediated) asthma; PKPD analysis of a biomarker, total IgE. British Journal of Clinical Pharmacology, 72: 306–320. doi: 10.1111/j.1365-2125.2011.03962.x
- Issue online: 11 JUL 2011
- Version of Record online: 11 JUL 2011
- Accepted manuscript online: 11 MAR 2011 04:59AM EST
- Received , 19 July 2010 , Accepted , 16 December 2010 , Accepted Article , 11 March 2011
- pharmacodynamic ;
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Omalizumab is a humanized anti-IgE monoclonal antibody that binds and captures circulating IgE, preventing interaction with receptors on mast cells and basophils, thereby interrupting the allergic cascade. It has a well-characterized efficacy and safety profile in patients with asthma. While omalizumab is known to reduce serum free IgE concentrations, effects on total IgE and IgE production are less well characterized.
WHAT THIS STUDY ADDS
• (i) Confirmation of prior hypotheses that IgE production can decrease with time when patients are given anti-IgE therapy; (ii) guidance on a biomarker, total IgE, which can be used to ascertain whether individual patients experience a change in their IgE production; and (iii) a way to assess whether patients' IgE production has been sufficiently down-regulated such that they may consider stopping anti-IgE therapy.
AIM To determine whether excessive IgE production by patients with atopic allergic asthma decreases with omalizumab therapy.
METHODS Omalizumab, free and total IgE data were obtained from an epidemiological study and six randomized, double-blind, placebo-controlled trials in patients with allergic asthma. The binding between omalizumab and IgE together with the production and elimination of IgE were modelled as previously, except that, in order to explain why total IgE was decreasing over a period of 5 years, the expression of IgE was allowed to change.
RESULTS The prior constant IgE production model failed to converge on the data once long-term observations were included, whereas models allowing IgE production to decrease fitted. A feedback model indicated that, on average, IgE production decreased by 54% per year. This model was further developed with covariate searches indicating clinically small but statistically significant effects of age, gender, body mass index and race on some parameters. Model predictions were checked internally and externally against 3–5 year data from paediatric and adult atopic asthmatic patients and externally against extensive total IgE data from a long-duration (>1 year) phase 1 study which was not used in the model building.
CONCLUSIONS A pharmacokinetic–pharmacodynamic model incorporating omalizumab–IgE binding and feedback for control of IgE production indicates that omalizumab reduces production of IgE. This raises the possibility that indefinite treatment may not be required, only for perhaps a few years. After the initial accumulation, total IgE should provide a means to monitor IgE production and guide individual treatment decisions.