Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patients with severe persistent allergic (IgE-mediated) asthma

center dot It had been hypothesized that there must be a relationship between free IgE concentrations and the signs and symptoms of asthma - after all, this is what drove the development of omalizumab. center dot However, although many statistical analyses of free IgE and spirometry data for patients equilibrated on omalizumab had shown a difference between placebo and treatment, no consistent time- and IgE-dependent relationship had been shown due to the narrow range of free IgE being studied and the sparse nature of the sampling and clinical measurements in Phase III trials. WHAT THIS STUDY ADDS center dot The above problem was solved using a pharmacokinetic-pharmacodynamic (PK-PD) model to estimate free IgE concentrations for all time points throughout and after treatment with omalizumab, together with patient daily diary data. center dot This allowed for the first time the direct correlation between free IgE and signs and symptoms of asthma to be observed. center dot Doses and regimens for omalizumab could then be derived, through PK-PD model simulation, for suppressing free IgE to a point correlated with an improvement in clinical symptoms. AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.