Asthma and lower airway disease
Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations

https://doi.org/10.1016/j.jaci.2008.09.050Get rights and content

Background

Physicians have questioned whether omalizumab can be discontinued or the dose reduced after clinical improvement is seen in patients with severe asthma.

Objectives

To examine the relationships among omalizumab, free IgE, and clinical outcomes in a randomized, placebo-controlled trial in patients with severe persistent allergic asthma following a posology based on pretreatment total IgE and body weight.

Methods

A pharmacokinetic-pharmacodynamic binding model was used to calculate free IgE, omalizumab, and total IgE concentrations during the 28-week treatment and 16-week follow-up of the INvestigation of Omalizumab in seVere Asthma TrEatment (INNOVATE) study. These were plotted against the mean changes in the total asthma symptom score, morning peak expiratory flow, and rescue medication use for physician-defined treatment responders and nonresponders.

Results

The model accurately fitted omalizumab and free and total IgE, allowing reconstruction of the entire time course for each patient. Free IgE was rapidly suppressed below the 50 ng/mL (20.8 IU/mL) target, although there was a notable period before clinical measures stabilized. After treatment cessation, free IgE and omalizumab returned toward baseline and, after a delay, asthma symptoms re-emerged. Model-derived omalizumab and free IgE concentrations correlated well with changes in clinical outcomes, particularly in omalizumab-treated responders. Asthma symptoms exhibited different correlations during response onset compared with response offset (hysteresis), indicative of physiological time delays between changes in IgE levels and pulmonary function.

Conclusion

Omalizumab and free IgE correlated well with clinical symptoms. Reducing omalizumab doses below those in the dosing table cannot be recommended; the resulting increase in free IgE would cause a deterioration in asthma control.

Section snippets

Methods

A robust PK-PD model15 was used to calculate serum concentrations of free IgE, omalizumab, and total IgE at any point during treatment with omalizumab, from information on the patient's body weight, baseline (total) IgE concentration, dosing history, and concentrations of omalizumab, free IgE, and total IgE during treatment. Model-derived omalizumab and free IgE concentrations were then correlated with mean changes in clinical measures (total asthma symptom score, morning peak expiratory flow

Results

There were a total of 10,872 observations (3221 omalizumab, 4450 total IgE, and 3201 free IgE) from 152 volunteers in the single-dose bioequivalence study and 476 patients in the multiple-dose INNOVATE study. Baseline demographic data are summarized in Table I.

Discussion

A previous mechanism-based population PK-PD model of the binding of an anti-IgE mAb15 has been used to calculate individual patient concentrations of drug and free IgE throughout and after treatment with omalizumab in a phase III clinical study,10 even though actual sampling was limited. To achieve this with good estimates of drug absorption parameters and to demonstrate that the model accurately describes the return of free IgE to baseline, data from a richly sampled bioequivalence study were

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    Supported by Novartis Pharma AG.

    Disclosure of potential conflict of interest: R. G. Slavin receives grant support from Schering-Plough and Accentia and is on the speakers' bureau for Genentech-Novartis. C. Ferioli is employed by Novartis Pharma AG. S. J. Tannenbaum owns stock in Novartis and is employed by Novartis Pharmaceuticals. C. Martin owns stock in Novartis and is employed by Novartis Horsham Research Center. M. Blogg owns stock in Novartis and is employed by Novartis. P. J. Lowe owns stock in Novartis and is employed by Novartis Pharmaceuticals.

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