Omalizumab binds to IgE and prevents binding of IgE to FcεRI (high-affinity IgE receptor) on basophils and mast cells, thereby reducing the amount of free IgE that is available to trigger the allergic cascade. Treatment of atopic subjects with omalizumab resulted in a marked down-regulation of FcεRI receptors on basophils.
Omalizumab binds to IgE and lowers free IgE levels. Subsequently, IgE receptors (FcεRI) on cells down-regulate. It is not entirely understood how this results in an improvement of CSU symptoms.
Omalizumab is a recombinant DNA-derived humanised monoclonal antibody that selectively binds to human immunoglobulin E (IgE). The antibody is an IgG1 kappa that contains human framework regions with the complementary-determining regions of a murine parent antibody that binds to IgE.
The in vitro histamine release from basophils isolated from omalizumab-treated subjects was reduced by approximately 90% following stimulation with an allergen compared to pre-treatment values.
In clinical studies in allergic asthma patients, serum free IgE levels were reduced in a dose-dependent manner within one hour following the first dose and maintained between doses. One year after discontinuation of omalizumab dosing, the IgE levels had returned to pre-treatment levels with no observed rebound in IgE levels after washout of the medicinal product.
In clinical studies in CSU patients, maximum suppression of free IgE was observed 3 days after the first subcutaneous dose. After repeated dosing once every 4 weeks, pre-dose serum free IgE levels remained stable between 12 and 24 weeks of treatment. After discontinuation of omalizumab, free IgE levels increased towards pre-treatment levels over a 16-week treatment-free follow-up period.
The pharmacokinetics of omalizumab have been studied in adult and adolescent patients with allergic asthma as well as in adult and adolescent patients with CSU. The general pharmacokinetic characteristics of omalizumab are similar in these populations.
After subcutaneous administration, omalizumab is absorbed with an average absolute bioavailability of 62%. Following a single subcutaneous dose in adult and adolescent patients with asthma or CSU, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 6-8 days. In patients with asthma, following multiple doses of omalizumab, areas under the serum concentration- time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after the first dose.
The pharmacokinetics of omalizumab are linear at doses greater than 0.5 mg/kg. Following doses of 75 mg, 150 mg or 300 mg every 4 weeks in patients with CSU, trough serum concentrations of omalizumab increased proportionally with the dose level.
Administration of omalizumab manufactured as a lyophilised or liquid formulation resulted in similar serum concentration-time profiles of omalizumab.
In vitro, omalizumab forms complexes of limited size with IgE. Precipitating complexes and complexes larger than one million Daltons in molecular weight are not observed in vitro or in vivo. Based on population pharmacokinetics, distribution of omalizumab was similar in patients with allergic asthma and patients with CSU. The apparent volume of distribution in patients with asthma following subcutaneous administration was 78 ± 32 ml/kg.
Clearance of omalizumab involves IgG clearance processes as well as clearance via specific binding and complex formation with its target ligand, IgE. Liver elimination of IgG includes degradation in the reticuloendothelial system and endothelial cells. Intact IgG is also excreted in bile. In asthma patients the omalizumab serum elimination half-life averaged 26 days, with apparent clearance averaging 2.4 ± 1.1 ml/kg/day. Doubling of body weight approximately doubled apparent clearance. In CSU patients, based on population pharmacokinetic simulations, omalizumab serum elimination half-life at steady state averaged 24 days and apparent clearance at steady state for a patient of 80 kg weight was 3.0 ml/kg/day.
The population pharmacokinetics of omalizumab were analysed to evaluate the effects of demographic characteristics. Analyses of these limited data suggest that no dose adjustments are necessary in patients with asthma for age (6-76 years), race/ethnicity, gender or body mass index.
The effects of demographic characteristics and other factors on omalizumab exposure were evaluated based on population pharmacokinetics. In addition, covariate effects were evaluated by analysing the relationship between omalizumab concentrations and clinical responses. These analyses suggest that no dose adjustments are necessary in patients with CSU for age (12-75 years), race/ethnicity, gender, body weight, body mass index, baseline IgE, anti-FcsRI autoantibodies or concomitant use of H2 antihistamines or LTRAs.
There are no pharmacokinetic or pharmacodynamic data in allergic asthma or CSU patients with renal or hepatic impairment.
The safety of omalizumab has been studied in the cynomolgus monkey, since omalizumab binds to cynomolgus and human IgE with similar affinity. Antibodies to omalizumab were detected in some monkeys following repeated subcutaneous or intravenous administration. However, no apparent toxicity, such as immune complex-mediated disease or complement-dependent cytotoxicity, was seen. There was no evidence of an anaphylactic response due to mast-cell degranulation in cynomolgus monkeys.
Chronic administration of omalizumab at dose levels of up to 250 mg/kg (at least 14 times the highest recommended clinical dose in mg/kg according to the recommended dosing table) was well tolerated in non-human primates (both adult and juvenile animals), with the exception of a dose-related and age- dependent decrease in blood platelets, with a greater sensitivity in juvenile animals. The serum concentration required to attain a 50% drop in platelets from baseline in adult cynomolgus monkeys was roughly 4- to 20-fold higher than anticipated maximum clinical serum concentrations. In addition, acute haemorrhage and inflammation were observed at injection sites in cynomolgus monkeys.
Formal carcinogenicity studies have not been conducted with omalizumab.
In reproduction studies in cynomolgus monkeys, subcutaneous doses up to 75 mg/kg per week (at least 8 times the highest recommended clinical dose in mg/kg over a 4-week period) did not elicit maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis and did not elicit adverse effects on foetal or neonatal growth when administered throughout late gestation, delivery and nursing.
Omalizumab is excreted in breast milk in cynomolgus monkeys. Milk levels of omalizumab were 0.15% of the maternal serum concentration.
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