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Does Obesity Influence Steroid Absorption, Metabolism, and In Vitro Steroid Response in Adults with Severe Asthma?
S156 Abstracts
594
A Novel Submicron Formulation of Nebulized Budesonide Significantly Improves the Fine Particle Fraction of Drug Available for Inhalation From Various Jet Nebulizers Compared to a Marketed Budesonide Suspension A. P. Bosco, M. C. Castillo, M. M. Luangvala; MAP Pharmaceuticals Inc, Mountain View, CA. RATIONALE: Conventional nebulized budesonide suspensions consist of large insoluble particles > 2 microns in aerodynamic size that cannot be carried by the smaller, more respirable droplets generated by jet nebulizers. A novel aqueous submicron budesonide formulation has been developed to improve delivery efficiency from jet nebulizers by carrying a greater mass of drug within these respirable droplets. METHODS The fine particle fraction (FPF; % of drug < 4.7 microns) was determined using the Next Generation Impactor (NGI). UDB (0.135 mg/ 1.5 mL, UDB 0.250 mg/1.5 mL) was compared to Pulmicort Respules (PR; 0.250 mg/2.0 mL, 0.500 mg/2.0 mL) when delivered by eight commonly used jet nebulizer & compressor combinations available in the US. Aerosol was sampled into the NGI at an operating flow rate of 15 LPM. Cups from each stage of the NGI were chemically assayed to recover the impacted mass of budesonide and determine the % of the total mass of drug < 4.7 microns. RESULTS: For all eight nebulizer/compressor combinations, UDB formulations generated a significantly larger FPF compared to each PR formulation (p < 0.01 to p < 0.001; paired t-test). The FPF of UDB ranged from 63-83%, while PR ranged from 44-74%. Only 6 of 16 PR combinations generated an FPF >60% while 10 of 16 UDB combinations generated an FPF >70%. CONCLUSIONS: At half of the nominal dose of PR, UDB nebulizes significantly more drug mass in the respirable fraction of droplets generated by a variety of commonly used jet nebulizers. This may provide significant therapeutic benefit by distributing drug more uniformly throughout the central and peripheral lung areas.
595
MONDAY
Does Obesity Influence Steroid Absorption, Metabolism, and In Vitro Steroid Response in Adults with Severe Asthma? J. M. Davidson, R. A. Covar, E. Brown, J. D. Spahn; National Jewish Health, Denver, CO. RATIONALE: Recent attention has focused upon the relationship between obesity and asthma severity. We sought to determine the role of body mass index (BMI) in relation to the pharmacokinetic (PK) and pharmacodynamic (PD) parameters in patients with severe asthma. METHODS: We performed prednisone (PN) PK and glucocorticoid (GC) PD studies in 221 adult severe asthmatics. PN absorption and clearance were determined utilizing a modified PK protocol as described by Hill et al., Clin Pharmcol Ther 1990;48:390-398. In vitro GC response was assessed by determining IC50 and Imax values for PN, dexamethasone, fluticasone propionate, and budesonide in peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA). Data for age, gender, body mass index (BMI), body surface area (BSA), asthma duration, medications and lung function were collected. RESULTS: The mean age 6 SEM of the study cohort (67% female) was 48 6 4 yr with an asthma duration of 20.7 6 1.1 yr. 64% required chronic oral GC treatment (25.6 6 1.9 mg/day for 5.5 6 0.8 yr), and the mean FEV1 was 59.3 6 1.7% predicted. 51% were obese (BMI > 30), 32% overweight (BMI 25-30), and 17 were normal (BMI < 25). BMI was positively associated with an increased number of steroid side effects (SSE) and FEV1/FVC ratio, but no association was noted between BMI and baseline PN requirement, PN absorption or clearance. In addition, BMI was not associated with steroid response, as measured by IC50 or Imax values. CONCLUSIONS: These data suggest that BMI is not associated with impaired PN absorption or clearance, nor is it associated with diminished in vitro steroid responsiveness in adults with severe asthma.
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
596
European Real-Life Experience Of Omalizumab (Xolair) And Maintenance Oral Corticosteroid Use In Patients With Severe Persistent Allergic Asthma M. Molimard1, R. Niven2, R. Buhl3, V. Le Gros4, A. Thielen5, J. Thirlwell6, Z. Panahloo6; 1CHU Pellegrin-Carreire, Bordeaux, France, 2North West Lung Centre, University Hospital of South Manchester, Manchester, United Kingdom, 3Mainz University Hospital, Mainz, Germany, 4Novartis Pharma SAS, Rueil-Malmaison, France, 5Novartis Pharma GmbH, Nuremberg, Germany, 6Novartis Horsham Research Centre, Horsham, United Kingdom. RATIONALE: Oral corticosteroids (OCS) impose a significant burden on patients and healthcare resources; therefore, treatments that limit their use are pivotal in asthma management as they can help reduce the burden associated with long-term steroid therapy. METHODS: Clinicians in France, UK and Germany prescribing omalizumab for >16 weeks’ duration to patients with severe persistent allergic asthma collected data regarding concomitant maintenance OCS use. Data were combined to analyze the OCS-sparing potential of omalizumab. OCS use was recorded at baseline and at a non-specific time point beyond 16 weeks from initiation of omalizumab. OCS dose was calculated as prednisolone equivalents. RESULTS: Data were available for 411 omalizumab-treated patients (France, n 5 108; UK, n 5 65; Germany, n 5 238). Of these, 199 (48.4%) were taking maintenance OCS at baseline (UK, n 5 33; France, n 5 64; Germany, n 5 102). In total, 110 (55.3%) patients on OCS at baseline stopped or reduced OCS dose at the time of data collection; 42 (21.1%) of whom stopped OCS. OCS dose was increased or remained unchanged in 88 (44.2%) patients. No post-baseline data were available for one patient. In all patients receiving maintenance OCS, mean percentage reduction from baseline in OCS dose was 32.8% (mean baseline dose, 19.6 mg; mean dose at time of data collection, 11.9 mg). In patients who stopped or reduced maintenance OCS, mean percentage reduction from baseline in OCS dose was 71.3% (mean baseline dose, 23.0 mg; mean dose at time of data collection, 8.0 mg). CONCLUSIONS: European real-life experience demonstrates the OCSsparing potential of omalizumab in some patients with severe persistent allergic asthma.
597
Step-Down Therapy in Asthmatic Children Receiving both Inhaled Corticosteroids and Leukotriene Receptor Antagonist P. Huynh, T. Morphew, A. Ratnayake, C. Luu, L. Scott, B. Nichols, K. Kwong; USC, Los Angeles, CA. RATIONALE: Treatment guidelines recommend periodic evaluation of asthma control. When asthma control has been achieved, the guidelines recommend that step down therapy is necessary to identify the minimum medication required to maintain control. Studies, however, are limited in guiding therapy reduction. Whether patients with asthma that is well controlled with the use of inhaled corticosteroids (ICS) and leukotriene receptor antagonist (LTRA) can receive step-down treatment with LTRA only has not yet been evaluated. METHODS: This is a retrospective observational study involving 474 children engaged in an asthma-specific disease management program. Asthma control maintenance was evaluated in three patient groups: Group 1 weaned off all anti-inflammatory medications (ICS and LTRA), Group 2 weaned to LTRA only, and Group 3 not weaned. Assessment of medication step-down and asthma control status was evaluated across subsequent visits. RESULTS: Step down in treatment from therapy that included both ICS and LTRA medications to LTRA only (Group 2) did not significantly reduce the likelihood of maintaining asthma control to the next visit compared to patients who were not weaned (Group 3) (77.1% vs. 83.9%, OR 5 0.65, p 5 0.31). However, patients weaned completely off all anti-inflammatory medications (ICS and LTRA) (Group 1) were significantly less likely to maintain asthma control to the next visit compared to patients who remained on therapy (Group 3) (71.4% vs. 83.9% OR 5 0.48, p 5 0.09). CONCLUSIONS: Children with asthma that is well controlled with the use of both inhaled corticosteroids (ICS) and leukotriene receptor antagonist (LTRA) can be weaned to LTRAwithout a reduction of asthma control.
594
A Novel Submicron Formulation of Nebulized Budesonide Significantly Improves the Fine Particle Fraction of Drug Available for Inhalation From Various Jet Nebulizers Compared to a Marketed Budesonide Suspension A. P. Bosco, M. C. Castillo, M. M. Luangvala; MAP Pharmaceuticals Inc, Mountain View, CA. RATIONALE: Conventional nebulized budesonide suspensions consist of large insoluble particles > 2 microns in aerodynamic size that cannot be carried by the smaller, more respirable droplets generated by jet nebulizers. A novel aqueous submicron budesonide formulation has been developed to improve delivery efficiency from jet nebulizers by carrying a greater mass of drug within these respirable droplets. METHODS The fine particle fraction (FPF; % of drug < 4.7 microns) was determined using the Next Generation Impactor (NGI). UDB (0.135 mg/ 1.5 mL, UDB 0.250 mg/1.5 mL) was compared to Pulmicort Respules (PR; 0.250 mg/2.0 mL, 0.500 mg/2.0 mL) when delivered by eight commonly used jet nebulizer & compressor combinations available in the US. Aerosol was sampled into the NGI at an operating flow rate of 15 LPM. Cups from each stage of the NGI were chemically assayed to recover the impacted mass of budesonide and determine the % of the total mass of drug < 4.7 microns. RESULTS: For all eight nebulizer/compressor combinations, UDB formulations generated a significantly larger FPF compared to each PR formulation (p < 0.01 to p < 0.001; paired t-test). The FPF of UDB ranged from 63-83%, while PR ranged from 44-74%. Only 6 of 16 PR combinations generated an FPF >60% while 10 of 16 UDB combinations generated an FPF >70%. CONCLUSIONS: At half of the nominal dose of PR, UDB nebulizes significantly more drug mass in the respirable fraction of droplets generated by a variety of commonly used jet nebulizers. This may provide significant therapeutic benefit by distributing drug more uniformly throughout the central and peripheral lung areas.
595
MONDAY
Does Obesity Influence Steroid Absorption, Metabolism, and In Vitro Steroid Response in Adults with Severe Asthma? J. M. Davidson, R. A. Covar, E. Brown, J. D. Spahn; National Jewish Health, Denver, CO. RATIONALE: Recent attention has focused upon the relationship between obesity and asthma severity. We sought to determine the role of body mass index (BMI) in relation to the pharmacokinetic (PK) and pharmacodynamic (PD) parameters in patients with severe asthma. METHODS: We performed prednisone (PN) PK and glucocorticoid (GC) PD studies in 221 adult severe asthmatics. PN absorption and clearance were determined utilizing a modified PK protocol as described by Hill et al., Clin Pharmcol Ther 1990;48:390-398. In vitro GC response was assessed by determining IC50 and Imax values for PN, dexamethasone, fluticasone propionate, and budesonide in peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA). Data for age, gender, body mass index (BMI), body surface area (BSA), asthma duration, medications and lung function were collected. RESULTS: The mean age 6 SEM of the study cohort (67% female) was 48 6 4 yr with an asthma duration of 20.7 6 1.1 yr. 64% required chronic oral GC treatment (25.6 6 1.9 mg/day for 5.5 6 0.8 yr), and the mean FEV1 was 59.3 6 1.7% predicted. 51% were obese (BMI > 30), 32% overweight (BMI 25-30), and 17 were normal (BMI < 25). BMI was positively associated with an increased number of steroid side effects (SSE) and FEV1/FVC ratio, but no association was noted between BMI and baseline PN requirement, PN absorption or clearance. In addition, BMI was not associated with steroid response, as measured by IC50 or Imax values. CONCLUSIONS: These data suggest that BMI is not associated with impaired PN absorption or clearance, nor is it associated with diminished in vitro steroid responsiveness in adults with severe asthma.
J ALLERGY CLIN IMMUNOL FEBRUARY 2009
596
European Real-Life Experience Of Omalizumab (Xolair) And Maintenance Oral Corticosteroid Use In Patients With Severe Persistent Allergic Asthma M. Molimard1, R. Niven2, R. Buhl3, V. Le Gros4, A. Thielen5, J. Thirlwell6, Z. Panahloo6; 1CHU Pellegrin-Carreire, Bordeaux, France, 2North West Lung Centre, University Hospital of South Manchester, Manchester, United Kingdom, 3Mainz University Hospital, Mainz, Germany, 4Novartis Pharma SAS, Rueil-Malmaison, France, 5Novartis Pharma GmbH, Nuremberg, Germany, 6Novartis Horsham Research Centre, Horsham, United Kingdom. RATIONALE: Oral corticosteroids (OCS) impose a significant burden on patients and healthcare resources; therefore, treatments that limit their use are pivotal in asthma management as they can help reduce the burden associated with long-term steroid therapy. METHODS: Clinicians in France, UK and Germany prescribing omalizumab for >16 weeks’ duration to patients with severe persistent allergic asthma collected data regarding concomitant maintenance OCS use. Data were combined to analyze the OCS-sparing potential of omalizumab. OCS use was recorded at baseline and at a non-specific time point beyond 16 weeks from initiation of omalizumab. OCS dose was calculated as prednisolone equivalents. RESULTS: Data were available for 411 omalizumab-treated patients (France, n 5 108; UK, n 5 65; Germany, n 5 238). Of these, 199 (48.4%) were taking maintenance OCS at baseline (UK, n 5 33; France, n 5 64; Germany, n 5 102). In total, 110 (55.3%) patients on OCS at baseline stopped or reduced OCS dose at the time of data collection; 42 (21.1%) of whom stopped OCS. OCS dose was increased or remained unchanged in 88 (44.2%) patients. No post-baseline data were available for one patient. In all patients receiving maintenance OCS, mean percentage reduction from baseline in OCS dose was 32.8% (mean baseline dose, 19.6 mg; mean dose at time of data collection, 11.9 mg). In patients who stopped or reduced maintenance OCS, mean percentage reduction from baseline in OCS dose was 71.3% (mean baseline dose, 23.0 mg; mean dose at time of data collection, 8.0 mg). CONCLUSIONS: European real-life experience demonstrates the OCSsparing potential of omalizumab in some patients with severe persistent allergic asthma.
597
Step-Down Therapy in Asthmatic Children Receiving both Inhaled Corticosteroids and Leukotriene Receptor Antagonist P. Huynh, T. Morphew, A. Ratnayake, C. Luu, L. Scott, B. Nichols, K. Kwong; USC, Los Angeles, CA. RATIONALE: Treatment guidelines recommend periodic evaluation of asthma control. When asthma control has been achieved, the guidelines recommend that step down therapy is necessary to identify the minimum medication required to maintain control. Studies, however, are limited in guiding therapy reduction. Whether patients with asthma that is well controlled with the use of inhaled corticosteroids (ICS) and leukotriene receptor antagonist (LTRA) can receive step-down treatment with LTRA only has not yet been evaluated. METHODS: This is a retrospective observational study involving 474 children engaged in an asthma-specific disease management program. Asthma control maintenance was evaluated in three patient groups: Group 1 weaned off all anti-inflammatory medications (ICS and LTRA), Group 2 weaned to LTRA only, and Group 3 not weaned. Assessment of medication step-down and asthma control status was evaluated across subsequent visits. RESULTS: Step down in treatment from therapy that included both ICS and LTRA medications to LTRA only (Group 2) did not significantly reduce the likelihood of maintaining asthma control to the next visit compared to patients who were not weaned (Group 3) (77.1% vs. 83.9%, OR 5 0.65, p 5 0.31). However, patients weaned completely off all anti-inflammatory medications (ICS and LTRA) (Group 1) were significantly less likely to maintain asthma control to the next visit compared to patients who remained on therapy (Group 3) (71.4% vs. 83.9% OR 5 0.48, p 5 0.09). CONCLUSIONS: Children with asthma that is well controlled with the use of both inhaled corticosteroids (ICS) and leukotriene receptor antagonist (LTRA) can be weaned to LTRAwithout a reduction of asthma control.