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Systemic availability (Lung deposition) of drug from two different dry-powder inhalers in children with asthma
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J ALLERGY CLIN IMMUNOL FEBRUARY 2003
Abstracts
34 Incidents Omalizumab Reduces the Rate of Asthma Deterioration-Related in Patients with Poorly Controlled Allergic Asthma J. G. Ayres ], R. Niven 2, G. Ayre 3, M. Blogg 3, H. Fox3; ]Chest Research Unit, Heartlands Hospital, Birmingham, UNITED KINGDOM, 2North West Lung Research Centre, Manchester, UNITED KINGDOM, 3Novartis Horsham Research Centre, Horsham, UNITED KINGDOM. RATIONALE: To evaluate the efficacy of omalizumab (Xolair| a monoclonal anti-immunoglobulin E antibody, for reducing the rate of asthmadeterioration related incidents (ADRIs) in patients with poorly controlled allergic asthma. METHODS: In a 52-week, open-label study, 312 patients (aged 12-75 yrs) receiving _>400 mcg/d (pediatric) or _>800 mcg/d (adult) inhaled beclomethasone dipropionate or equivalent for poorly controlled, moderate-to-severe allergic asthma were randomized (2:1) to current asthma therapy (CAT) with or without subcutaneous omalizumab (at least 0.016 mg/kg/IgE [IU/mL) per 4 wks). The primary efficacy variable was the annualized rate of ADRIs, ie, >1 of the following events due to asthma: course of oral steroids or antibiotics, missed school/work attendance, unscheduled physician visit, or emergency room visit/hospitalization. RESULTS: Baseline characteristics were comparable for the two groups (omalizumab, n=206; CAT alone, n=106), with 99% of patients being treated according to GINA step 3/4. Among evaluable patients, treatment with omalizumab significantly reduced the mean rate of ADRIs vs CAT alone (4.92 and 9.76 per patient-year, respectively; p<0.001). The percentage of patients who remained ADRl-free was increased for omalizumab-treated patients vs CAT alone (36% [69/191] and 20% [18/89], respectively; p=0.008). These results were paralleled by significantly improved lung function and fewer exacerbations for those treated with omalizumab, which proved safe and well tolerated. CONCLUSIONS: The findings of this naturalistic study indicate that add-on therapy with omalizumab is effective in reducing the rate of ADRIs in patients with moderate-to-severe allergic asthma who remain poorly controlled despite conventional treatment.
Funding: Novartis Pharma AG and Genentech lnc
535 Chamber Fluticasone Propionute (FP) CFC Delivered via Valved Holding with Facemask for 12 Weeks Improved Asthma Control in Children Aged 24-47 Months with Asthma C. C. C r i m t, R. A. Nathan 2, J. W. Baker 3, G. W. Bensch4, M. A. Faris 5, N. E. Herje ~, C. A. Scott 5, W. Wu 5, C. C. ReisnerS; JRespiratory Clinical Development and Medical Affairs, GlaxoSmithKline, Research Triangle Park, NC, 2Asthma and Allergy Associates, Colorado Springs, CO, 3Allergy Associates Research Center, Portland, OR, 4Bensch Research Associates, Stockton, CA, -SGlaxoSmithKline, Research Triangle Park, NC. RATIONALE: To evaluate the efficacy and safety of fluticasone propionate CFC MDI for 12 weeks in children aged 24-47 months with symptomatic asthma. METHODS: In this double-blind, parallel-group trial, 324 children with symptomatic asthma were randomized to receive either FP 44 mcg, FP 88 mcg or placebo (Pla) BID delivered via AeroChamber PlusTM or OptiChamber| and facemask. Patients using monteleukast, cromolyn, nedocromil, and/or theophylline prior to screening were allowed to continue use of those medications. Daily diary parental rated asthma symptoms (0-3 point scale), rescue albuterol use, study medication use, and adverse events were collected. RESULTS: Treatment with FP 88mcg BID vs placebo demonstrated significant reductions in mean daily asthma symptoms (Pla: -0.52; FP 44: -0.54; FP 88: -0.69) and rescue albuterol use (Pla: -1. I; FP 44: -1.5; FP 8 8 : - 1 . 7 puffs/day), and significant improvements in the % of symptom free days (Pla: 34%; FP 44: 38%; FP 88: 47%), lower percentage of subjects experiencing treatment failure (Pla: 22%; FP 44:13%; FP 88:12%), and significant improvements in all other efficacy parameters except daytime symptoms where improvement in trends were shown (Pla: -0.58; FP 44: -0.58; FP 88: -0.73). Improvements with FP 44mcg BID vs placebo were not significant. While most subjects (80-88%) reported non-serious adverse events common during childhood, the incidence of individual drug-related adverse events was low (<=2%).
CONCLUSIONS: Treatment with FP 88mcg BID for 12 weeks significantly improved asthma control in children aged 24-47 months with asthma. Treatment was safe and well tolerated.
Funding: GlaxoSmithKline
536 ferent Systemic Availability (Lung Deposition)of Drug From Two DifDry-Powder Inhalers in Children with Asthma S. Pedersen, L. Agertoft; Dept. of Pediatrics, Kolding Hospital, University of Southern Denmark, Odense, DENMARK. AIM: To compare the systemic availability (lung deposition) of budesonide (BUD) inhaled from Turbuhaler and fluticasone propionate (FP) inhaled from Diskus in children with asthma. METHOD: In a randomized cross-over design plasma levels of BUD and FP were measured for 21 hours on 5 separate days: (1) Intravenous infusion of 200 lag BUD, (2) Intravenous infusion oI" 200 lag FP (3) Inhalation of 800 lag BUD via Turbuhaler (4) Inhalation of 750 lag FP via Diskus (5) Inhalation of both 800 lag BUD and 750 lag FP on the same day. Charcoal was ingested before inhalation to eliminate drug uptake from the gastrointestinal tract. RESULTS: 15 patients aged 8 to 15 years completed all 5 study days. The mean systemic bioavailability (lung deposition) of drug after Turbuhaler and Diskus inhalation was 30,8% (24.2 CV%, BUD) and 8.0% (61.2 CV%, FP) when the drugs were administered on separate days and 29.5% (49.7 CV%, BUD) and 7.6% (58.7 CV%, FP) when the two drugs were inhaled on the same day. The mean estimated Turbuhaler/Diskus ratio of lung deposition (systemic availability) was 3.9 (95% CI 3.0, 4.9). CONCLUSIONS: Systemic availability of drug and estimated lung deposition is around 4 times higher in children after inhalation from BUD Turbuhaler than after inhalation from FP Diskus. The design of pharmacokinetic studies with glucocorticosteroids can be markedly simplified since the various treatments do not have to be administered on separate study days.
Funding: Vejle County Hospitals Research Fund
537 tion Budesonide/Formoterol and Fluticasone/Salmeterol CombinaInhalers Delay Immediate Albuterol Recovery Following Acute Bronchoconstriction D. K. C. Lee, G. P. Currie, W. J. Cockburn, B. J. Lipworth; Asthma and Allergy Research Group, Dundee, UNITED KINGDOM. BACKGROUND: Inhalers combining long-acting ~-agonists (LABA) and corticosteroids tICS) are indicated at Step 3 of current guidelines. We evaluated the effects of LABA/ICS combination vs. 1CS alone on pulmonary function, bronchoprotection, acute albuterol recovery following methacholine challenge, and surrogate inflammatory markers in moderate persistent ~tsthmatics. METHODS: 29 patients with mean FEVI_+SEM of 78_+3% predicted completed a randomized, double-blind, double-dummy, cross-over study. Patients received either 4 weeks of budesonide 400 Ixg/formoterol 12 lag (BUD/FM) combination bid followed by I week of BUD 400 lag alone bid, or 4 weeks of fluticasone propionate 250 ~tg/salmeterol 50 ~tg (FP/SM) combination bid followed by 1 week of FP 250 lag alone bid. Measurements were made at baseline and following each randomized treatment. RESULTS: The fall in FEV L following methacholine challenge as % change from pre-challenge baseline FEV 1 were not significantly different in all 4 groups; BUD/FM (22_+1%), BUD (24_+1%), FP/SM (23_+1%) and FP (23_+1%). Subsequent albuterol recovery over 30 minutes (primary outcome) following methacholine challenge (AUC%.min) was delayed (p<0.05) with BUD/FM (486.7_+35.5) vs. BUD (281.1_+52.8), and with FP/SM (553.1_+34.1) vs. FP (368.3-+46.7). FEV] (% predicted) increase from pre-treatment baseline was higher (p<0.05) for BUD/FM (8_+1%) vs. BUD (2-+1%). and for FP/SM (8-+1%l vs. FP (2-+1%). Decreases in exhaled NO and serum ECP from baseline were significant for each group, but were not different comparing combination inhalers vs. respective ICS alone. There were also no differences between respective combination inhalers or between respective ICS alone. CONCLUSION: Combination inhalers delay immediate albuterol recovery after acute bronchoconstriction and do not potentiate anti-inflammatory activity, compared to respective ICS alone.
Funding: Asthma and Allergy Resear~'h Group
J ALLERGY CLIN IMMUNOL FEBRUARY 2003
Abstracts
34 Incidents Omalizumab Reduces the Rate of Asthma Deterioration-Related in Patients with Poorly Controlled Allergic Asthma J. G. Ayres ], R. Niven 2, G. Ayre 3, M. Blogg 3, H. Fox3; ]Chest Research Unit, Heartlands Hospital, Birmingham, UNITED KINGDOM, 2North West Lung Research Centre, Manchester, UNITED KINGDOM, 3Novartis Horsham Research Centre, Horsham, UNITED KINGDOM. RATIONALE: To evaluate the efficacy of omalizumab (Xolair| a monoclonal anti-immunoglobulin E antibody, for reducing the rate of asthmadeterioration related incidents (ADRIs) in patients with poorly controlled allergic asthma. METHODS: In a 52-week, open-label study, 312 patients (aged 12-75 yrs) receiving _>400 mcg/d (pediatric) or _>800 mcg/d (adult) inhaled beclomethasone dipropionate or equivalent for poorly controlled, moderate-to-severe allergic asthma were randomized (2:1) to current asthma therapy (CAT) with or without subcutaneous omalizumab (at least 0.016 mg/kg/IgE [IU/mL) per 4 wks). The primary efficacy variable was the annualized rate of ADRIs, ie, >1 of the following events due to asthma: course of oral steroids or antibiotics, missed school/work attendance, unscheduled physician visit, or emergency room visit/hospitalization. RESULTS: Baseline characteristics were comparable for the two groups (omalizumab, n=206; CAT alone, n=106), with 99% of patients being treated according to GINA step 3/4. Among evaluable patients, treatment with omalizumab significantly reduced the mean rate of ADRIs vs CAT alone (4.92 and 9.76 per patient-year, respectively; p<0.001). The percentage of patients who remained ADRl-free was increased for omalizumab-treated patients vs CAT alone (36% [69/191] and 20% [18/89], respectively; p=0.008). These results were paralleled by significantly improved lung function and fewer exacerbations for those treated with omalizumab, which proved safe and well tolerated. CONCLUSIONS: The findings of this naturalistic study indicate that add-on therapy with omalizumab is effective in reducing the rate of ADRIs in patients with moderate-to-severe allergic asthma who remain poorly controlled despite conventional treatment.
Funding: Novartis Pharma AG and Genentech lnc
535 Chamber Fluticasone Propionute (FP) CFC Delivered via Valved Holding with Facemask for 12 Weeks Improved Asthma Control in Children Aged 24-47 Months with Asthma C. C. C r i m t, R. A. Nathan 2, J. W. Baker 3, G. W. Bensch4, M. A. Faris 5, N. E. Herje ~, C. A. Scott 5, W. Wu 5, C. C. ReisnerS; JRespiratory Clinical Development and Medical Affairs, GlaxoSmithKline, Research Triangle Park, NC, 2Asthma and Allergy Associates, Colorado Springs, CO, 3Allergy Associates Research Center, Portland, OR, 4Bensch Research Associates, Stockton, CA, -SGlaxoSmithKline, Research Triangle Park, NC. RATIONALE: To evaluate the efficacy and safety of fluticasone propionate CFC MDI for 12 weeks in children aged 24-47 months with symptomatic asthma. METHODS: In this double-blind, parallel-group trial, 324 children with symptomatic asthma were randomized to receive either FP 44 mcg, FP 88 mcg or placebo (Pla) BID delivered via AeroChamber PlusTM or OptiChamber| and facemask. Patients using monteleukast, cromolyn, nedocromil, and/or theophylline prior to screening were allowed to continue use of those medications. Daily diary parental rated asthma symptoms (0-3 point scale), rescue albuterol use, study medication use, and adverse events were collected. RESULTS: Treatment with FP 88mcg BID vs placebo demonstrated significant reductions in mean daily asthma symptoms (Pla: -0.52; FP 44: -0.54; FP 88: -0.69) and rescue albuterol use (Pla: -1. I; FP 44: -1.5; FP 8 8 : - 1 . 7 puffs/day), and significant improvements in the % of symptom free days (Pla: 34%; FP 44: 38%; FP 88: 47%), lower percentage of subjects experiencing treatment failure (Pla: 22%; FP 44:13%; FP 88:12%), and significant improvements in all other efficacy parameters except daytime symptoms where improvement in trends were shown (Pla: -0.58; FP 44: -0.58; FP 88: -0.73). Improvements with FP 44mcg BID vs placebo were not significant. While most subjects (80-88%) reported non-serious adverse events common during childhood, the incidence of individual drug-related adverse events was low (<=2%).
CONCLUSIONS: Treatment with FP 88mcg BID for 12 weeks significantly improved asthma control in children aged 24-47 months with asthma. Treatment was safe and well tolerated.
Funding: GlaxoSmithKline
536 ferent Systemic Availability (Lung Deposition)of Drug From Two DifDry-Powder Inhalers in Children with Asthma S. Pedersen, L. Agertoft; Dept. of Pediatrics, Kolding Hospital, University of Southern Denmark, Odense, DENMARK. AIM: To compare the systemic availability (lung deposition) of budesonide (BUD) inhaled from Turbuhaler and fluticasone propionate (FP) inhaled from Diskus in children with asthma. METHOD: In a randomized cross-over design plasma levels of BUD and FP were measured for 21 hours on 5 separate days: (1) Intravenous infusion of 200 lag BUD, (2) Intravenous infusion oI" 200 lag FP (3) Inhalation of 800 lag BUD via Turbuhaler (4) Inhalation of 750 lag FP via Diskus (5) Inhalation of both 800 lag BUD and 750 lag FP on the same day. Charcoal was ingested before inhalation to eliminate drug uptake from the gastrointestinal tract. RESULTS: 15 patients aged 8 to 15 years completed all 5 study days. The mean systemic bioavailability (lung deposition) of drug after Turbuhaler and Diskus inhalation was 30,8% (24.2 CV%, BUD) and 8.0% (61.2 CV%, FP) when the drugs were administered on separate days and 29.5% (49.7 CV%, BUD) and 7.6% (58.7 CV%, FP) when the two drugs were inhaled on the same day. The mean estimated Turbuhaler/Diskus ratio of lung deposition (systemic availability) was 3.9 (95% CI 3.0, 4.9). CONCLUSIONS: Systemic availability of drug and estimated lung deposition is around 4 times higher in children after inhalation from BUD Turbuhaler than after inhalation from FP Diskus. The design of pharmacokinetic studies with glucocorticosteroids can be markedly simplified since the various treatments do not have to be administered on separate study days.
Funding: Vejle County Hospitals Research Fund
537 tion Budesonide/Formoterol and Fluticasone/Salmeterol CombinaInhalers Delay Immediate Albuterol Recovery Following Acute Bronchoconstriction D. K. C. Lee, G. P. Currie, W. J. Cockburn, B. J. Lipworth; Asthma and Allergy Research Group, Dundee, UNITED KINGDOM. BACKGROUND: Inhalers combining long-acting ~-agonists (LABA) and corticosteroids tICS) are indicated at Step 3 of current guidelines. We evaluated the effects of LABA/ICS combination vs. 1CS alone on pulmonary function, bronchoprotection, acute albuterol recovery following methacholine challenge, and surrogate inflammatory markers in moderate persistent ~tsthmatics. METHODS: 29 patients with mean FEVI_+SEM of 78_+3% predicted completed a randomized, double-blind, double-dummy, cross-over study. Patients received either 4 weeks of budesonide 400 Ixg/formoterol 12 lag (BUD/FM) combination bid followed by I week of BUD 400 lag alone bid, or 4 weeks of fluticasone propionate 250 ~tg/salmeterol 50 ~tg (FP/SM) combination bid followed by 1 week of FP 250 lag alone bid. Measurements were made at baseline and following each randomized treatment. RESULTS: The fall in FEV L following methacholine challenge as % change from pre-challenge baseline FEV 1 were not significantly different in all 4 groups; BUD/FM (22_+1%), BUD (24_+1%), FP/SM (23_+1%) and FP (23_+1%). Subsequent albuterol recovery over 30 minutes (primary outcome) following methacholine challenge (AUC%.min) was delayed (p<0.05) with BUD/FM (486.7_+35.5) vs. BUD (281.1_+52.8), and with FP/SM (553.1_+34.1) vs. FP (368.3-+46.7). FEV] (% predicted) increase from pre-treatment baseline was higher (p<0.05) for BUD/FM (8_+1%) vs. BUD (2-+1%). and for FP/SM (8-+1%l vs. FP (2-+1%). Decreases in exhaled NO and serum ECP from baseline were significant for each group, but were not different comparing combination inhalers vs. respective ICS alone. There were also no differences between respective combination inhalers or between respective ICS alone. CONCLUSION: Combination inhalers delay immediate albuterol recovery after acute bronchoconstriction and do not potentiate anti-inflammatory activity, compared to respective ICS alone.
Funding: Asthma and Allergy Resear~'h Group