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Efficacy and Safety of Budesonide Inhalation Suspension in Pediatric Asthma: Japan, Phase III Clinical Trials
353
Progress Toward the Development of Inhibitors of 11betaHydroxysteroid dehydrogenase 2: Inhibition of Cortisol Catabolism in the Lung R. Bateman1, D. Rauh2, K. Shokat2; 1U.C. San Francisco, San Francisco, CA, 2Cellular and Molecular Pharmacology, U.C. San Francisco, San Francisco, CA. RATIONALE: In lung tissue, the anti-inflammatory steroid cortisol is converted to inactive cortisone by 11beta-Hydroxysteroid dehydrogenase 2 (11beta-HSD2). Therefore, inhibition of 11beta-HSD2 activity in lung tissue may suppress the inflammatory response in asthma. METHODS: We have developed a novel inhibitor of a structurally related enzyme, Carbonyl reductase 1 (CBR1) and have elucidated the mechanism of inhibition both kinetically and crystallographically [Tanaka, et al (2005) PloS Biol. 3, 764-776]. The affinity of this compound for CBR1 is mediated through hydrogen-bond interactions with catalytic residues conserved in 11beta-HSD2. Using the structure as a model, we have applied our knowledge of the binding mode to inform the development of a library of compounds to target the homologous but not yet structurally described 11beta-HSD2. RESULTS: We have developed an efficient synthetic route to produce numerous compounds well suited to inhibit 11beta-HSD2. These compounds retain the putative pharmacophore necessary for interaction with conserved catalytic amino acid residues and possess additional substituents that should provide 11beta-HSD2 specificity. We are in the process of implementing an in vitro activity assay to screen for inhibitors of this enzyme. CONCLUSIONS: Using techniques of structure based drug design we have developed and synthesized a library of compounds likely to include potent 11beta-HSD2 inhibitors. Structure activity relationships identified from the in vitro assay should allow further optimization of potency and specificity. Funding: Sandler Program for Asthma Research
355
Relative Amount of Fluticasone Delivered by HFA-MDI to Children of Different Ages Y. R. Khan; University of Florida, Gainesville, FL. RATIONALE: We hypothesized that less fluticasone propionate (FP) is delivered by MDI to the airways of children <5 yr who passively inhale through a mask/valved holding chamber (VHC) than to older children who inhale deeply and breath hold. The 1-hr steady-state FP plasma concentration was used as an indirect measure of the relative amount deposited in the lungs and a direct measure of systemic exposure. METHODS: Sixty children with well controlled persistent asthma received FP 2x110 g BID for 3 days, delivered by HFA-MDI through a device they used effectively. This higher dose is routine in our clinic. 100% adherence, documented by electronic monitor, was required. Five groups of 12 each were studied; 1) 12-18 yr by actuator alone; 2) 5-9 yr by actuator alone; 3) 5-9 yr by antistatic VHC/mouthpiece (AeroChamber MAX); 4) 5-9 yr by antistatic VHC/mask; and 5) 1-4 yr by antistatic VHC/mask. FP was measured by an LC-MS/MS assay with a 13% CV for precision at 5 pg/mL. RESULTS: The mean±SD concentrations in pg/mL were: 12-18 yr actuator, 76±61; 5-9 yr actuator, 87±80; 5-9 yr VHC/mouthpiece, 207±149; 5-9 yr VHC/mask, 140±61; and 1-4 yr VHC/mask,165±58. The mean concentration in the 12-18 yr actuator group was significantly lower than VHC groups (p=0.003), but not different from the 5-9 yr actuator alone group. CONCLUSIONS: There was a device but not an age-related difference in deposition. The antistatic VHC improved deposition of HFA-FP and compensated for passive inhalation in children 1-4 yr. Funding: Supported in part by a grant from GlaxoSmithKline Funding: Glaxo Smith Kline
356
354
Novel Pressurised Metered Dose Inhaler Aerosol Delivery of Fluticasone Propionate via Tempo® in Humans S. B. Shrewsbury1, N. M. Mohsen2, S. P. Newman3, G. Pitcairn3, T. A. Armer4; 1Clinical & Regulatory Affairs, MAP Pharmaceuticals, Mountain View, CA, 2Senior Scientist, Sheffield Pharmaceuticals, Ann Arbor, MI, 3Pharmaceutical Profiles, Nottingham, UNITED KINGDOM, 4Product Development, MAP Pharmaceuticals, Mountain View, CA. RATIONALE: Aerosol drug delivery by pMDI remains popular but problematic. Poor coordination, high oropharyngeal deposition and little peripheral airway deposition limit conventional MDIs. MAP has developed a novel pMDI (Tempo) which promises to overcome these limitations with a synchronous trigger, plume control and vortexing flow control chambers. METHODS: Fluticasone propionate (FP) studied via originator actuator and via Tempo: 1) In vitro particle size characterization at 28.3 and 45 L/min by Andersen Cascade Impactor. 2) In vivo inhaled 99mTc radiolabeled FP in 12 healthy volunteers in a randomized, crossover study. RESULTS: 1) Fine particle fraction at 28.3 and 45 L/min was 88.6% and 89.2% for Tempo FP versus 40.4 % and 43.1% for originator. 2.i) Oropharyngeal deposition was reduced from 76.8% (originator) to 18.3% (Tempo). 2.ii) Lung deposition increased from 13.8% (originator) to 41.5% (Tempo). 2.iii) Dose variability was reduced by 50% with Tempo. CONCLUSIONS: The Tempo system allows delivery at pre-specified time within an inspiratory maneuver; provides greater respirable proportion of metered dose; reduces oropharyngeal deposition resulting in greater absolute dose reaching peripheral lung, with greater consistency across a range of lung functions and inspiratory flows. Improved lung deposition and dose variability may allow higher payload and the use of more potent and narrow therapeutic range drugs requiring accurate biotargetting to be delivered by pMDI. Tempo clinical trials are underway to further confirm these findings. Funding: MAP Pharmaceuticals Efficacy and Safety of Budesonide Inhalation Suspension in Pediatric Asthma: Japan, Phase III Clinical Trials A. Akasawa1, H. Mikawa2, S. Nishima3; 1National Center for Child Health and Development, Tokyo, JAPAN, 2Kansai Denryoku Hospital School of Nursing for Advanced Practice, Osaka, JAPAN, 3National Hospital Organization Fukuoka National Hospital, Fukuoka, JAPAN. RATIONALE: To investigate the efficacy and safety of budesonide inhalation suspension (BIS) 0.25 - 0.5 mg twice daily (bid) or 0.5 - 1.0 mg once daily (qd) in Japanese children with asthma. METHODS: A randomized, open-label, parallel-group, 24-wk treatment study was conducted, followed by an open-label, long-term extension study (OLES). Children aged 6 mo-4 y with moderate to severe asthma were included. Mean change in the frequency of asthma attacks, adverse events (AEs), and plasma cortisol levels were evaluated throughout the study. RESULTS: Of 60 patients, 32 were randomized to 0.25 mg bid and 28 to 0.5 mg qd; 12 needed to double their dose at wk 6. 54 entered the OLES. At wk 12, the mean change from baseline in the frequency of asthma attacks per wk was -6.99 (p<0.001); the reduction was maintained through wk 24. Dosing of qd and bid showed similar efficacy. By wk 12, AEs judged to be drug related were cheilitis, oral candidiasis, and stomatitis. One patient was discontinued from the study due to oral candidiasis and stomatitis by wk 12. No other drug-related AEs were observed from wk12-24; AE profiles were similar in the OLES. Mean plasma cortisol levels were significantly decreased at wk 12 and 24 compared with baseline; however, no further decrease was observed in the OLES. No signs or symptoms suggesting adrenal insufficiency were observed at week 48. CONCLUSIONS: Administration of BIS at up to 1.0 mg/d is effective for pediatric asthma and well tolerated up to 48 wk. Funding: AstraZeneca KK
SUNDAY
Abstracts S91
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
Progress Toward the Development of Inhibitors of 11betaHydroxysteroid dehydrogenase 2: Inhibition of Cortisol Catabolism in the Lung R. Bateman1, D. Rauh2, K. Shokat2; 1U.C. San Francisco, San Francisco, CA, 2Cellular and Molecular Pharmacology, U.C. San Francisco, San Francisco, CA. RATIONALE: In lung tissue, the anti-inflammatory steroid cortisol is converted to inactive cortisone by 11beta-Hydroxysteroid dehydrogenase 2 (11beta-HSD2). Therefore, inhibition of 11beta-HSD2 activity in lung tissue may suppress the inflammatory response in asthma. METHODS: We have developed a novel inhibitor of a structurally related enzyme, Carbonyl reductase 1 (CBR1) and have elucidated the mechanism of inhibition both kinetically and crystallographically [Tanaka, et al (2005) PloS Biol. 3, 764-776]. The affinity of this compound for CBR1 is mediated through hydrogen-bond interactions with catalytic residues conserved in 11beta-HSD2. Using the structure as a model, we have applied our knowledge of the binding mode to inform the development of a library of compounds to target the homologous but not yet structurally described 11beta-HSD2. RESULTS: We have developed an efficient synthetic route to produce numerous compounds well suited to inhibit 11beta-HSD2. These compounds retain the putative pharmacophore necessary for interaction with conserved catalytic amino acid residues and possess additional substituents that should provide 11beta-HSD2 specificity. We are in the process of implementing an in vitro activity assay to screen for inhibitors of this enzyme. CONCLUSIONS: Using techniques of structure based drug design we have developed and synthesized a library of compounds likely to include potent 11beta-HSD2 inhibitors. Structure activity relationships identified from the in vitro assay should allow further optimization of potency and specificity. Funding: Sandler Program for Asthma Research
355
Relative Amount of Fluticasone Delivered by HFA-MDI to Children of Different Ages Y. R. Khan; University of Florida, Gainesville, FL. RATIONALE: We hypothesized that less fluticasone propionate (FP) is delivered by MDI to the airways of children <5 yr who passively inhale through a mask/valved holding chamber (VHC) than to older children who inhale deeply and breath hold. The 1-hr steady-state FP plasma concentration was used as an indirect measure of the relative amount deposited in the lungs and a direct measure of systemic exposure. METHODS: Sixty children with well controlled persistent asthma received FP 2x110 g BID for 3 days, delivered by HFA-MDI through a device they used effectively. This higher dose is routine in our clinic. 100% adherence, documented by electronic monitor, was required. Five groups of 12 each were studied; 1) 12-18 yr by actuator alone; 2) 5-9 yr by actuator alone; 3) 5-9 yr by antistatic VHC/mouthpiece (AeroChamber MAX); 4) 5-9 yr by antistatic VHC/mask; and 5) 1-4 yr by antistatic VHC/mask. FP was measured by an LC-MS/MS assay with a 13% CV for precision at 5 pg/mL. RESULTS: The mean±SD concentrations in pg/mL were: 12-18 yr actuator, 76±61; 5-9 yr actuator, 87±80; 5-9 yr VHC/mouthpiece, 207±149; 5-9 yr VHC/mask, 140±61; and 1-4 yr VHC/mask,165±58. The mean concentration in the 12-18 yr actuator group was significantly lower than VHC groups (p=0.003), but not different from the 5-9 yr actuator alone group. CONCLUSIONS: There was a device but not an age-related difference in deposition. The antistatic VHC improved deposition of HFA-FP and compensated for passive inhalation in children 1-4 yr. Funding: Supported in part by a grant from GlaxoSmithKline Funding: Glaxo Smith Kline
356
354
Novel Pressurised Metered Dose Inhaler Aerosol Delivery of Fluticasone Propionate via Tempo® in Humans S. B. Shrewsbury1, N. M. Mohsen2, S. P. Newman3, G. Pitcairn3, T. A. Armer4; 1Clinical & Regulatory Affairs, MAP Pharmaceuticals, Mountain View, CA, 2Senior Scientist, Sheffield Pharmaceuticals, Ann Arbor, MI, 3Pharmaceutical Profiles, Nottingham, UNITED KINGDOM, 4Product Development, MAP Pharmaceuticals, Mountain View, CA. RATIONALE: Aerosol drug delivery by pMDI remains popular but problematic. Poor coordination, high oropharyngeal deposition and little peripheral airway deposition limit conventional MDIs. MAP has developed a novel pMDI (Tempo) which promises to overcome these limitations with a synchronous trigger, plume control and vortexing flow control chambers. METHODS: Fluticasone propionate (FP) studied via originator actuator and via Tempo: 1) In vitro particle size characterization at 28.3 and 45 L/min by Andersen Cascade Impactor. 2) In vivo inhaled 99mTc radiolabeled FP in 12 healthy volunteers in a randomized, crossover study. RESULTS: 1) Fine particle fraction at 28.3 and 45 L/min was 88.6% and 89.2% for Tempo FP versus 40.4 % and 43.1% for originator. 2.i) Oropharyngeal deposition was reduced from 76.8% (originator) to 18.3% (Tempo). 2.ii) Lung deposition increased from 13.8% (originator) to 41.5% (Tempo). 2.iii) Dose variability was reduced by 50% with Tempo. CONCLUSIONS: The Tempo system allows delivery at pre-specified time within an inspiratory maneuver; provides greater respirable proportion of metered dose; reduces oropharyngeal deposition resulting in greater absolute dose reaching peripheral lung, with greater consistency across a range of lung functions and inspiratory flows. Improved lung deposition and dose variability may allow higher payload and the use of more potent and narrow therapeutic range drugs requiring accurate biotargetting to be delivered by pMDI. Tempo clinical trials are underway to further confirm these findings. Funding: MAP Pharmaceuticals Efficacy and Safety of Budesonide Inhalation Suspension in Pediatric Asthma: Japan, Phase III Clinical Trials A. Akasawa1, H. Mikawa2, S. Nishima3; 1National Center for Child Health and Development, Tokyo, JAPAN, 2Kansai Denryoku Hospital School of Nursing for Advanced Practice, Osaka, JAPAN, 3National Hospital Organization Fukuoka National Hospital, Fukuoka, JAPAN. RATIONALE: To investigate the efficacy and safety of budesonide inhalation suspension (BIS) 0.25 - 0.5 mg twice daily (bid) or 0.5 - 1.0 mg once daily (qd) in Japanese children with asthma. METHODS: A randomized, open-label, parallel-group, 24-wk treatment study was conducted, followed by an open-label, long-term extension study (OLES). Children aged 6 mo-4 y with moderate to severe asthma were included. Mean change in the frequency of asthma attacks, adverse events (AEs), and plasma cortisol levels were evaluated throughout the study. RESULTS: Of 60 patients, 32 were randomized to 0.25 mg bid and 28 to 0.5 mg qd; 12 needed to double their dose at wk 6. 54 entered the OLES. At wk 12, the mean change from baseline in the frequency of asthma attacks per wk was -6.99 (p<0.001); the reduction was maintained through wk 24. Dosing of qd and bid showed similar efficacy. By wk 12, AEs judged to be drug related were cheilitis, oral candidiasis, and stomatitis. One patient was discontinued from the study due to oral candidiasis and stomatitis by wk 12. No other drug-related AEs were observed from wk12-24; AE profiles were similar in the OLES. Mean plasma cortisol levels were significantly decreased at wk 12 and 24 compared with baseline; however, no further decrease was observed in the OLES. No signs or symptoms suggesting adrenal insufficiency were observed at week 48. CONCLUSIONS: Administration of BIS at up to 1.0 mg/d is effective for pediatric asthma and well tolerated up to 48 wk. Funding: AstraZeneca KK
SUNDAY
Abstracts S91
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2