Bioequivalence of fluticasone propionate and salmeterol (FS) given by the FS Spiromax® and Seretide Accuhaler® systems
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OBJECTIVE: To determine pharmacokinetic (PK) profiles of fluticasone propionate (FP) and salmeterol (SAL) in healthy volunteers following administration as two inhalations from the FS Spiromax 500/50 µg and Seretide Accuhaler 50/500 µg inhalers, without (study 1, n = 79) and with charcoal block (study 2, n = 77). Safety was also assessed. MATERIALS AND METHODS: In two single-center, open-label, randomized two-period crossover studies, PK parameters were calculated from plasma drug concentrations obtained pre-dose through 36 hours post-dose. Bioequivalence was established if the 90% confidence intervals for the geometric mean ratios of the area under the plasma drug concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t) and the maximum observed plasma concentration (Cmax) for the comparison of both FP and SAL were within 0.80 - 1.25. RESULTS: In study 1, in subjects administered FS Spiromax, the mean (standard deviation (SD)) FP AUC0-t and Cmax were 1,622.64 (419.44) pg×h/mL and 151.36 (40.37) pg/mL, respectively, vs. 1,487.52 (341.25) pg×h/mL and 137.57 (33.64) pg/mL with Seretide Accuhaler. Mean (SD) SAL AUC0-t and Cmax with FS Spiromax were 408.42 (155.40) pg×h/mL and 269.48 (105.74) pg/mL, respectively, vs. 401.79 (125.32) pg×h/mL and 265.66 (87.28) pg/mL with Seretide Accuhaler. Comparable data were seen in study 2 with charcoal block. Bioequivalence of FS Spiromax with Seretide Accuhaler was observed both without and with charcoal block for FP and SAL for both AUC0-t and Cmax. Both study treatments were well tolerated, with a similar incidence of adverse events reported with the single use of FS Spiromax (23% study 1, 16% study 2) and Seretide Accuhaler (22%, 15%). CONCLUSION: FS Spiromax 500/50 µg (± charcoal block) was bioequivalent to Seretide Accuhaler 50/500µg.
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Albuterol multidose dry powder inhaler efficacy and safety versus placebo in children with asthma.

BACKGROUND: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) that does not require coordination of actuation with inhalation has been developed. OBJECTIVE: To evaluate the efficacy and safety of albuterol MDPI versus placebo MDPI after chronic dosing in children with asthma. METHODS: This phase III, double-blind, parallel-group study included children with asthma (ages, 4-11 years) with forced expiratory volume in 1 second (FEV1) of 50-95% of predicted. After a 14-day run-in period wherein the patients continued their current asthma therapy and received single-blind placebo MDPI, they were randomized to albuterol MDPI 90 µg per inhalation, two inhalations four times daily (total daily dose, 720 µg), or placebo for 3 weeks. Pulmonary function was assessed on days 1 and 22. Efficacy and safety were evaluated by measuring the baseline-adjusted percent-predicted FEV1 (PPFEV1) area under the time curve over 6 hours (AUC0-6) after the dose and adverse events, respectively. RESULTS: The full analysis set included 184 patients. Patients treated with albuterol MDPI versus patients treated with placebo MDPI had significantly greater baseline-adjusted PPFEV1 AUC0-6 over 3 weeks (least squares mean difference, 25.0%•hour, which favored albuterol; p < 0.001). The benefit of albuterol (mean change in PPFEV1) was evident 5 minutes after dosing and lasted several hours; the maximal effect was noted 1 to 2 hours after dosing. Albuterol MDPI was well tolerated. CONCLUSIONS: In children with persistent asthma, albuterol MDPI improved pulmonary function significantly better than placebo MDPI over 3 weeks of treatment. Clinical efficacy was evident within 5 minutes of dosing and maintained for >2 hours. Four times daily administration was well tolerated.

Albuterol multidose dry powder inhaler and albuterol hydrofluoroalkane versus placebo in children with persistent asthma.

BACKGROUND: Many children struggle with albuterol hydrofluoroalkane (HFA) inhalers. Albuterol multidose dry powder inhaler (MDPI) may simplify rescue bronchodilator use in children. OBJECTIVE: To demonstrate the comparability of albuterol MDPI and albuterol HFA in children with asthma. METHODS: This phase II, multicenter, double-blind, double-dummy, single-dose, five-period, crossover study randomized patients (ages 4-11 years) with persistent asthma and prestudy forced expiratory volume in 1 second (FEV1) of 60-90% of predicted to 1 of 10 treatment sequences that contained albuterol MDPI (90 and 180 µg), albuterol HFA (90 and 180 µg), and placebo MDPI and placebo HFA. Efficacy was evaluated by measuring the area under the baseline-adjusted percent-predicted FEV1-time curve over 6 hours (PPFEV1 AUC0-6) after dosing. Safety was evaluated by adverse events. RESULTS: The full analysis set included 61 patients. Albuterol MDPI and albuterol HFA significantly improved PPFEV1 AUC0-6 versus placebo (p ≤ 0.0107). Mean improvement (± standard error [SE]) in PPFEV1 AUC0-6 versus placebo with albuterol MDPI at 90 and 180 µg was similar (21.2 ± 4.87 [95% confidence interval {CI}, 11.60-30.81], and 22.6 ± 4.87 [95% CI, 13.00-32.20], %·hour, respectively). Mean improvement (± SE) with albuterol HFA 180 µg was significantly (p = 0.0226) greater versus albuterol HFA 90 µg (23.7 ± 4.85 [95% CI, 14.13-33.23], and 12.5 ± 4.85 [95% CI, 2.93-22.05], %·hour, respectively). All doses of albuterol were well tolerated. CONCLUSION: Albuterol MDPI 90 and 180 µg and albuterol HFA 180 µg provided similar and significant FEV1 improvements versus placebo; albuterol HFA 90 µg was significant versus placebo but seemed less effective based on absolute improvements in FEV1. ClinicalTrials.gov identifier: NCT01899144.

Pharmacokinetics and pharmacodynamics of albuterol multidose dry powder inhaler and albuterol hydrofluoroalkane in children with asthma.

BACKGROUND: Many children struggle with the use of albuterol hydrofluoroalkane (HFA) inhalers. Albuterol multidose dry powder inhaler (MDPI) may simplify rescue bronchodilator use in children. OBJECTIVE: To compare the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of albuterol MDPI and albuterol HFA after a single inhaled dose in children with asthma. METHODS: This single-center, open-label, two-period crossover study randomized children to albuterol MDPI or HFA 180 µg on two treatment days with a 4- to 14-day washout. Plasma albuterol concentrations were measured before the dose and up to 10 hours after the dose to determine the primary PK values of area under the plasma concentration-versus-time curve from time 0 to the last measurable concentration (AUC0-t), maximum observed concentration (Cmax), and AUC from time 0 extrapolated to infinity (AUC0-inf). Heart rate and blood pressure before the dose and after the dose were monitored for PD effects, and adverse events (AE) were monitored for overall safety. RESULTS: Fifteen children, ages 6-11 years, were included (PK, n = 13 for time to Cmax and terminal half-life of elimination; n = 12 for AUC and Cmax due to incomplete data). AUC0-t (geometric mean ratio [GMR] 1.056 [90% confidence interval {CI}, 0.88-1.268]) and AUC0-inf (GMR 0.971 [90% CI, 0.821-1.147]) were comparable between treatments. Cmax was larger for albuterol MDPI versus HFA (GMR 1.340 [90% CI, 1.098-1.636]). PD parameters between the treatments were comparable. No deaths, serious AEs, treatment-emergent AEs, or withdrawals due to AEs were reported for either treatment. CONCLUSION: Albuterol MDPI and albuterol HFA had comparable PK and PD in children after a single 180-µg dose. ClinicalTrails.gov identifiers NCT01899144 and NCT02126839.

Prospective, open-label evaluation of a new albuterol multidose dry powder inhaler with integrated dose counter.

BACKGROUND: Albuterol multidose dry powder inhaler (MDPI) with an integrated dose counter allows patients to track the number of remaining doses and to simplify dosing by eliminating the need to coordinate inhalation with actuation associated with metered-dose inhalers. OBJECTIVE: To evaluate the functionality, reliability, and accuracy of the albuterol MDPI integrated dose counter in a real-world clinical setting. METHODS: This open-label, phase III study enrolled patients ages ≥4 years with asthma or chronic obstructive pulmonary disease. Patients who demonstrated adequate MDPI inhaler technique and ≥90% compliance with dosing and diary completion during a run-in period qualified for treatment with albuterol MDPI with a dose counter (2 inhalations/dose; 90 µg/inhalation) twice daily for up to 50 days. Patient-reported counter readings and patient-reported actuations were recorded in daily diaries and were used to assess dose counter accuracy. An ease-of-use and satisfaction questionnaire was given at the final visit. RESULTS: A total of 317 patients were enrolled in the study. The dose-cycle undercount (i.e., actuation occurred, but the counter display did not count down) was 2.05 per 200 actuations. The estimated mean ± standard error absolute value of the total discrepancy size after 200 actuations was 2.07 ± 0.140. Most patients (83%) were somewhat or very satisfied, and >90% were satisfied with ease of holding and/or handling, using and taking, and inhaling a dose from the device. The albuterol MDPI was generally well tolerated. CONCLUSION: The albuterol MDPI dose counter functioned reliably and accurately. Albuterol MDPI was well tolerated, with a high degree of patient satisfaction in a real-world setting. CLINICAL TRIAL NUMBER: NCT01857323.

Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Albuterol (Salbuterol) Multi-dose Dry-Powder Inhaler and ProAir(®) Hydrofluoroalkane for the Treatment of Persistent Asthma: Results of Two Randomized Double-Blind Studies.

BACKGROUND AND OBJECTIVE: Metered-dose inhalers require patients to coordinate inhalation with actuation. The present albuterol multi-dose dry-powder inhaler (mDPI) does not require patients to coordinate inspiration with actuation, thereby simplifying delivery of albuterol to the lungs. The aim of the present study was to compare the efficacy, pharmacokinetics, pharmacodynamics, extrapulmonary pharmacodynamics, and safety of albuterol (salbuterol) delivered via a ProAir® hydrofluoroalkane (HFA) metered-dose inhaler and an mDPI. METHODS: Two double-blind, randomized, double-dummy, crossover, multicenter, placebo-controlled studies in persistent asthma patients were conducted. Study 1: 47 adult patients were treated with cumulative doses of albuterol mDPI or ProAir HFA (90 µg/inhalation; 1 + 1 + 2 + 4 + 8 inhalations) or placebo. Study 2: 71 patients aged ≥12 years were randomly assigned to receive 90 or 180 µg of albuterol mDPI or ProAir HFA, or placebo. Primary efficacy endpoints were baseline-adjusted forced expiratory volume in 1 s (FEV1) at 30 min (30-min FEV1) after each cumulative dose (Study 1) and FEV1 area under the effect curve over 6 h (FEV1 AUEC0-6) after dosing (Study 2). RESULTS: Study 1: differences, with corresponding 90% confidence intervals, between albuterol mDPI and ProAir HFA in FEV1 after each cumulative dose and in FEV1 AUEC0-6 after the final dose were within pre-established equivalence limits. The difference in FEV1 at high vs. low doses was significant for both active treatments (p < 0.0001). Active treatments were similar in systemic exposure, extrapulmonary pharmacodynamics, and safety. Study 2: mean FEV1 AUEC0-6 was significantly greater than for placebo for both doses of albuterol mDPI and ProAir HFA (p < 0.0001). Albuterol mDPI was comparable to ProAir HFA at 90 and 180 µg. Both study treatments were generally well tolerated. CONCLUSION: The bronchodilatory efficacy and pharmacokinetic/pharmacodynamic profiles of albuterol mDPI and ProAir HFA are comparable, with a safety profile consistent with that of inhaled albuterol.

Twelve- and 52-week safety of albuterol multidose dry powder inhaler in patients with persistent asthma.

OBJECTIVE: Evaluate the safety of albuterol multidose dry powder inhaler (MDPI), a novel, inhalation-driven device that does not require coordination of actuation with inhalation, in patients with persistent asthma. METHODS: We report pooled safety data from two 12-week, multicenter, randomized, double-blind, repeat-dose, parallel-group studies and the 12-week double-blind phase of a 52-week multicenter safety study as well as safety data from the 40-week open-label phase of the 52-week safety study. In each study, eligible patients aged ≥ 12 years with persistent asthma received placebo MDPI or albuterol MDPI 180 µg (2 inhalations × 90 µg/inhalation) 4 times/day for 12 weeks. In the 40-week open-label phase of the 52-week safety study, patients received albuterol MDPI 180 µg (2 inhalations × 90 µg/inhalation) as needed (PRN). RESULTS: During both 12-week studies and the 12-week double-blind phase of the 52-week study, adverse events were more common with placebo MDPI (50%; n = 333) than albuterol MDPI (40%; n = 321); most frequent were upper respiratory tract infection (placebo MDPI 11%, albuterol MDPI 10%), nasopharyngitis (6%, 5%), and headache (6%, 4%). Incidences of ß2-agonist-related events (excluding headache) during the pooled 12-week dosing periods were low (≤ 1%) in both groups. The safety profile with albuterol MDPI PRN during the 40-week open-label phase [most frequent adverse events: nasopharyngitis (12%), sinusitis (11%), upper respiratory tract infection (9%)] was similar to that observed during the 12-week pooled analysis. CONCLUSIONS: The safety profile of albuterol MDPI 180 µg in these studies was comparable with placebo MDPI and consistent with the well-characterized profile of albuterol in patients with asthma.

Novel albuterol multidose dry powder inhaler in patients with exercise-induced bronchoconstriction: A single-dose, double-blind, randomized, 2-way crossover study.

BACKGROUND: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) was developed that eliminates the need to coordinate device actuation with inhalation as is required with conventional metered-dose inhalers. OBJECTIVE: To evaluate albuterol MDPI efficacy and safety in patients with exercise-induced bronchoconstriction (EIB). METHODS: This single-dose, double-blind, 2-way crossover study randomized adolescents and adults with EIB (≥20% fall from pre-exercise challenge FEV(1)) to treatment sequences of albuterol MDPI (180 µg [2 inhalations of 90 µg each])/placebo MDPI (n = 19) or the reverse sequence (n = 19). FEV(1) was measured 30 and 5 min predose, 30 min postdose (ie, 5 min before treadmill exercise challenge; baseline) and 5, 10, 15, 30, and 60 min after exercise challenge. The primary efficacy endpoint was maximum percentage fall from baseline in FEV(1) up to 60 min post-exercise challenge. RESULTS: Mean maximum percentage fall in FEV(1) within 60 min post-exercise challenge was 6.2 ± 1.4% for albuterol MDPI versus 22.4 ± 1.4% for placebo MDPI (between-treatment difference: -16.2%; 95% CI: -20.2% to -12.1%; P < 0.0001). A significantly higher percentage of albuterol MDPI-treated patients were protected against EIB (<10% maximum FEV(1) fall post-exercise challenge) versus placebo MDPI (84.2% vs 15.8%; P < 0.0001). Protection with albuterol MDPI was evident within 5 min and maintained through 30 min; recovery was complete for both groups at 60 min. Treatment with a single dose of albuterol MDPI was generally well tolerated. CONCLUSIONS: Albuterol MDPI provides clinically significant protection from EIB in adolescents and adults with EIB; no new safety issues were observed with short-term albuterol MDPI use. ClinicalTrials.gov identifier NCT01791972.

Prospective, open-label assessment of albuterol sulfate hydrofluoroalkane metered-dose inhaler with new integrated dose counter.

Metered-dose inhalers (MDIs) allow patients who require therapy for various respiratory diseases to deliver these therapies directly to the airways via inhalation. MDIs are designed to contain more propellant than required for administration of the labeled number of actuations; therefore, the amount of active medication/actuation remaining after administration of the labeled number of actuations may result in a lower than therapeutic dose of active medication. An MDI with an integrated dose counter provides the only reliable means by which a patient can track the amount of medication remaining in the MDI. This study evaluated the functionality, reliability, accuracy, and patient satisfaction with albuterol sulfate hydrofluoroalkane (HFA) MDI with a new integrated dose counter in the clinical setting. Patients aged ≥4 years with asthma, chronic obstructive pulmonary disease, or both, participated in this phase 4, prospective, open-label study. Treatment was twice-daily dosing with albuterol HFA MDI at 90 micrograms with dose counter for either 5 or 7 weeks. Concordance/agreement between daily patient recordings of actuations and counter readings was assessed with five discrepancy types: fire not count (undercount; primary end point), count not fire (overcount), fire count up within a dose (counter reading increased, instead of decreased, after MDI was actuated), count unknown fire (counter number at the beginning of a dosing session was less than counter number at the end of the previous session), and count up unknown fire (counter number at the beginning of a dosing session was greater than counter number at the end of the previous session). Responses to twelve questions designed to evaluate confidence, ease of use, and patient satisfaction were also analyzed. Overall discrepancy rate was 1.87 per 200 actuations. Primary end point (fire not count rate) was 0.30 per 200 actuations. Overall, ~95-97% of patients were "very satisfied" or "somewhat satisfied" with the albuterol HFA MDI with dose counter, its ease of use, and the ability to tell when it should be replaced. The albuterol HFA MDI with new integrated dose counter functioned reliably and accurately in the clinical setting. Overall patient satisfaction was high with the albuterol HFA MDI with new integrated dose counter and the device was shown to function reliably and accurately. Clinicaltrials.gov identifier: NCT01302587.