Once-daily fluticasone furoate is efficacious in patients with symptomatic asthma on low-dose inhaled corticosteroids.

BACKGROUND: Fluticasone furoate (FF) is an inhaled corticosteroid (ICS) with 24-hour activity in development as a once-daily treatment for the long-term management of asthma. OBJECTIVE: To assess the efficacy and safety of 4 doses of once-daily FF administered using a dry powder inhaler in patients (≥12 years) with moderate asthma, uncontrolled on low-dose ICS (fluticasone propionate [FP] 200 µg/day or equivalent). METHODS: This double-blind, placebo-controlled, dose-ranging study randomized 622 patients to 1 of 6 treatments: FF (100, 200, 300, or 400 µg) once daily in the evening, FP 250 µg twice daily (active control), or placebo for 8 weeks. The primary endpoint was the change from baseline in predose evening forced expiratory colume in 1 second (FEV1) at week 8. RESULTS: At week 8, relative to placebo, all doses of FF once daily and FP twice daily demonstrated significantly (P < .001) greater increases from baseline and greater than 200-mL increases in predose FEV1. There was no evidence of a dose-response relationship between FF doses. Improvement with once-daily FF was similar to or greater than that for twice-daily FP. Secondary efficacy endpoint findings generally supported the efficacy of FF 100 to 400 µg once daily, although statistically significant improvements versus placebo in symptom-free 24-hour periods were only reported for FF 400 µg. There were few withdrawals due to lack of efficacy. Oral candidiasis was reported in 0 to 4% of patients; 24-hour urinary cortisol excretion ratios were similar across active treatment groups and not significantly different from placebo. CONCLUSION: FF 100 to 400 µg once daily in the evening is effective and well tolerated in patients with asthma uncontrolled on low-dose ICS, with 100 µg and 200 µg, considered the most applicable doses in this asthma population. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00603278.

Pharmacokinetic, pharmacodynamic, efficacy, and safety data from two randomized, double-blind studies in patients with asthma and an in vitro study comparing two dry-powder inhalers delivering a combination of salmeterol 50 microg and fluticasone propionate 250 microg: implications for establishing bioequivalence of inhaled products.

BACKGROUND: The use of dry-powder inhalers (DPIs) to administer respiratory medicines is increasing, and new DPIs are likely to be developed because of expiring patents. However, there is considerable debate concerning the extent to which DPIs are interchangeable without altering disease control or the safety profile of the treatment. OBJECTIVE: This study was designed to compare the pharmacokinetic (PK), pharmacodynamic (PD), efficacy, and safety data for 2 DPIs delivering a combination of salmeterol 50 microg plus fluticasone propionate (FP) 250 microg (SFC 50/250) to investigate assumptions of bioequivalence. METHODS: Three studies compared SFC 50/250 delivery using a reservoir powder inhalation device (RPID) and a Diskus multiple-dose inhaler: an in vitro assessment of fine-particle-mass (FPM) profiles of the emitted doses; a PK/PD study of SFC 50/250 administered in two 14-day crossover treatment periods to 22 adults with moderate, persistent asthma to determine the equivalence of the RPID and Diskus inhaler in terms of drug delivery and systemic exposure; and a 12-week clinical efficacy and safety study of SFC 50/250 in 270 patients > or =12 years of age with moderate, persistent asthma to assess the equivalence of the RPID and Diskus inhaler based on peak expiratory flow (PEF) rates. FPM was summed from the quantity of active pharmaceutical ingredient deposited on stages 1 to 5 of a cascade impactor, representing an aerodynamic particle size range of 0.8 to 6.2 microm. Systemic exposure to SFC 50/250 was declared no greater with RPID than with the Diskus inhaler if the upper limit of the 90% CI for the ratio of FP AUC for the 2 devices was below the upper limit of the equivalence range (ie, <1.25). Adverse events, clinical laboratory test results, and vital signs were recorded throughout the 2 clinical studies. RESULTS: In vitro, mean FPM values for the RPID and Diskus inhaler, respectively, were 13.1 and 12.8 microg/dose for salmeterol (P = NS) and 66.8 and 66.2 microg/dose for FP (P = NS). The only notable differences were mean FP for particle sizes 2.3 to 3.2 microm (21.4 microg/dose for RPID, 25.6 microg/dose for Diskus) and for sizes 4.0 to 6.2 microm (17.3 microg/dose for RPID, 11.7 microg/dose for Diskus). In the PK/PD study, there were 22 patients (16 men and 6 women), most (86%) of whom were white. Mean (SD) age was 26.0 (5.0) years (range, 19-35 years), and mean (SD) weight was 67.3 (8.9) kg. The 2 inhalers did not meet the criteria for declaring bioequivalence: estimated ratios (RPID:Diskus) were 2.00 (90% CI, 1.56 to 2.55) for FP AUC up to the time point of next dosing and 1.92 (90% CI, 1.64 to 2.25) for salmeterol maximum observed plasma concentration at the end of the dosing interval (at steady state). Urine cortisol (0-24 hours) was significantly lower for the RPID than for the Diskus inhaler (ratio, 0.74 [95% CI, 0.57 to 0.96]; P = 0.026); no significant difference in plasma cortisol was noted between the 2 inhalers (ratio, 0.85 [95% CI, 0.7 to 1.04]). A small but statistically significant increase in maximum heart rate (5 beats/min) was noted in the RPID group (ratio, 1.05 [95% CI, 1.01 to 1.10]; P = 0.029). No notable differences in other PD end points were observed. Drug-related adverse events occurred in both groups (2 [dysphagia and tremor] in the RPID group and 3 [2 cases of dysphonia, 1 case of mucous-membrane irritation] in the Diskus group). There were 270 patients (136 females, 134 males) in the clinical efficacy and safety study, most (94%) of whom were white; mean (SD) age was 37.2 (17.0) years (range, 11-77 years) in the RPID group and 35.4 (17.2) years (range, 12-77 years) in the Diskus group. The RPID and the Diskus inhaler met the predefined equivalence criteria (+/-15 L/min) in terms of mean change in morning PEF from baseline: 3.9 L/min (95% CI, -3.1 to 11.0). The 2 SFC 50/250 inhalers were well tolerated; the most frequently reported adverse event was bronchitis, reported by 12% of the patients in the RPID group and 9% of those in the Diskus group. The only serious adverse event, which occurred in the RPID group and was related to bronchial infection, was considered unrelated to treatment. CONCLUSIONS: In vitro particle size distribution data were potentially superimposable for the RPID and the Diskus inhaler. The 2 devices were considered to be clinically equivalent in terms of mean morning PEF but were not considered equivalent in terms of PK systemic exposure. The 2 SFC 50/250 inhalers were well tolerated and had comparable safety profiles; no serious adverse events were attributed to the study product.

Tolerability of a salmeterol xinafoate/fluticasone propionate hydrofluoroalkane metered-dose inhaler in adolescent and adult patients with persistent asthma: a 52-week, open-label, stratified, parallel-group, multicenter study.

BACKGROUND: Many patients with asthma require an inhaled long-acting beta(2)-agonist (LABA) in addition to an inhaled corticosteroid to adequately control their disease. OBJECTIVE: The purpose of this study was to assess the long-term tolerability of a salmeterol xinafoate/ fluticasone propionate (SFC) hydrofluoroalkane metered-dose inhaler (MDI) at 3 different doses BID. METHODS: This 52-week, open-label, stratified, parallel-group study assessed SFC in patients with persistent asthma. Patients, aged > or = 12 years, with a diagnosis of asthma for > or = 6 months, and a percent predicted forced expiratory volume in 1 second (FEV(1)) or peak expiratory flow (PEF) between 40% and 90% were enrolled between January 1999 and June 1999. The last patient completed the 12-month study in June 2000. Patients were allowed to continue their current asthma treatment during run-in, with the exception that short-acting beta(2)-agonists (SABAs), LABAs, and oral bronchodilators were not to be used 6, 12, and 24 hours, respectively, prior to the randomization visit. During the open-label randomized treatment period, patients were instructed to discontinue all other asthma medications with the exception of the albuterol MDI to use on an as-needed basis. Patients were assigned to treatment based on their existing asthma regimen: SABA monotherapy or LABA with or without fluticasone propionate (FP) <250 microg/d or equivalent (group 1); FP 250 to 500 microg/d or equivalent with or without LABA (group 2); and FP >500 to 1000 microg/d or equivalent with or without LABA (group 3). Patients administered 2 inhalations BID of SFC hydrofluoroalkane at doses of 25/50 microg/actuation (group 1), 25/125 microg/actuation (group 2), or 25/250 pg/actuation (group 3). The primary end point was tolerability as assessed by adverse events (AEs). AEs were determined via diary cards and investigator inquiry at visits. Serious AEs were defined as death, any life-threatening event, hospitalization, disability, congenital anomaly in the patient's offspring, or other important medical events judged by the investigator to be serious. Other outcomes included clinical laboratory tests (hematology, chemistry, electrolytes), 24-hour urinary-free cortisol excretion, 12-lead electrocardiograms, oropharyngeal examinations, vital signs, clinic visit lung function tests (FEV(1) and PEF), daily diary card entries of morning PEF, and rescue medication usage. RESULTS: Of the 372 patients assessed for eligibility, 325 from 22 centers across Canada were enrolled and randomized to treatment. Group 1 consisted of 98 patients (55% women; 86% white; mean age, 37 years; mean [SD] weight, 79 [20] kg). Group 2 consisted of 109 patients (46% women; 94% white; mean age, 44 years; mean [SD] weight, 80 [17] kg). Group 3 consisted of 118 patients (47% women; 90% white; mean age, 45 years; mean [SD] weight, 80 [18] kg). A total of 15 adolescents (aged 12-17 years) comprised 11%, 2%, and 2% of groups 1, 2, and 3, respectively. Treatments were well tolerated, and 274 (84%) of the 325 patients enrolled completed the study. Upper respiratory tract infection was the most common AE reported: 52%, 37%, and 49% of patients in groups 1, 2, and 3, respectively. Twenty (6%) patients withdrew because of an AE, with worsening asthma being the most frequent reason (n = 9). None of the serious AEs (11 [3 %]) were considered drug related by the investigators. Improvements in FEV(1) and PEF and re- duction in symptomatic albuterol use occurred during the first 4 weeks and were maintained in all groups throughout the 52-week study. CONCLUSIONS: BID doses of SFC hydrofluoroalkane 50/100 pg, 50/250 pg, and 50/500 pg administered via MDI for 52 weeks were well tolerated in this population of adolescents and adults with persistent asthma.