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.