జర్నల్ ఆఫ్ బయోక్వివలెన్స్ & బయోఎవైలబిలిటీ

నైరూప్య

Bioequivalence and Dose Proportionality of Inhaled Fluticasone Furoate

Ann Allen, Jo Bal, Alison Moore, Sally Stone and Lee Tombs

Fluticasone furoate (FF), a new inhaled corticosteroid delivered via the ELLIPTA dry powder inhaler, is being developed as a once-daily inhaled treatment for asthma. Study 1 was a part-randomised, open-label, four-way crossover, single- and repeat-dose study in healthy subjects (n=36) to assess whether the systemic exposure of FF increased proportionately across different strengths of FF (50 μg, 100 μg and 200 μg) and to determine the absolute bioavailability of FF inhalation powder. Study 2 was a randomised, open-label, replicate, six-way crossover, single-dose study in healthy subjects (n=30) to determine the bioequivalence of FF inhalation powder (single-strip configuration) compared with FF inhalation powder (two-strip configuration) and with fluticasone furoate/vilanterol (FF/VI) inhalation powder. A population pharmacokinetic analysis was also conducted on sparse samples collected from asthma patients in five Phase III studies conducted with FF/ VI or FF.

Overall, FF systemic exposure, as measured by single-dose AUC(0-∞), was dose proportional whilst Cmax showed a less than proportional increase. Inhaled absolute bioavailability of FF was 14%. Bioequivalence was not demonstrated for FF single-strip compared with either FF two-strip or FF/VI since the estimated 90% confidence interval for the ratio of adjusted geometric means for AUC and Cmax did not fall completely between 0.8000-1.2500. However, this difference was in line with the higher respirable mass delivered by the batch of single-strip product used in this study.

Although the formal bioequivalence study showed higher exposure with FF single-strip ELLIPTA compared with FF two-strip or FF/VI, the results of the population PK analysis of data in asthmatics show that there is no notable difference in systemic exposure between the FF configurations (single-strip, two-strip or FF/VI). In healthy subjects all treatments were generally safe and no new safety issues were apparent at these supra-therapeutic inhaled doses of FF (up to 1200 μg) and high intravenous FF dose (250 μg).