Open‐Label, Randomized, 6‐Way Crossover, Single‐Dose Study to Determine the Pharmacokinetics of Batefenterol (GSK961081) and Fluticasone Furoate When Administered Alone or in Combination

Abstract

To investigate the pharmacokinetics of inhaled batefenterol (BAT) and fluticasone furoate (FF) given alone or in combination via ELLIPTA® dry powder inhaler (DPI-E), and BAT monotherapy via DISKUS® DPI (DPI-D). In this open-label, 6-way crossover study, 48 healthy subjects were randomized to 1 of 6 treatment sequences, comprising 6 single-dose treatment regimens: (1) BAT 1200 μg via DPI-D; (2) BAT 1200 μg via DPI-E without a lactose-filled second strip; (3) BAT 1200 μg via DPI-E with a lactose-filled second strip; (4) BAT/FF 1200/300 μg via DPI-E; (5) FF 300 μg via DPI-E with a lactose-filled second strip; and (6) BAT/FF 900/300 μg via DPI-E. Pharmacokinetic data were analyzed using noncompartmental methods. Plasma BAT area under the curve (AUC) and maximum plasma concentration (Cmax ) were similar for all treatments containing BAT 1200 μg (geometric least-squares means [GLSM] ratio, 0.90-1.06). Plasma FF AUC and Cmax were reduced following BAT/FF 1200/300 μg and 900/300 μg versus FF 300 μg monotherapy (GLSM ratio, 0.62-0.77). BAT 1200 μg administered via DPI-E, alone or in combination with FF, resulted in similar systemic exposure versus BAT administered by DPI-D. FF exposure was reduced when administered in combination with BAT compared with FF alone.

Open‐Label, Crossover Study to Determine the Pharmacokinetics of Fluticasone Furoate and Batefenterol When Administered Alone, in Combination, or Concurrently

“…13 In the present study, there was no reduction in the systemic exposure of FF with repeated administration of BAT/FF at therapeutic doses. 13 In the present study, there was no reduction in the systemic exposure of FF with repeated administration of BAT/FF at therapeutic doses.…”

“…This limit was lower than that used in the previous study (25 pg/mL), 13 as the bioanalytical methodology was re-developed to obtain adequate PK data at the therapeutic dose of BAT (300 μg). Upon collection, blood samples were centrifuged; plasma samples were then harvested and frozen within 2 hours and stored at −20°C or below until they were sent for analysis (Aptuit Srl, Verona, Italy, for BAT concentration; York Bioanalytical Solutions Ltd, York, UK, for FF concentration).…”

“…13,14 Assuming a constant variance for repeat and single doses and achievement of BAT and FF steady state by day 8, the same sample size was considered sufficient for repeat-dose analysis. Based on this sample size and assuming a within-subject coefficient of variation in log (AUC) for single doses of FF and BAT of 32% and 27%, respectively, the precision for comparisons of single-dose AUC and C max was calculated to be at least 13% of the observed point estimate, with precision expressed as the half-width of the 90% confidence interval (CI).…”

“…13 In that study, FF exposure following single-dose administration of BAT combined with FF (BAT/FF) was reduced compared with administration of FF alone. 13 In that study, FF exposure following single-dose administration of BAT combined with FF (BAT/FF) was reduced compared with administration of FF alone.…”

“…13 Finally, single high doses of FF/vilanterol (VI; 300/75 μg) and FF (300 μg) formulated with magnesium stearate (MgSt) were included to provide within-study comparisons of PK data with other FF formulations. In this study, the PK of BAT/FF 300/100 μg administered via Dry Powder Inhaler-ELLIPTA (DPI-E, owned by or licensed to the GlaxoSmithKline group of companies) 13 was compared with that of BAT or FF monotherapy.…”