PT  - JOURNAL ARTICLE
AU  - Ann Allen
AU  - Kelly Hardes
AU  - Rodger Kempsford
AU  - Lee Tombs
TI  - The pharmacokinetics (PK) and pharmacodynamics (PD) of the fluticasone furoate (FF) and vilanterol (VI) combination in subjects with hepatic impairment
DP  - 2012 Sep 01
TA  - European Respiratory Journal
PG  - P2157
VI  - 40
IP  - Suppl 56
4099  - http://erj.ersjournals.com/content/40/Suppl_56/P2157.short
4100  - http://erj.ersjournals.com/content/40/Suppl_56/P2157.full
SO  - Eur Respir J2012 Sep 01; 40
AB  - Introduction: A combination of the novel corticosteroid FF and long-acting beta2 agonist VI (FF/VI) is being developed as a once-daily inhaled treatment for asthma and COPD.Objectives: To investigate the effect of hepatic impairment (HI) on FF and VI PK and PD.Methods: Open-label, repeat dose (7 day) study in subjects with mild, moderate or severe HI (Child-Pugh classification) and healthy subjects (HS) (matched with moderate HI). Subjects received FF/VI 200/25mcg or 100/12.5mcg (severe HI) once daily. FF and VI PK (Day 7) parameter point estimates and 90% confidence intervals (CIs) were constructed for the ratio of geometric means (HI:HS). Systemic PD effects of FF (0–24h weighted mean serum cortisol) and VI (0–4h heart rate and serum potassium) were assessed on Day 7.Results: There was no effect of HI on dose-normalised VI Cmax or AUC(0–24) and no clinically relevant effects of FF/VI on heart rate or serum potassium compared with HS. Dose-normalised FF systemic exposure (AUC(0–24); Day 7) was higher in subjects with mild, moderate and severe HI (ratio vs. HS [90% CI]: 1.34 [0.82, 2.20], 1.83 [1.11, 2.99] and 1.75 [1.05, 2.91], respectively. Serum cortisol was only reduced in subjects with moderate HI (average 34% reduction (90% CI: 11%, 51%) compared with HS. A similar effect would be predicted in severe HI with FF/VI 200/25mcg.Conclusions: In subjects with HI there was no increase in VI systemic exposure or systemic effects. FF exposure was increased by ≤3-fold in subjects with HI and was associated with a reduction in serum cortisol of approximately 30%.Funded by GSK (HZA111789; NCT01266941).