The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects

Authors


Correspondence

Dr Rodger Kempsford, GlaxoSmithKline R&D, Stevenage, Hertfordshire SG1 2NY, UK.

Tel.: +44 (0) 1438 76 6351

Fax: +44 (0) 1438 76 8097

E-mail: rodger.d.kempsford@gsk.com

Abstract

Aim

To investigate the effects of the cytochrome P450 3A4 (CYP3A4) inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics of fluticasone furoate (FF) and vilanterol trifenatate (VI).

Methods

Two double-blind, randomized, placebo-controlled, two-way crossover studies in healthy subjects. In study 1, subjects received single doses of ketoconazole (400 mg) or placebo on days 1–6, with a single dose of inhaled VI (25 μg) on day 5. Pharmacodynamic and PK data were obtained up to 48 h following the VI dose. In study 2, subjects received once daily ketoconazole (400 mg) or placebo for 11 days, with FF/VI (200/25 μg) for the final 7 days. Pharmacodynamic and PK data were obtained up to 48 h following the day 11 dose.

Results

In study 1, there was no effect of co-administration of ketoconazole and VI on pharmacodynamic or PK parameters. In study 2, co-administration of ketoconazole and FF/VI had no effect on 0–4 h maximal heart rate or minimal blood potassium {treatment difference [90% confidence interval (CI)] –0.6 beats min–1 (−5.8, 4.5) and 0.04 mmol l−1 (−0.03, 0.11), respectively}, whilst there was a 27% decrease in 24 h weighted mean serum cortisol [treatment ratio (90% CI) 0.73 (0.62, 0.86)]. Co-administration of ketoconazole increased [percentage change (90% CI)] FF area under the curve (0-24) and maximal plasma concentration by 36% (16, 59) and 33% (12, 58), respectively, and VI area under the curve (0–t′) and maximal plasma concentration by 65% (38, 97) and 22% (8, 38), respectively.

Conclusion

Co-administration of FF/VI or VI with ketoconazole resulted in a less than twofold increase in systemic exposure to FF and VI. There was no increase in β-agonist systemic pharmacodynamic effects, while serum cortisol was decreased by 27%. Co-administration of FF/VI with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions.

Ancillary