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The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects
Author(s) -
Kempsford Rodger,
Allen Ann,
Bal Joanne,
Rubin David,
Tombs Lee
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12019
Subject(s) - fluticasone propionate , ketoconazole , pharmacokinetics , pharmacodynamics , pharmacology , medicine , fluticasone , anesthesia , inhalation , antifungal , dermatology
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 I n 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 C o‐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.