Abstract
Rationale: A combination of the novel corticosteroid FF and long acting beta2-agonist VI administered via dry powder inhaler (FF/VI) is being developed as a once-daily treatment for asthma and COPD. Both FF and VI are predominantly metabolised via CYP3A4 and their PK and PD could be affected by CYP3A4 inhibition.
Objective: To investigate the effects of the strong CYP3A4 inhibitor ketoconazole on the PK and PD of FF and VI.
Methods: Double-blind, randomised, placebo (P)-controlled, repeat dose, two-way crossover study. Healthy male and female subjects [N=18] received once daily oral ketoconazole (400mg) or P for 11 days with FF/VI (200/25mcg) for the final 7 days. PD and PK data were obtained up to 48h following the Day 11 dose.
Results: Co-administration of ketoconazole and FF/VI had no effect on 0-4h maximum heart rate or minimum blood potassium (treatment difference [90%CI] -0.6bpm [-5.8, 4.5] and 0.04mmol/L [-0.03, 0.11], respectively) whilst there was a measurable but clinically insignificant decrease in 24h weighted mean serum cortisol (treatment ratio [90%CI] 0.73 [0.62, 0.86]). Co-administration of ketoconazole increased (percent change [90%CI]) FF AUC(0-24) and Cmax by 36% [16, 59] and 33% [12, 58] and VI AUC(0 t') and Cmax by 65% [38, 97] and 22% [8, 38], respectively. Both treatments were well tolerated and there were no serious adverse events or withdrawals.
Conclusion: Co-administration of FF/VI with ketoconazole resulted in a less than two-fold increase in systemic exposure to FF and VI with no clinically significant systemic effects.
Funded by GSK (HZA105548; NCT01165125)
- © 2011 ERS