Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Repeat Doses of GW870086: Two Randomised Studies

Ann      Allen; Philippe      Bareille; Kelly      Hardes; Jonathan      Robertson

Abstract

Aim and Methods: We conducted two studies in healthy male subjects to assess the effect on serum cortisol levels of the novel inhaled corticosteroid GW870086, dosed at 6 mg, 12 mg and 15 mg/day (dry powder inhaler; NCT00549497) for 3 days and 5 mg and 8.75 mg/day (nebules; NCT01160003) for 14 days.

Results: In the 3-Day Study, the greatest suppression of serum cortisol weighted mean (0-24 hour) of GW870086, compared with placebo, was observed on Day 1 (29% suppression at the 15 mg dose). In the 14-Day Study, the greatest suppression was 15% for GW870086 5 mg. None of these values was considered clinically significant. After 3 days’ dosing, GW870086 was absorbed slowly (t_max: 0.8-3.5 hours) and eliminated with a t_1/2 of 22.7 hours; the highest systemic exposure (AUC) was 26.7 ng.hour/mL. After 14 days, GW870086 t_max was 0.3-0.4 hours and t_1/2 25.0-29.6 hours; the highest AUC was 16.7 ng.hour/mL. No safety issues were identified in these studies.

Conclusion: At estimated therapeutic and supratherapeutic doses, which achieved high exposure (AUC) in both studies, GW870086 did not exhibit the usual level of hypothalamic-pituitary-adrenal axis suppression that would be expected with traditional inhaled corticosteroids.

Keywords: Cortisol, GW870086, pharmacokinetics, safety.

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