The pharmacokinetics of conventional and bioenhanced tablet formulations of danirixin (GSK1325756) following oral administration in healthy, elderly, human volunteers
Danirixin (GSK1325756) is a small, high-affinity, selective, and reversible CXCR2 antagonist being developed for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the relative bioavailability, including inter-subject variability, of a conventional immediate-release (IR) formulation and two prototype bioenhanced formulations of danirixin under gastric acid suppression in a healthy, elderly population.
A single-center, crossover study was conducted with healthy male and female volunteers aged 65-80 years. Participants were randomized to receive 50 mg of danirixin IR in both fed and fasted states, and 50 mg of Bioenhanced Formulations 1 and 2 in the fasted state. Additionally, all subjects received 20 mg of omeprazole daily, starting 4 days before the first treatment and continuing through the final dosing period.
Twenty subjects were randomized and completed the study. Bioenhanced Formulation 2 in the fasted state showed the highest adjusted geometric means for AUC(0-t), AUC(0-inf), AUC(0-24), and C max. Danirixin IR showed higher adjusted means in the fed state compared to the fasted state. All formulations exhibited significant inter-subject variability (CVb >100 %). The overall incidence of adverse events (AEs) was 10% for danirixin IR (both fed and fasted states) and 15-20% for the bioenhanced formulations. Most AEs were mild, with no serious AEs reported.
Concomitant use of omeprazole resulted in considerable inter-subject variability in danirixin exposure. The bioenhanced formulations were unable to overcome the impact of omeprazole on exposure and variability across subjects.