Abstract
Background:AZD5069 is an oral C-X-C chemokine receptor 2 (CXCR2) antagonist targeting neutrophil-driven inflammation and is in clinical evaluation for the treatment of inadequately controlled asthma. AZD5069 is primarily metabolised by CYP3A isoenzymes,1 but the impact of CYP3A inhibition on systemic AZD5069 exposure in humans is not known.
Aims:To evaluate the effect of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics and effect on blood neutrophil counts of AZD5069.
Methods:Fifteen healthy male volunteers received single oral doses of AZD5069 15mg, alone and after pre-treatment with ketoconazole 400 mg once daily for 4 days. In addition to standard safety and laboratory evaluations, serial blood samples for assessment of pharmacokinetics and blood neutrophil counts were drawn up to 72 hours post-dose.
Results:Compared with AZD5069 alone, co-administration of AZD5069 and ketoconazole increased the geometric mean AUC 2.11-fold (90% CI: 1.92–2.32) and Cmax 1.65-fold (90% CI: 1.45–1.87). Blood neutrophil counts decreased when AZD5069 was administered alone and were further decreased following the combination of AZD5069 and ketoconazole. This correlated with the increase in AZD5069 exposure. The neutrophil counts returned to baseline within 48 h after dosing.
Conclusions:Co-administration of AZD5069 and ketoconazole resulted in a 2-fold increase in systemic exposure of AZD5069 and a greater reduction in blood neutrophil counts than AZD5069 alone. The clinical relevance of this has yet to be determined.
1. Gardiner P, et al. The mechanisms and routes of clearance of the CXCR2 antagonist AZD5069 in human. AAPS 2013, TX, USA. W4280
Funding:AstraZeneca.
- © 2014 ERS