title: The pharmacokinetics of conventional and bioenhanced tablet formulations of danirixin (GSK1325756) following oral administration in healthy, elderly, human volunteers.
abstract: Danirixin (GSK1325756) is a small, high-affinity, selective and reversible CXCR2 antagonist in development for treatment of chronic obstructive pulmonary disease. The objective of the study was to evaluate the relative bioavailability, including the inter-subject variability, of a conventional immediate-release (IR) formulation and two prototype bioenhanced formulations of danirixin during gastric acid suppression in a healthy, elderly population. A single-centre, crossover study in healthy male and female volunteers aged 65-80 years was conducted. Subjects were randomised to receive danirixin 50 mg IR in the fed and fasted states and danirixin 50 mg Bioenhanced Formulation 1 and 2 in the fasted state. All subjects also received omeprazole 20 mg each morning beginning 4 days prior to the first treatment period and continuing through danirixin dosing in the final treatment period. Twenty subjects were randomised and completed the study. Bioenhanced Formulation 2 in the fasted state demonstrated the highest adjusted geometric means for AUC(0-t), AUC(0-inf), AUC(0-24) and C max. Danirixin IR demonstrated adjusted means that were higher in the fed state compared with the fasted state. For all formulations tested, there was substantial inter-subject variability (CVb >100 % for all formulations). The overall incidences of adverse events (AEs) were 10 % for danirixin IR (both in the fed and fasted states) and 15-20 % for the bioenhanced formulations. The majority of AEs were mild in intensity. There were no serious AEs. Concomitant use of omeprazole resulted in large inter-subject variability in the exposure to danirixin. Bioenhanced formulation strategies could not overcome the effect of omeprazole on exposure and variability between subjects.
authors: Clinical Discovery, Respiratory Therapy Area Unit, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA, bruce.e.miller@gsk.com.
authors: Bruce E
authors: BE
authors: Miller
authors: Kevin
authors: K
authors: Smart
authors: Sunil
authors: S
authors: Mistry
authors: Claire L
authors: CL
authors: Ambery
authors: Jackie C
authors: JC
authors: Bloomer
authors: Paul
authors: P
authors: Connolly
authors: Dominic
authors: D
authors: Sanderson
authors: Trevor
authors: T
authors: Shreeves
authors: Rachel
authors: R
authors: Smith
authors: Aili L
authors: AL
authors: Lazaar
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000368:Aged; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004347:Drug Interactions; D004739:England; D005215:Fasting / Q000097:blood; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D009853:Omeprazole / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019518:Postprandial Period; D054328:Proton Pump Inhibitors / Q000008:administration & dosage; D019141:Respiratory System Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D013607:Tablets
chemical_list: D010880:Piperidines; D054328:Proton Pump Inhibitors; D019141:Respiratory System Agents; D013450:Sulfones; D013607:Tablets; D009853:Omeprazole; C581951:danirixin