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Abstract: This study compared the pharmacokinetics of azithromycin (AZI) following administration of extended-release (ER) and immediate-release (IR) formulations in plasma and sinus mucosa in patients with chronic rhinosinusitis. Patients (n =71) were randomised 1:1 to receive a single dose of AZI-ER 2g or up to three doses of AZI-IR 500mg daily. Paired plasma and sinus tissue samples were taken during endoscopic sinus surgery at 2–168h (four patients per time point) after the first dose. Samples were measured by a validated liquid chromatography/mass spectrometry assay. Pharmacokinetics were determined using composite concentration–time profiles. Comparison between formulations showed that within the first 24h, the AZI area under the plasma concentration–time curve (AUC24) for ER was 5.2- and 7.0-fold higher than IR in plasma and sinus tissue, respectively. Comparison between matrices showed that the AUC24 and AUC168 in sinus tissue were 28.2- and 62.2-fold higher than in plasma for the ER formulation, whilst the AUC24 in sinus tissue was 21.1-fold higher than in plasma for IR formulation. These results indicated that AZI has good penetration into sinus tissue regardless of formulation; however, dosing of AZI-ER (2g) increased AZI exposure within the first 24h compared with the Day 1 dose of 500mg IR regimen. [Copyright &y& Elsevier]