Clinical Pharmacokinetics and Gastrointestinal Tolerability of a Novel Extended-Release Microsphere Formulation of Azithromycin

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Abstract
A novel oral, extended-release, microsphere formulation of azithromycin (AZSR) was developed to improve the gastrointestinal tolerability profile while allowing administration of an entire treatment course of azithromycin in a single dose. Several phase I clinical pharmacology studies were conducted to (i) identify a well-tolerated single-dose formulation that met a predefined exposure target; and (ii) evaluate the effect of food and antacid on the absorption of this formulation. Of these, five pivotal studies are described here. The pharmacokinetic profile of AZSR was compared with that of the commercially available immediate-release azithromycin formulation (AZM) in an open-label, crossover, single-dose study (Study A), and their gastrointestinal tolerability profiles were compared in an observer-blind, parallel group, single-dose study (Study B). The effects of food (a high-fat meal and a standard meal) and antacid (a single 20mL dose of Maalox® Regular Strength, containing magnesium hydroxide, aluminium hydroxide and simethicone) on the absorption of azithromycin from AZSR were evaluated in three separate open-label, crossover, single-dose studies (Studies C, D and E). Healthy adult subjects were enrolled in all five studies, and all subjects were evaluable for tolerability. The dose used for all azithromycin formulations was 2.0g. Serum azithromycin concentrations were determined using a validated high-performance liquid chromatography/electrochemical detection method, and pharmacokinetic parameters were analysed using noncompartmental methods. 377 subjects received a single 2.0g dose of azithromycin as AZSR and/or AZM in the five studies. Compared with AZM, AZSR had a slower absorption rate (57% decrease in the mean peak concentration [Cmax] and an approximate 2.5-hour delay in the time to reach Cmax [tmax]), with a mean relative bioavailability of 82.8%, which met the predefined exposure target (at least 80% bioavailability relative to AZM). Compared with AZM, AZSR was associated with significantly lower rates of nausea and vomiting. A high-fat meal increased the mean area under the serum concentration-time curve [AUC] from time zero to 72 hours post-dose (AUC72h) by 23% and increased the Cmax of azithromycin by 115%. A standard meal increased the mean Cmax by 119% but had no clinically significant effect on the AUC72h. AZSR appeared to be better tolerated in the fasted state than in the fed state. The AUC72h and Cmax of AZSR were not significantly affected by co-administration with a single dose of antacid. The extended-release microsphere formulation of azithromycin, AZSR, allows administration of an entire therapeutic course of azithromycin as a well-tolerated single 2.0g dose. This formulation should be administered on an empty stomach and can be co-administered with antacids.

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