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 20 mL 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 2.0 g. 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 2.0 g 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 [C(max)] and an approximate 2.5-hour delay in the time to reach C(max) [t(max)]), 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 (AUC(72 h)) by 23% and increased the C(max) of azithromycin by 115%. A standard meal increased the mean C(max) by 119% but had no clinically significant effect on the AUC(72 h). AZSR appeared to be better tolerated in the fasted state than in the fed state. The AUC(72 h) and C(max) 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 2.0 g dose. This formulation should be administered on an empty stomach and can be co-administered with antacids.
"Both the high fat meal and the standard meal increased the rate of drug absorption (2-fold higher C max values, and 2-to 4-hour shortening of time to maximal concentration) but were associated with an increased incidence of nausea and vomiting. It was assumed that meal-triggered gastric acid secretions led to faster release of azithromycin from the microspheres (Chandra et al 2007). Because of the decreased tolerability of the formulation when taken with food, it was suggested that azithromycin microspheres be taken on an empty stomach. "
[Show abstract][Hide abstract] ABSTRACT: Few adequately designed clinical trials have addressed optimal treatment duration in lower respiratory tract infections. Drugs possessing favourable pharmacokinetic and pharmacodynamic profiles may obtain early bacterial eradication allowing shorter treatment duration. This may be associated with a number of advantages including reduced resistance induction, increased compliance, lesser adverse events, and cost containment. Recently, a novel 2.0 g single dose of azithromycin microspheres has been compared with 7-day levofloxacin 500 mg or extended release clarithromycin in over 400 patients with community-acquired pneumonia. Clinical cure and bacteriological eradication rates, hospitalizations, and deaths were similar between azithromycin and comparators. Azithromycin 2.0 g microspheres proved as effective as 7 days of levofloxacin 500 mg in acute exacerbation of chronic bronchitis patients across all degrees of obstruction severity. In both settings Azithromycin microspheres obtained clinical cure in most patients harbouring macrolide-resistant Streptococcus pneumoniae strains. The drug was well tolerated in clinical studies and in healthy volunteers with modest and transitory adverse events. An undoubted advantage of single-dose azithromycin administration is the facility in ensuring that patients complete their prescribed course of therapy. A further advantage of single-dose therapy is the potential for use as directly-observed therapy, which may be useful in specific clinical conditions.
International Journal of Nanomedicine 02/2007; 2(4):551-9. · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nuclear-based techniques for the detection of bulk explosives are described. These techniques are shown to provide the only feasible approach for meeting the operational criteria of high throughput of screening luggage and cargo against concealed explosives in air transportation. The nuclear-based techniques are characterized by probing the screened object (e.g. luggage) with highly penetrating radiation, i.e. neutrons or energetic gamma rays. High-energy gamma rays produced by the probing radiation are characteristic to the elemental composition of the objects. The gamma rays are detected by an array of detectors placed near the object. The intensity, energy, and spatial distribution of the detected radiation and their relationship to the primary radiation allow a computer to determine the presence or absence of explosives. The nature of neutron interactions, the gamma detectors used, and the data analysis on which the decision is based are discussed.< >
IEEE Aerospace and Electronic Systems Magazine 01/1990; 4(12-4):17 - 20. DOI:10.1109/62.46985 · 0.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pharmacokinetic profiles of azithromycin given as a single-dose regimen (2.0-g extended-release microspheres) were characterized in serum and white blood cells (WBC) and compared with those of a 3-day regimen (a 500-mg immediate-release tablet once daily; total dose, 1.5 g) in an open-label, randomized, parallel-group study of 24 healthy adult subjects. Serial blood samples were collected up to 5 days after the start of dosing for both regimens. Safety assessments were conducted throughout the study. A single 2.0-g dose of azithromycin microspheres achieved significantly higher exposures in serum and WBC during the first 24 h after the start of dosing than a 3-day regimen: an approximately threefold higher area under the curve from time zero to 24 h postdose (AUC(0-24)) and an approximately twofold higher mean peak concentration on day 1. The single-dose regimen provided total azithromycin exposures in serum and WBC similar to those of the 3-day regimen, as evidenced by the similar AUC(0-120) and trough azithromycin concentrations in serum and WBC (mononuclear leukocytes [MNL] and polymorphonuclear leukocytes [PMNL]). For both regimens, the average total azithromycin exposures in MNL and PMNL were approximately 300- and 600-fold higher than those in serum. Azithromycin concentrations in MNL and PMNL remained above 10 microg/ml for at least 5 days after the start of dosing for both regimens. This "front-loading" of the dose on day 1 is safely achieved by the extended-release microsphere formulation, which maximizes the drug exposure at the time when the bacterial burden is likely to be highest.
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