JAC Advance Access published online on February 4, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn032
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Original research |
Pharmacokinetics of azithromycin in serum, bronchial washings, alveolar macrophages and lung tissue following a single oral dose of extended or immediate release formulations of azithromycin
1 Division of Thoracic Surgery, Cardiothoracic Department, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy 2 Pfizer Inc., New York, NY, USA 3 Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Via Roma 55, 56126 Pisa, Italy
* Corresponding author. Tel: +39-050-830148; E-mail: m.deltacca{at}med.unipi.it
Received 30 May 2007; returned 4 August 2007; revised 29 November 2007; accepted 10 January 2008
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Abstract |
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Objectives: Antibacterial efficacy of azithromycin could be improved by achieving higher concentrations at the sites of infection. Azithromycin extended release (azithromycin-ER) formulation was developed to enable a higher dosage of 2 g to be administered as a single oral dose without decreasing the safety profile. The aim of this study was to compare the pharmacokinetics of azithromycin in serum, epithelial lining fluid (ELF), alveolar macrophages (AMs) and lung tissue following a single oral dose of azithromycin-ER or azithromycin immediate release (azithromycin-IR) formulation.
Patients and methods: A total of 64 patients, diagnosed with lung cancer, requiring open-chest surgery for lung resection, completed the study. Subjects were randomized to receive oral administration of either a single 2 g dose of azithromycin-ER (32 subjects) or a single 500 mg dose of azithromycin-IR (32 subjects). Simultaneously, subjects within each treatment group were randomized to one of eight specific nominal post-dose time points for bronchoalveolar lavage and lung tissue sampling.
Results: For azithromycin-IR formulation, the AUC0–24 in serum, ELF, AMs and lung tissue was 3.1, 2.3, 1674 mg·h/L and 130 mg·h/kg, respectively. For azithromycin-ER formulation, the AUC0–24 in serum, ELF, AMs and lung tissue were 10.0, 17.6, 7028 mg·h/L and 505 mg·h/kg, respectively. The AUC0–24 ratio following administration of azithromycin-ER relative to azithromycin-IR was 3.2, 7.7, 4.2 and 3.9 in serum, ELF, AMs and lung tissue, respectively.
Conclusions: Within the first 24 h, a single 2 g azithromycin-ER dose produced dose-related increase in systemic exposure compared with a single 500 mg azithromycin-IR dose, which resulted in higher levels of azithromycin in ELF, AMs and lung tissue. Both formulations had similar safety profiles. By achieving high azithromycin exposure early in the course of treatment, without compromising tolerability, azithromycin-ER shows the potential for improved antibacterial efficacy compared with azithromycin-IR.
Key Words: antibiotic accumulation , macrolides , azalides , respiratory tract
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Introduction |
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Azithromycin is an azalide antibiotic related to the macrolide family. For the treatment of most community-acquired respiratory tract infections, 500 mg is administered daily for 3 days, or 500 mg on day 1 and 250 mg daily on days 2–5; both regimens comprise a total dose of 1.5 g of azithromycin.1
The efficacy of azithromycin is best correlated with the pharmacodynamic parameter of AUC/MIC.2,3 Higher AUC values, achieved by accelerated dosing or ‘front-loading’ (i.e. giving the entire dose of therapy as one dose), could result in improved antibacterial efficacy. This relationship has been demonstrated in animal models of infection by Girard et al.,4 who investigated the comparative in vivo activity of azithromycin following 1–3 days dosing regimens on Haemophilus influenzae otitis media infections induced in Mongolian gerbils. The results indicated more rapid bacterial clearance associated with the 1 day course of azithromycin entire dose versus the extended (2 or 3 days) dosing regimens.4
In previous studies by our group, the administration of a higher dose of azithromycin immediate release (azithromycin-IR) was associated with increased local concentrations of the drug.5,6 However, because of the risk of increased incidence of adverse events (AEs), particularly at the level of the gastrointestinal tract, a single 2 g dose oral formulation of azithromycin extended release (azithromycin-ER) has been developed to achieve greater local exposure without decreasing the safety profile of the drug.
Since azithromycin-ER formulation allows for the oral administration of a higher single 2 g dose, it is expected that azithromycin lung concentrations during early therapy should be greater than those observed with 500 mg of azithromycin-IR following a single oral dose. The present trial was therefore designed to evaluate the lung tissue concentrations after a single oral dose of azithromycin-ER formulation, as well as to compare the pharmacokinetics of ER and IR formulations during the first 24 h following treatment.5,6 Bronchoalveolar lavage (BAL) was obtained from the same patients to evaluate azithromycin concentrations in epithelial lining fluid (ELF) as well as alveolar macrophages (AMs).
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Materials and methods |
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Subjects, experimental design and specimen collection
Sixty-six subjects diagnosed with lung cancer, requiring open-chest surgery for lung resection, were enrolled at a single site and 64 patients completed the study. Subjects were randomized to receive oral administration of either a single 500 mg dose of azithromycin-IR (34 subjects) or a single 2 g dose of azithromycin-ER (32 subjects). Simultaneously, subjects within each treatment group were randomized to one of eight specific nominal post-dose time points for BAL and lung tissue sampling based on the procedures reported in previous studies.5,6 Of the 64 subjects who completed the trial, 48 were smokers (<20 packs/year) and 16 were non-smokers. The experimental protocol was approved by the local University Hospital Ethics Committee. All enrolled subjects provided their informed consent before beginning the investigation.
BAL and lung tissue samples were collected from four subjects per time point per treatment at the following sampling time intervals: 2, 4, 8, 12, 16, 24, 48 and 72 h post-dose. Serial blood samples (10 mL each) were also collected from all subjects at the following time points: pre-dose and 2, 4, 8, 12, 16, 24, 48 and 72 h post-dose.
BAL was performed immediately prior to surgery using standard bronchoscopic techniques. A fibre optic bronchoscope was inserted into a normal lung lobe. A total of five 50 mL aliquots of normal saline were instilled into the lung and were immediately aspirated into a trap. The first aspirate was kept separately, whereas the second through the fifth aspirates were pooled (pooled aspirate). The total volume of the first and the pooled aspirates was recorded.
BAL aspirates were centrifuged to separate cellular elements from supernatant. Aliquots (2 mL) of supernatant from the first and the pooled aspirates were frozen separately at –80°C and used subsequently for determination of urea concentration. In addition, 10 mL aliquots of supernatant from the first and pooled aspirates were frozen separately at –80°C until assay for azithromycin concentration.
Cell pellets from the first and pooled aspirate samples were re-suspended separately in PBS (pH 8.0) to a total volume of 10% of the recovered lavage fluid volume. The re-suspended cells were then stored at –80°C until analysed for azithromycin concentration.
At the time of surgery, five lung tissue specimens (
0.5 g each) of macroscopically (at least 10 mm) normal lung tissue were obtained from each patient. Each specimen was rinsed in PBS (pH 7.4) to remove excess blood, blotted with sterile gauze and weighed. Microscopic examination of a small fragment of each specimen was conducted to confirm the normal structure of lung tissue. Specimens with histological abnormalities were rejected. Lung tissue specimens were stored at –80°C until assay of azithromycin concentration.
Blood samples were kept at room temperature for 30 min until they clotted and were centrifuged at 1700 g for 10 min at 4°C. Serum was then obtained and stored at –80°C until subsequent analysis.
Determination of azithromycin concentration in BAL, AMs and lung tissue
Bronchoalveolar lavage. BAL supernatant was assayed for azithromycin concentration using a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method, as described in the Bioanalytical methods section. Azithromycin concentrations were only determined in the pooled aspirate, whereas samples from the first aspirate were not assayed, due to possible contamination from cells of upper airways. Azithromycin concentrations in BAL supernatant were then converted to predicted concentrations in ELF.
An estimate of ELF volume in each subject’s pooled aspirate was calculated by means of the urea dilution method reported by Conte et al.,7 as a modification of the method described by Rennard et al.8 The hypothesis behind the urea dilution method is that there is an equal diffusion of urea throughout the body, and hence the urea concentrations in serum and ELF are the same. Thus, ELF volume was estimated on the basis of the following relationship:
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The concentration of azithromycin in ELF (AZELF) was determined using the following relationship:
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Alveolar macrophages. Re-suspended cell pellets were assayed for azithromycin concentration using a validated LC/MS/MS method. At the time of assay, each cell pellet was thawed and a 50 µL aliquot was extracted using liquid–liquid extraction as described below in the Bioanalytical methods section. Azithromycin concentrations were only determined in cell pellets obtained from pooled aspirates, whereas cell pellets from the first aspirate were not assayed due to possible contamination from cells of upper airways. Azithromycin concentrations were reported as amount per litre of the re-suspended cell pellet suspension. Since cell pellets were re-suspended in buffer to 10% of the recovered BAL volume, a 10-fold adjustment to cell counts was done for determination of azithromycin concentrations in AMs.
The volume of AMs in the cell pellet (VAM), obtained from the pooled aspirate, was determined from the total cell count of the pooled aspirate and a mean macrophage cell volume of 2.42 µL/106 cells as previously reported.7,9 The concentration of azithromycin in AMs (AZAM) was calculated from the following relationship:
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Lung tissue. Weighed lung tissue samples were homogenized in buffer, and homogenates were assayed for azithromycin using a validated LC/MS/MS method (see Bioanalytical methods section). Concentrations of azithromycin were reported as mg/kg of lung tissue.
Serum samples were analysed for azithromycin by BAS Analytics (West Lafayette, IN, USA) using a validated high-performance liquid chromatography/electrochemical detection method. Azithromycin was extracted from serum by liquid–liquid extraction. A 50 µL aliquot of 9-N-propargylazithromycin (internal standard) in 50% acetonitrile (v/v) was added to 1.0 mL of serum. The sample was alkalinized with 1.0 mL of 0.06 M Na2CO3 and 2.0 mL of methyl-t-butyl ether (MTBE) were then added. Samples were centrifuged to separate phases, and tubes were kept at –60°C to freeze lower aqueous layer. Organic phase (upper layer) was transferred to a new tube, evaporated under nitrogen in a 40–50°C water bath, reconstituted in 250 µL of reconstituting solution (75% PBS/25% acetonitrile), adjusted to pH 6.0 and vortexed. In order to eliminate late eluting peaks in the chromatogram, reconstituted sample was washed with 500 µL of hexane, gently mixed and centrifuged. A 60 µL aliquot was injected into a liquid chromatography/electrochemistry system (Bioanalytical Systems PM-80 isocratic pump with an LC-26A on-line vacuum degasser and Bioanalytical Systems LC-4C electrochemical detector) set up with a ZirChrom polybutadiene-coated zirconium column (150x4.6 mm, 3 µm) and an alkaline (65% PBS/35% acetonitrile) mobile phase. Tertiary amine on macrolide desosamine ring was detected at high potential. Extraction recovery of azithromycin and internal standard from the serum was 72% and 81%, respectively. The dynamic range of serum assay was 0.0104–1.00 mg/L. Accuracy of the quality control samples (QCs) used during analysis ranged from 4.3% to 7.0% (as judged by percent deviation from nominal value) with a precision of 
2.7% (as judged by relative standard deviation).
Azithromycin concentrations in BAL and AMs were analysed by BAS Analytics using a validated LC/MS/MS method.10 Azithromycin was extracted by a liquid–liquid extraction by adding 100 µL of D3-azithromycin (internal standard) in acetonitrile/water (1:1, v/v) to 50 µL of matrix, followed by addition of 1 mL of 0.06 M Na2CO3, 1 mL of purified water and 2 mL of MTBE. After brief vortex, samples were centrifuged and the upper ether layer was transferred to a clean tube and evaporated under nitrogen. The dried extract was reconstituted with 100 µL of mobile phase (73% 0.05 M ammonium acetate/27% acetonitrile, v/v) and vortexed. A 50 µL aliquot was injected into LC/MS/MS system (Bioanalytical Systems PM-80 isocratic pump with a LC-26A on-line vacuum degasser and MicroMass 4 LC tandem quadrupole mass spectrometer with electrospray source) set up with a Dupont Zorbax XDB-8 Eclipse C-8 narrow bore column (150x2.1 mm, Agilent Technologies). The mass spectrometer was operated in the positive ionization mode and monitored the transition ions m/z 749.5
591.4 and 752.6594.4 for azithromycin and D3-azithromycin, respectively. Due to a limited supply of control matrices of BAL and AMs, the assay was validated using human serum as primary matrix for preparation of calibration standards and validation samples were prepared in the primary (serum) and secondary (100% BAL and 50% BAL/50% dithiothreitol and AMs) matrices. The dynamic range for the assay was 0.010–0.250 mg/L. The accuracy of QCs used during sample analysis ranged from –0.55% to 5.0% (as judged by percent deviation from nominal value), with a precision of 2.0% (as judged by relative standard deviation) for azithromycin.
Lung tissue samples were analysed by BAS Analytics using a liquid–liquid extraction followed by LC/MS/MS method. A 25 µL aliquot of D3-azithromycin (internal standard) in acetonitrile/water (1:1, v/v) was added to lung tissue sample (250 mg tissue in 5 mL of acetonitrile). The homogenate (50 µL) was fortified with 1 mL of 0.06 M Na2CO3, 1 mL of purified water and 2 mL of MTBE. After brief vortex, samples were centrifuged and the upper ether layer was transferred into a clean tube and evaporated under nitrogen. The dried extract was reconstituted with 100 µL of mobile phase (73% 0.05 M ammonium acetate/27% acetonitrile, v/v) and vortexed. A 10 µL aliquot was injected into an LC/MS/MS system and detected as described above for BAL assay. The dynamic range for the lung tissue assay was 0.0250–1.25 mg/L in homogenate (equivalent to 5.00–25 mg/kg in lung tissue). The accuracy of QCs used during sample analysis ranged from –1.4% to 1.8%, with a precision of 2.8%.
Pharmacokinetic analysis was carried out with WinNonlin (V.3.2, Pharsight®, Mountain View, CA, USA) using standard non-compartmental methods. Since serial serum samples were collected from each subject, serum concentration–time data from each subject were analysed by non-compartmental methods. For lung tissue, ELF and AMs azithromycin concentrations were averaged for four subjects per time point for each treatment; the mean concentration–time profile for each matrix was then subjected to non-compartmental analyses. Furthermore, since pre-dose samples were not collected for lung tissue, ELF and AMs, pre-dose concentrations were assumed as zero for pharmacokinetic analyses. Cmax was estimated directly from the observed concentration versus time data, with Tmax defined as the time of the first occurrence of Cmax. AUC from time zero to the last time (Tlast) quantifiable concentration [AUC(0–Tlast)] was determined using the linear trapezoidal rule. Partial AUC within the first 24 h after dosing (AUC0–24) was also determined using the trapezoidal rule.
No formal statistical analyses were conducted and the data were reported as mean ± SD, unless otherwise stated; n indicates the number of patients.
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Results |
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Subject demographics were similar in both treatment groups (Table 1). Thirty-two subjects were included in azithromycin-ER arm (28 males, 4 females) and 34 subjects in azithromycin-IR arm (23 males, 11 females). Two subjects in azithromycin-IR arm discontinued for reasons not related to study medication. The mean age of subjects in all groups was between 63.0 and 66.4 years and subjects ranged in age from 36 to 79 years.
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Serum
Consistent with the higher dose for azithromycin-ER, systemic exposure of azithromycin (as judged by Cmax and AUC values) exhibited a dose-related increase compared with azithromycin-IR (Figure 1 and Table 2). Within the first 24 h after dosing, the mean AUC0–24 value for azithromycin-ER was 3.2-fold higher compared with azithromycin-IR (Table 3). For both formulations, median Tmax value was 4.0 h (Table 2).
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Epithelial lining fluid
Following administration of azithromycin-IR, mean azithromycin concentrations in ELF remained fairly low for 24 h post-dose, followed by occurrence of peak concentration at 48 h post-dose (Figure 2). In contrast, mean concentrations around 0.5 mg/L were seen in the azithromycin-ER group until 16 h post-dose, followed by a spike in ELF concentrations, with peak occurring at 48 h post-dose (Figure 2). Overall, mean azithromycin concentrations in ELF were markedly higher for azithromycin-ER relative to azithromycin-IR. Within the first 24 h after dosing, the AUC0–24 values were 7.7-fold higher for azithromycin-ER than for azithromycin-IR (Table 3). Other pharmacokinetic parameters based on analyses of composite concentration–time profiles are presented in Table 4. Across all time points, the coefficient of variation (%CV) of mean azithromycin concentrations in ELF ranged from 115% to 200% and from 85% to 200% for azithromycin-IR and azithromycin-ER groups, respectively.
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Alveolar macrophages
Pooled alveolar cells from BAL aspirates were found to contain a heterogeneous population of cells, of which macrophages were 85% and neutrophils 10% of total cell numbers. Therefore, owing to the predominance of macrophages, the azithromycin concentration in cells from BAL aspirates largely reflected the drug distribution into macrophages and, consistent with this assumption, the designation of ‘AMs’ has been used throughout this article. Following administration of azithromycin-IR, azithromycin concentrations in AMs remained fairly low for 12 h post-dose, followed by occurrence of peak concentration (194 mg/L azithromycin-IR and 669 mg/L azithromycin-ER) at 16 h post-dose. Within the first 24 h after dosing, the AUC0–24 values for AMs were 4.2-fold higher for azithromycin-ER (7028 mg·h/L) than for azithromycin-IR (1674 mg·h/L; Table 3 and Figure 3). Across all time points, the %CV of mean azithromycin concentrations in AMs ranged between 35% and 158% and 37% and 177% for azithromycin-IR and azithromycin-ER groups, respectively.
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Lung tissue
Mean azithromycin concentration–time profiles in lung tissue are shown in Figure 4. Since samples were collected from four subjects per time point per formulation, the concentration–time curve is a composite profile similar to that obtained for ELF and AMs. Regardless of the formulation, the mean profiles indicate that once azithromycin enters the lung tissue, the concentrations remain sustained for a prolonged time. Mean concentration–time values were subjected to non-compartmental analysis and resultant pharmacokinetic parameters are presented in Table 4. Following administration of azithromycin-IR or azithromycin-ER, detectable concentrations were found in all four subjects/treatment randomized to the first sampling time point of 2 h, which suggests a rapid drug distribution. However, peak concentration of azithromycin lagged behind the peak concentration observed in the serum. Within the first 24 h after dosing, the AUC0–24 values were 3.9-fold higher for azithromycin-ER than for azithromycin-IR (Table 3). Across all time points, the %CV of mean azithromycin concentrations in the lung ranged between 33% and 126% and 35% and 81% for azithromycin-IR and azithromycin-ER treatments, respectively.
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Safety and tolerability
Three of the 32 subjects in azithromycin-ER group experienced five digestive AEs (three nausea and two diarrhoea) that were considered by the investigator to be treatment related. Of these five digestive events, four were mild and one was moderate in severity. No other treatment-related AEs were observed in either group. There were no discontinuations due to study treatment in either group. Serious AEs were reported in nine subjects (four azithromycin-ER and five azithromycin-IR), none of which was considered to be related to study treatment. There was no evidence of ECG interval prolongation in both treatment groups. No deaths occurred during the study.
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Discussion |
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In this randomized, open-label study, the pharmacokinetics of two azithromycin formulations, azithromycin-ER and azithromycin-IR, were evaluated in serum, lung tissue and bronchial washings (consisting of ELF and AMs) in cancer subjects requiring lung resection, in whom antibiotic prophylaxis was not contraindicated. Evidence was thus obtained that a single 2 g dose of azithromycin-ER resulted in an enhanced systemic distribution compared with 500 mg of azithromycin-IR within 24 h from oral administration.
Azithromycin-ER is formulated to release azithromycin at a slower rate and lower concentration in the lumen of the gastrointestinal tract compared with currently available azithromycin-IR formulations, thereby bypassing motilin receptors implicated in the development of digestive AEs, especially nausea and vomiting.11,12 In comparison with multiple-dose IR formulations, a better profile of gastrointestinal tolerability together with the achievement of greater lung concentrations during the 24 h period after administration would allow for a higher, single-dose of azithromycin-ER to be taken orally.
Therefore, a well-tolerated, single-dose azithromycin-ER is expected to be efficacious and improve patient compliance, as well as to minimize premature discontinuation of treatment and transfer of resistance genes among subpopulations of bacteria.
The serum pharmacokinetics of azithromycin, following the administration of azithromycin-IR and azithromycin-ER, are consistent with previous studies.13,14 Regardless of formulation, the pharmacokinetic profile of azithromycin was characterized by rapid absorption and rapid elimination of both azithromycin-IR and azithromycin-ER. Comparing the single doses of 500 mg of azithromycin-IR and 2 g of azithromycin-ER, the systemic exposure of azithromycin increased in a dose-related manner, based on serum Cmax and AUC values. With regard for pulmonary compartments, administration of 2 g of azithromycin-ER resulted in higher exposure within the first 24 h after dosing compared with azithromycin-IR, leading to higher AUC0–24 values in the lung tissue, AMs and ELF. These data are in agreement with results from pre-clinical animal infection models,4 which demonstrated an improved antibacterial efficacy of azithromycin when the whole dose was given as a single oral dose rather than as split dosing over 2 or 3 days, and support the premise of ‘front-loading’ the dose of azithromycin for treatment of bacterial infections. Therefore, azithromycin-ER, which enables the achievement of improved AUC/MIC ratios within the first 24 h from its administration, has the potential to ameliorate clinical outcomes. Indeed, hospitalized patients who received antibiotics within 4 h of admission have been shown to have a shorter length of hospitalization and reduced mortality.15,16
It has been proposed that azithromycin concentration at the site of infection (e.g. in ELF) is more predictive of antimicrobial effects of this antibiotic against extracellular pathogens associated with lower respiratory tract infections than systemic measures, such as serum concentration.17,18 In the present study, individual subject concentrations of azithromycin in ELF ranged from 0 to 3.54 mg/L and from 0 to 6.81 mg/L for azithromycin-IR and azithromycin-ER, respectively, providing support to the pharmacokinetic advantages of azithromycin-ER. Conte et al.7 examined azithromycin concentrations in ELF following a single oral dose of 500 mg of azithromycin-IR, but they were unable to detect azithromycin in any ELF sample.7 This may be due to low assay sensitivity (90 ng/mL) for measurement of azithromycin in BAL supernatants,7 whereas assay sensitivity was 10 ng/mL in the present study. In another investigation by Capitano et al.,19 azithromycin concentrations in ELF, following oral administration of azithromycin-IR, were comparable to those observed in the present study with azithromycin-ER at 4, 8 and 12 h time points. However, in our study, at 24 h time point, azithromycin concentration in ELF samples from patients treated with azithromycin-ER was double than that obtained for azithromycin-IR by Capitano et al.19 (1.98 mg/L versus 0.94 mg/L). It is also noteworthy that the 7.7-fold ELF concentration difference between the two treatments is higher than that observed in serum, lung tissue and AMs, due to the fact that more ELF samples from azithromycin-IR group were below quantifiable levels and that in such samples azithromycin concentrations were considered zero for the purpose of pharmacokinetic analyses. The higher AUC0–24 values for azithromycin-ER group, compared with azithromycin-IR, suggest that azithromycin-ER is able to induce ELF uptake much earlier than azithromycin-IR, as indicated by its increased slope at 16–24 h versus 24 h.
As judged by the slope of the ascending portion of mean lung concentration–time curves, it appears that lung azithromycin uptake was faster in the azithromycin-ER group compared with the azithromycin-IR group. This can be explained by the first-order processes of drug distribution between central (i.e. serum) and peripheral (i.e. lung tissue) compartments. However, concentrations in the lung were sustained over a prolonged period, with only a slight log-linear decline in the terminal phase for azithromycin-IR and no noticeable decline for azithromycin-ER, suggesting an extensive binding of the drug in lung tissue.
The present azithromycin concentrations in AMs were somewhat higher than those reported by Conte et al.7 in healthy volunteers. The exact reasons for this variation are unclear, but they might include underlying disease (i.e. cancer) in the current study and other inter-study differences. Nevertheless, our data confirm the observation that azithromycin achieves high concentrations in AMs. Of note, high azithromycin levels in macrophages may serve as a reservoir of the antibiotic, allowing sustained tissue levels even after serum concentration decline. In a previous study on healthy subjects, azithromycin-ER reached higher levels in macrophages at 8 h post-dosing compared with azithromycin-IR.10 These results are consistent with the present lung tissue data, which show azithromycin concentrations in AMs to be markedly higher for azithromycin-ER than for azithromycin-IR.
Azithromycin breakpoints for MIC values of Streptococcus pneumoniae are 0.5, 1 and 
2 mg/L for sensitive, intermediate and resistant organisms, respectively.1 At the site of pulmonary infection (i.e. in ELF), the present AUC0–24 values for azithromycin-IR and azithromycin-ER were 2.3 and 17.6 mg·h/L, respectively, suggesting a potent effect of azithromycin-ER on pulmonary pathogens. The ratio of unbound AUC0–24 to MIC has been suggested to be the most predictive pharmacodynamic parameter for azithromycin efficacy. In addition, plasma AUC/MIC values of at least 10 (non-neutropenic host) and 25–30 (neutropenic host) have been recommended for in vivo suppression of S. pneumoniae.20 Based on these parameters, the present values of AUC0–24 in ELF support the efficacy of a single 2 g oral dose of azithromycin-ER for the treatment of lower respiratory tract infections due to susceptible strains of S. pneumoniae.
In the present study, both azithromycin formulations demonstrated favourable tolerability and safety profiles. Treatment-related AEs were limited to five episodes of mild-to-moderate nausea or diarrhoea in azithromycin-ER group. There were no treatment-related serious AEs or discontinuations during the study. Neither azithromycin-ER nor azithromycin-IR were associated with ECG interval prolongation. These results are in agreement with previous studies in which azithromycin-ER demonstrated a comparable safety profile to levofloxacin and clarithromycin in large phase 3 clinical trials including 700 patients with community-acquired pneumonia, acute bacterial sinusitis and acute exacerbations of chronic bronchitis.21–23
In conclusion, a single oral dose of 2 g of azithromycin-ER resulted in a dose-related increase in systemic exposure compared with a single oral dose of 500 mg of azithromycin-IR and such increment translates into an enhanced distribution of azithromycin into lung, ELF and AMs. By increasing the azithromycin concentration in the lung, azithromycin-ER possesses the potential to ensure an improved antibacterial efficacy against respiratory infections.
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This study was sponsored by Pfizer Inc.
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Editorial support was provided by Dr Michael Lappin at PAREXEL and was funded by Pfizer Inc.
The University of Pisa (Division of Pharmacology and Chemotherapy, M. D. T. and G. P.; Cardiothoracic Department, A. M. and M. L.) has received funds from Pfizer for research on azithromycin extended release pulmonary pharmacokinetics.
M. D. T., A. M., M. L. and G. P. are not members of any Pfizer advisory board for azithromycin and they do not have any conflict of interest that might affect the conclusions of the present article.
B. D., A. F., P. J. de C. and S. S. are employed by Pfizer Inc. and own stocks in the company.
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Acknowledgements |
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We would like to acknowledge the contribution of Professor Romano Danesi, MD, PhD, and Professor Corrado Blandizzi, MD, from the University of Pisa, the rest of the team at the University of Pisa and Dr Grover Foster, PhD, from Pfizer for their contributions throughout the study.
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References |
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