Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326, USA
Received 5 July 2002; returned 8 August 2002; revised 18 September 2002; accepted 20 September 2002
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Abstract |
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Keywords: azithromycin, ceftriaxone, pharmacokinetics
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Introduction |
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Materials and methods |
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A computer-generated randomization scheme was used to assign subjects to the following dosing regimens in random order: (i) ceftriaxone 1 g (Rocephin Lot: U6231, exp. 6/04) intravenous (iv) in 100 mL of 5% dextrose in water every 24 h for three consecutive days; (ii) azithromycin 500 mg iv (Zithromax Lot: 203617, exp. 9/1/02) in 500 mL of 5% dextrose in water every 24 h for three consecutive days; and (iii) ceftriaxone 1 g iv in 100 mL of 5% dextrose in water every 24 h for 10 days with azithromycin 500 mg iv in 500 mL of 5% dextrose in water every 24 h for the first 3 days of ceftriaxone dosing. Ceftriaxone and azithromycin doses were infused by gravity over 30 and 60 min , respectively. During the combination regimen, ceftriaxone was administered first followed immediately by the azithromycin infusion.
Subjects were required to fast for at least 8 h before each dose and to remain fasting for the 4 h subsequent to study drug administration for the first and third day of each study arm. Additionally, subjects avoided caffeinated and alcoholic beverages for 48 h before and for the duration of each study arm. Dosing periods of any arms containing azithromycin were separated by at least 30 days, whereas the period consisting of only ceftriaxone was spaced by at least a 7 day period from the last ceftriaxone dose.
Plasma samples were collected before the first doses of both medications and then repeatedly over the next four (0.5, 1, 2, 4, 8, 12, 24, 24.5, 25, 36, 48, 48.5, 49, 50, 52, 56, 60, 72, 84 and 96 h) and 10 days (0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 24.5, 25, 25.5, 26, 36, 48, 48.5, 49, 49.5, 50, 51, 52, 54, 56, 60, 72, 96, 120, 144, 168, 192, 216 and 240 h) for ceftriaxone and azithromycin, respectively. Intense plasma sampling occurred for both drugs on days 1 and 3 of dosing during all study arms. In addition to plasma samples, during azithromycin-containing dosing periods, 2530 mL aliquots of blood were collected in EDTA-containing tubes for the isolation of WBCs at pre-dose, 2, 24, 26, 48, 50, 72, 120, 192 and 240 h. Isolation of polymorphonuclear leucocyte (PMN) and monocyte/lymphocyte (M/L) fractions was conducted as described previously.6
All specimens were stored at 80°C and shipped frozen overnight in a sufficient quantity of dry ice to Emprexe Analytical, LLC (Buffalo, NY, USA) for sample analyses. All heparinized plasma ceftriaxone samples were quantified using a validated reverse phase, high pressure liquid chromatographic (HPLC) assay with cefuroxime as the internal standard. Linearity was observed over the calibration curve range 1.00250 mg/L and the assay had a limit of detection of 0.131 mg/L for ceftriaxone in human plasma (signal to noise ratio = 5). The overall precision (percentage relative standard deviation; %RSD) and accuracy (analytical recovery; %AR) of the assay were determined from the plasma quality control samples analysed during the analysis of study samples, and calculated as 4.82% (4.115.31%) and 100% (97.8104%), respectively. Ceftriaxone demonstrated stability in heparinized human plasma for up to 111 days when stored at 70°C, as well as after three freezethaw cycles. Prepared samples were stable on the autosampler for up to 30 h at 4°C.
Azithromycin plasma specimens were assayed using a reverse phase, LC/MS/MS assay that was validated to quantify azithromycin in heparinized human plasma samples using erythromycin as the internal standard. Linearity was observed over the calibration curve range 0.00252.0 mg/L with a limit of quantification of 0.0025 mg/L. The overall %RSD and %AR of the assay were 5.53% (4.146.96%) and 102% (101103%), respectively. Azithromycin demonstrated stability in heparinized human plasma for up to 504 days when stored at 70°C, as well as after three freezethaw cycles. Prepared samples were stable on the autosampler for up to 23 h at 4°C. The quantification of azithromycin in PMNs and M/Ls was carried out using a reverse phase, LC/MS/MS assay that was validated to quantify azithromycin in human neutrophils and monocytes using erythromycin as the internal standard. Linearity was observed over the calibration curve range 0.0102.0 mg/L with a limit of quantification of 0.010 mg/L. Back-calculated concentrations in neutrophils were generated using azithromycin/erythromycin peak area response ratios. For neutrophils, the overall precision and accuracy of the assay were determined from the leucocyte quality control samples analysed during the analysis of study samples, and calculated as 8.75% (3.1813.7%) and 94.8% (92.596.8%), respectively. For monocytes, the overall precision and accuracy of the assay were calculated as 7.92% (5.8111.4%) and 94.2% (91.796.5%), respectively.
All of the assays (more detailed methodology can be found at http://www.emprexe.com) were specific for their test compounds and internal standards (when used) in the presence of acetylsalicylic acid, acetaminophen, caffeine, ibuprofen, naproxen, ketoprofen and salicylic acid.
Pharmacokinetic parameter analysis
All plasma data were analysed by non-compartmental methods with the TopFit Version 2.0 computer program. Weighting was set at 1/Y2. The single-dose and steady-state (third dose for both) pharmacokinetic parameters that were evaluated for azithromycin and ceftriaxone included: peak plasma concentration (Cmax); terminal elimination half-life (T1/2); area under the plasma concentrationtime curve from zero to infinity (AUCi) calculated via the linear trapezoidal method; total clearance (CLt); and volume of distribution (Vd). PMN and M/L azithromycin concentrations were calculated as described previously.6 PMN and M/L exposure curves were then calculated by the linear trapezoidal method from time zero to the last sampling time point at 240 h (AUC240).
Statistical analysis
Twelve subjects provided at least a 90% power to detect a 30% difference in the mean AUC and Cmax of azithromycin using a 5% significance level. Summary study subject demographics and pharmacokinetic parameter values were produced with the SigmaStat Version 2.03 computer program (SPSS, Inc.). Plasma azithromycin and ceftriaxone pharmacokinetic parameters and azithromycin PMN and M/L exposure curves were compared between the test arm (ceftriaxone/azithromycin combination) and control arms (azithromycin only, ceftriaxone only) using paired t-tests of log-transformed data and the above-mentioned software. Statistical significance was defined as P 0.05.
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Results |
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Six subjects reported mild to moderate adverse events that may have been or were related to study therapy. Three subjects reported mild nausea or dyspepsia during the azithromycinceftriaxone combination regimen. One subject reported mild diarrhoea during the ceftriaxone-only regimen. Two subjects reported mild to moderate headaches during the combination regimen (both subjects) and during the azithromycin-only regimen (one subject). One person reported mild hand pain during the azithromycin infusion, which may have been temperature related. Between two of the regimens, one subject reported moderate tongue and throat inflammation that was noted to possibly be thrush. No serious adverse events were reported during the study.
As shown in Table 1, when azithromycin was administered concurrently with ceftriaxone, it did not result in any statistically or clinically significant changes in ceftriaxones pharmacokinetic parameter profile either when it was dosed once or to steady state. When the reverse was examined (Table 2), although there was a statistically significant decrease in steady-state azithromycin exposure, this 1% change was not considered clinically relevant in the least. The remaining azithromycin plasma pharmacokinetic parameters after both one and three doses did not demonstrate any significant changes when ceftriaxone was administered concurrently.
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Discussion |
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In terms of pharmacokinetics of azithromycin and ceftriaxone, the addition of one drug did not have a significant adverse effect on the other either when studied after single doses of the two or at steady state. Although there should be no debate over the choice of three doses as being steady state for ceftriaxone, the same cannot be said for azithromycin. In the case of azithromycin, although the drugs half-life is only 14 h after a single dose, this rapidly increases to at least 70 h within two to three doses of starting a regimen, and steady-state conditions are only achieved after prolonged periods. Consequently, in this study we used three doses as an assumed steady-state as it was the average length of dosing utilized for the treatment of CAP patients during clinical trials with the drug.8,9 Therefore, the potential for an interaction between the two drugs was studied using clinically relevant regimens, albeit not pharmacokinetically ideal ones. Although there was no pharmacodynamic testing conducted during this study, the lack of a pharmacodynamic interaction between these drugs can be inferred from previous studies. In two past clinical trials, patients initially treated with a combination of a macrolide and a non-pseudomonal third-generation cephalosporin not only had less mortality than patients placed on other antibiotic regimens but also had a significantly shorter length of stay in hospital.10,11 These results would suggest a possible additive or synergic effect between these drugs rather than any type of antagonism.
In conclusion, the co-administration of ceftriaxone and azithromycin does not result in any clinically significant interactions and is a well tolerated combination.
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Acknowledgements |
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Footnotes |
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References |
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2
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