Department of Medical Microbiology, City Hospital NHS Trust, Birmingham B18 7QH, UK
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Abstract |
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Introduction |
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Materials and methods |
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The hospital ethics committee granted approval for the study and all volunteers gave written informed consent. All volunteers underwent a full medical assessment, including haematological and biochemical blood analysis, urinalysis, a urine drugs screen and an ECG. One subject was found to have mildly raised bilirubin levels, suggesting Gilbert's syndrome, but this did not preclude him from entering the study. All other investigations were within normal limits. To induce blister formation, and hence inflammatory fluid, two cantharidine-impregnated plasters were placed on the subjects' forearms 16 h before the study.
A dose of gemifloxacin 320 mg (GlaxoSmithKline) was given orally with water to the fasted subjects, followed by a light breakfast after 3 h. There were no restrictions on fluid intake. Before dosing, and at 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 h post-dose, samples of venous blood were collected and blister fluid aspirated. The blisters were resealed each time with Opsite spray dressing (Smith & Nephew, Hull, UK). Urine was collected 06, 612 and 1224 h post-dose. At 24 h post-dose the volunteers were assessed for evidence of adverse events, and further blood and blister samples were taken.
Drug analysis
All samples were analysed within 2 h of collection. A microbiological assay was used to measure the concentration of gemifloxacin in the specimens collected. Assay plates containing Iso-Sensitest agar (Oxoid, Basingstoke, UK) were flooded with a suspension of Escherichia coli 4004 (Bayer AG, Wuppertal, Germany) adjusted to an OD of 0.004 at 630 nm in sterile distilled water. The calibrator ranges were 0.0151 mg/L, 0.061 mg/L and 0.1252 mg/L for plasma, blister and urine samples, respectively. Calibrators, internal controls and quality assurance samples were prepared in human serum (Bradsure Biologicals, Market Harborough, UK), in 70% human serum in pH 7 phosphate buffer (to simulate the protein content of the blister fluid), and phosphate buffer (pH 7) for the assay of gemifloxacin in plasma, inflammatory exudate and urine, respectively.
The lower limit of quantification was 0.015 mg/L. The between-assay coefficients of variation ranged from 7.3 to 11.7% for concentrations between 0.1 and 1.5 mg/L, and the correlation coefficient (r2) for the quality assurance samples over a concentration range of 0.019 and 1.8 mg/L was 0.9678.
Pharmacokinetic analysis
Standard non-compartmental analysis was used to determine the pharmacokinetic parameters. The maximum concentration of gemifloxacin in plasma or blister fluid (Cmax) and time to reach Cmax (Tmax), the area under the plasma or skin blister fluid concentration curve up to the last measurable concentration (AUClast), the area under the plasma or skin blister fluid concentration curve extrapolated to infinity (AUC0), and the elimination half-life (t
) in plasma or skin blister fluid were calculated by the noncompartmental model 200 of WINONLIN version 4.2a (Pharsight Inc., Apex, NC, USA). The percentage penetration of the drug into inflammatory fluid was calculated by comparing the AUC0
taken from the blister fluid data with that from the plasma data.
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Results |
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The mean concentrationtime profiles found in plasma and inflammatory fluid following the administration of gemifloxacin 320 mg are shown in the Figure and the derived pharmacokinetic parameters are summarized in the Table
. The mean Cmax of gemifloxacin in plasma was 2.33 mg/L, with a Tmax of 1.20 h after oral administration. The mean terminal t
from plasma was 5.94 h (range 5.226.68 h). The AUClast and AUC0
were 10.38 and 10.98 mgh/L, respectively.
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The mean urinary excretion of the drug in the 24 h period following the oral dose was 36.1%.
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Discussion |
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The tissue penetration data were limited by the yield of inflammatory fluid obtained from the blisters. Only five subjects provided adequate data for analysis. The mean penetration of gemifloxacin into inflammatory exudate was found to be 61.19%. This level of tissue penetration is thought to be related to the degree of protein binding, which for gemifloxacin is approximately 60% (GlaxoSmithKline, unpublished data), similar to that of trovafloxacin (64%).8 In contrast, quinolones with less protein binding, such as gatifloxacin and ciprofloxacin, have a higher percentage tissue penetration. For the full 24 h of this study the concentration of gemifloxacin in inflammatory fluid exceeded the MIC90 for organisms such as Staphylococcus aureus (methicillin susceptible) and Streptococcus pyogenes (0.06 mg/L). Twenty four hours after dosing, the mean blister fluid concentration of gemifloxacin was 0.08 mg/L (range 0.070.09). This suggests that skin and soft tissue infections caused by these organisms should be amenable to treatment with gemifloxacin and a once-daily dosing regimen would be feasible.
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Acknowledgments |
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Notes |
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References |
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2
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6 . Allen, A., Bygate, E., Teillol-Foo, M., Oliver, S., Johnson, M. R. & Ward, C. (1999). Multiple-dose pharmacokinetics and tolerability of gemifloxacin following oral doses to healthy volunteers. In Abstracts of the Twenty-first International Congress of Chemotherapy, Birmingham, UK, 1999. Journal of Antimicrobial Chemotherapy 44, Suppl. A, Abstract P418, p. 133.
7 . Allen, A., Bygate, E., Coleman, K., McAllister, P. R. & Teillol-Foo, M. (1999). In vitro activity and single-dose pharmacokinetics of the (+) and () enantiomers of gemifloxacin. In Abstracts of the Twenty-first International Congress of Chemotherapy, Birmingham, UK, 1999. Journal of Antimicrobial Chemotherapy 44, Suppl. A, Abstract P449, p. 139.
8 . Wise, R., Mortiboy, D., Child, J. & Andrews, J. M. (1996). Pharmacokinetics and penetration into inflammatory fluid of trovafloxacin (CP-99,219). Antimicrobial Agents and Chemotherapy 40, 479.[Abstract]
Received 31 May 2000; returned 19 August 2000; revised 27 November 2000; accepted 20 December 2000