Pharmacokinetics and tissue penetration of gemifloxacin following a single oral dose

T. Gee, J. M. Andrews, J. P. Ashby, G. Marshall and R. Wise,*

Department of Medical Microbiology, City Hospital NHS Trust, Birmingham B18 7QH, UK


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The pharmacokinetics and tissue penetration of gemifloxacin were determined during a 24 h period following oral administration of a single 320 mg dose to each of 10 healthy male volunteers. Concentrations of the drug in plasma, inflammatory blister fluid and urine were determined using a microbial assay. A peak plasma concentration (mean ± S.D.) of 2.33 ± 0.5 mg/L was reached at 1.20 ± 0.4 h. Mean penetration into inflammatory fluid was 61.19 ± 10.4%. A peak concentration of 0.74 ± 0.3 mg/L was reached in the inflammatory fluid at a mean time of 3.40 ± 1.7 h. The mean elimination half-life from serum and inflammatory fluid was 5.94 ± 0.4 and 6.27 ± 2.4 h, respectively. Urinary excretion of the drug at 24 h post-dose was 36.11% of the total given. These results demonstrate that gemifloxacin penetrates into the site of inflammation and reaches sufficient concentrations to inhibit many pathogens.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Gemifloxacin (FACTIVE; GlaxoSmithKline, Harlow, UK) is a new fluoroquinolone that possesses enhanced activity against Gram-positive cocci, in particular Streptococcus pneumoniae.1,2 It has been shown to have higher affinity than other quinolones for S. pneumoniae topoisomerase IV, including isolates displaying resistance mutations.3 The aim of this study was to assess the pharmacokinetics and tissue penetration of this drug following administration of a single oral dose of 320 mg. Tissue penetration was quantified using a blister technique. Blister fluid mimics an inflammatory exudate and hence is a model of likely pharmacokinetics at the site of infection.4


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The subjects studied were 10 healthy male volunteers with a mean age of 27.1 years (S.D. 7.4), a mean height of 178 cm (S.D. 5.0) and a mean weight of 78.3 kg (S.D. 5.6). Exclusion criteria included any history of serious illness, allergy to fluoroquinolones, alcohol and drug abuse, any acute illness 14 days before the study, or use of any medication (other than simple analgesics) over the same time period.

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 0–6, 6–12 and 12–24 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 0.015–1 mg/L, 0.06–1 mg/L and 0.125–2 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–{infty}), and the elimination half-life (t1/2) 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–{infty} taken from the blister fluid data with that from the plasma data.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Gemifloxacin was well tolerated by all 10 volunteers. No physical, biochemical or haematological abnormalities attributable to gemifloxacin administration were detected. One volunteer complained of a short-lived mild headache at 2 h post-dose.

The mean concentration–time profiles found in plasma and inflammatory fluid following the administration of gemifloxacin 320 mg are shown in the FigureGo and the derived pharmacokinetic parameters are summarized in the TableGo. 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 t1/2 from plasma was 5.94 h (range 5.22–6.68 h). The AUClast and AUC0–{infty} were 10.38 and 10.98 mg•h/L, respectively.



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Figure. Gemifloxacin concentration in (a) plasma and (b) blister fluid over 24 h following a single oral dose of 320 mg. (Bars represent standard deviations of results from 10 subjects.)

 

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Table. Pharmacokinetic parameters of gemifloxacin in 10 healthy male volunteers following a single 320 mg dose
 
Blisters were successfully raised in eight volunteers, but only five blisters provided enough inflammatory fluid throughout the day to allow adequate data for pharmacokinetic analysis. Gemifloxacin penetrated into the inflammatory fluid moderately rapidly, the mean Tmax being 3.40 h (range 2–6 h). The mean Cmax in the inflammatory fluid was 0.74 mg/L (range 0.30–1.12 mg/L). The mean t1/2 of gemifloxacin from the inflammatory exudate was similar to that from plasma (6.27 h). Greater individual variation was observed in the inflammatory fluid data than in the plasma data. The mean percentage penetration of gemifloxacin into inflammatory fluid was 61.2% (range 49.1– 75.6%).

The mean urinary excretion of the drug in the 24 h period following the oral dose was 36.1%.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Previous studies characterizing the pharmacokinetics of gemifloxacin have employed high performance liquid chromatography techniques to evaluate the concentration of gemifloxacin.57 In this study, a microbiological assay was used. This is feasible because gemifloxacin does not produce active metabolites (GlaxoSmithKline, unpublished data). Pharmacokinetic data generated in this study are generally similar to those previously published. Two such recent studies suggest that gemifloxacin is rapidly absorbed (bioavailability about 71%; GlaxoSmithKline, unpublished data), with a maximum plasma concentration achieved approximately 1 h after dosing (Tmax), followed by a bi-exponential decline in concentration.5,6 Our data suggest a Tmax of 1.20 h with a greater plasma Cmax (2.33 mg/L compared with 1.48 mg/L5 and 2.01 mg/L6). We also found a marginally greater AUC0–{infty} (10.38 mg•h/L compared with 9.30 mg•h/L5 and 8.92 mg•h/L6). These earlier trials report a similar half-life from plasma (6.65 h5 and 5.87 h6) to that calculated in our study (5.94 h) following a 320 mg oral dose of the same formulation.

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 0.07–0.09). 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.


    Acknowledgments
 
We thank GlaxoSmithKline for their financial support of this study.


    Notes
 
* Corresponding author. Tel: +44-121-554-3801; Fax: +44-121-551-7763; E-mail: r.wise{at}bham.ac.uk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Wise, R. & Andrews, J. M. (1999). The in-vitro activity and tentative breakpoint of gemifloxacin, a new fluoroquinolone. Journal of Antimicrobial Chemotherapy 44, 679–88.[Abstract/Free Full Text]

2 . Hardy, D., Amsterdam, D., Mandell, L. A. & Rotstein, C. (2000). Comparative in vitro activities of ciprofloxacin, gemifloxacin, grepafloxacin, moxifloxacin, ofloxacin, sparfloxacin, trovafloxacin and other antimicrobial agents against bloodstream isolates of gram-positive cocci. Antimicrobial Agents and Chemotherapy 44, 802–5.[Abstract/Free Full Text]

3 . Morrissey, I. & George, J. T. (2000). Purification of pneumococcal type II topoisomerases and inhibition by gemifloxacin and other quinolones. Journal of Antimicrobial Chemotherapy 45, Suppl. S1, 101–6.[Abstract/Free Full Text]

4 . Wise, R., Gillett, A. P., Cadge, B., Durham, R. & Baker, S. (1980) The influence of protein binding upon tissue fluid levels of six beta-lactam antibiotics. Journal of Infectious Diseases 142, 77–82.[ISI][Medline]

5 . Allen, A., Bygate, E., Oliver, S., Johnson, M. R., Ward, C., Cheon, A. J. et al. (1999). Pharmacokinetics and tolerability of gemifloxacin (SB-265805) after administration of single oral doses to healthy volunteers. Antimicrobial Agents and Chemotherapy 44, 1604–8.[Abstract/Free Full Text]

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, 47–9.[Abstract]

Received 31 May 2000; returned 19 August 2000; revised 27 November 2000; accepted 20 December 2000