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Antimicrobial Agents and Chemotherapy, June 1999, p. 1508-1510, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Pharmacokinetics and Inflammatory-Fluid Penetration
of Moxifloxacin following Oral or Intravenous Administration
Richard
Wise,*
Jennifer M.
Andrews,
Gill
Marshall, and
Giles
Hartman
Department of Medical Microbiology, City
Hospital NHS Trust, Birmingham, United Kingdom
Received 6 November 1998/Returned for modification 24 February
1999/Accepted 26 March 1999
 |
ABSTRACT |
A single 400-mg oral or intravenous (i.v.) dose of moxifloxacin was
given to each of eight healthy male volunteers, and 6 weeks later the
dose was administered by the other route. The concentrations of the
drug in plasma, cantharidin-induced inflammatory fluid, and urine were
measured over the subsequent 24 h. The mean maximum concentrations
observed in plasma were 4.98 µg/ml after oral dosing and 5.09 µg/ml
after i.v. dosing. The mean maximum concentrations attained in the
inflammatory fluid were 2.62 and 3.23 µg/ml, respectively. The mean
elimination half-lives from plasma were 8.32 and 8.17 h,
respectively. The overall penetration into the inflammatory fluid was
103.4 and 104.2%. Over 24 h 15% of the drug was recovered in the
urine when administered by either route.
| |
TEXT |
Moxifloxacin (Bay 12-8039) is a
methoxy fluoroquinolone which shows enhanced activity against
gram-positive bacterial pathogens in particular Streptococcus
pneumoniae strains, including those resistant to penicillin
(2, 8). Preliminary information suggests that moxifloxacin
has an elimination half-life (t1/2) appropriate
to once-daily dosing (5, 6). In this crossover study, the
pharmacokinetics and penetration of moxifloxacin into an inflammatory
exudate (7) were examined following a single 400-mg dose
given by the oral or intravenous (i.v.) route.
Eight healthy male volunteers between the ages of 26 and 41 years (mean
age, 33.5 years; mean height, 175 cm; mean weight, 72 kg) were
enrolled. They had no history of serious illness, atopy, alcohol or
drug abuse, or an acute illness in the 14 days prior to the start of
the study. They had not received any prescribed or over-the-counter
medication in the 14 days prior to the first dose of moxifloxacin.
Approval for this study was granted by the Hospital Ethical Committee
of City Hospital Trust and all volunteers gave written informed
consent. All volunteers underwent a full history and examination,
including echocardiogram (ECG), and were shown to have normal
hematological and biochemical profiles and normal urinalysis.
Each volunteer received 400 mg of oral or i.v. moxifloxacin
(administered over 1 h) in a random order and 6 weeks later (to allow blister healing) received the agent by the other route.
On the evening prior to the study 0.2% cantharidin-impregnated
plasters (2 by 1 cm) were attached to the subjects' forearms to induce
blister formation. Plasma samples were obtained from the contralateral
arm following insertion of an i.v. catheter kept patent by flushing
with 0.9% saline (Antigen Pharmaceuticals, Rosecrea, Ireland).
The dose was given to the fasting subjects by either route with 200 ml
of water. The subjects then fasted for a further 4 h except for
water ad libitum. About 10 ml of venous blood was collected predose and
then at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h postdose.
Between 50 and 100 µl of inflammatory fluid was aspirated with a fine
needle prior to administration of the dose and then at 1, 2, 3, 4, 6, 8, 12, and 24 h. The blister was resealed with a plastic spray
dressing (Opsite, Smith & Nephew, Hill, England). Urine was collected 0 to 4, 4 to 8, 8 to 12, and 12 to 24 h postdose. At 30 h
postdose the routine hematological and biochemical tests were repeated.
Prior to the study a cross-validation procedure was undertaken by Bayer
AG (Leverkusen, Germany). Spiked samples were assayed by the
microbiological procedure described below and a high-performance liquid
chromatography method (5). Linear regression analysis
comparison of the two methods gave a correlation coefficient
r of 0.988.
Drug analysis.
All samples were analyzed within 1 h of
collection. Concentrations of moxifloxacin in plasma, inflammatory
fluid, and urine were measured by a microbiological assay. Assay plates
containing Iso-Sensitest agar (Oxoid, Basingstoke, England) were
flooded with a suspension of Escherichia coli 4004 (Bayer
AG) in order to give nonconfluent growth. The calibrator range was 0.04 to 1.5 µg/ml. Internal controls and quality assurance samples were prepared in human plasma (Bradsure Biologicals, Market Harborough, England) or in 70% human plasma (to simulate the protein content of
the blister fluid) and phosphate buffer (pH 7) for the assay of
moxifloxacin in plasma inflammatory exudate and urine, respectively.
The lower limit of detection was 0.02 µg/ml. The coefficient of
variation within the assays was 8.0%. Quality control samples were
included; the mean + 2 standard deviations for these samples was
14.8%.
Standard noncompartmental analysis was used to determine the
pharmacokinetic parameters. The maximum concentration of moxifloxacin
in plasma (
Cmax), the time to
Cmax (
Tmax), the area
under the
plasma or skin blister fluid curve up to the last measurable
concentration
(AUC
last), the area under the plasma or skin
blister fluid curve
extrapolated to infinity
(AUC
0-
), and the
t1/2 in
plasma or skin blister fluid were calculated by the noncompartmental
model 200 of PCNONLIN (version 4.2a; Scientific Consulting Inc.,
Apex, N.C.).
The mean concentration found in plasma and inflammatory fluid are shown
in Fig.
1 and
2; the derived pharmacokinetic parameters
are summarized in Table
1. The data was
collected for seven of
the eight volunteers because one volunteer had
an adverse event
that required withdrawal from the study (see below).
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FIG. 1.
Drug concentrations in plasma and blister fluid
following oral administration of 400 mg of moxifloxacin.
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FIG. 2.
Drug concentrations in plasma and blister fluid
following i.v. administration of 400 mg of moxifloxacin.
|
|
The mean
Cmaxs of moxifloxacin were remarkably
similar, being 4.98 and 5.09 µg/ml following oral and i.v.
administration,
respectively. The time at which the
Cmax occurred was 1 h after
oral
administration and at the end of the infusion following i.v.
administration. The mean terminal
t1/2s from
plasma were also
similar, being 8.32 and 8.17 h after oral and
i.v. dosing, respectively.
The AUC
last and
AUC
0- for both routes of administration
were remarkably
similar; hence, the extent of bioavailability
of the oral formulation
is approximately 100%.
Moxifloxacin penetrated into the inflammatory fluid rapidly, with the
mean
Tmax following oral administration being
3.86 h
and that following i.v. administration being 2.4 h.
Individual
variation was greater after the former mode of
administration.
The mean
Cmax following the oral
dose was 2.62 µg/ml, and that
following the i.v. dose was 3.23 µg/ml, but the ranges were
similar.
The
t1/2s for moxifloxacin from the inflammatory
exudate were slightly greater than those from plasma, being a mean of
10.0
and 9.54 h following oral and i.v. administration,
respectively.
The percentage penetration of moxifloxacin into
inflammatory fluid,
calculated by comparing the AUC
0-
for measurements
taken in the inflammatory exudate with that for
measurements taken
in plasma, were 103.4% after oral administration
and 104.2% after
i.v. administration, and the ranges of these data
were similar.
The degree of penetration was greater than that which we
reported
for trovafloxacin (64% after oral administration)
(
7) and similar
to that of ciprofloxacin (102.8%)
(
1). This may be related
to the higher protein binding of
trovafloxacin (87.9%) (
7)
in comparison to that of
moxifloxacin (48%) (
5).
The mean urinary elimination of the drug in the 48 h following the
oral dose was 15.1%, remarkably similar to that after i.v.
administration, 15.2%. The mean total clearance was 147.8 ml/min
after
oral dosing and 151.5 ml/min after i.v. dosing, with mean
renal
clearances of 22.3 and 23.0 ml/min, respectively. The mean
urinary
concentrations following the oral and i.v. doses, respectively,
were
55.1 and 127 µg/ml at 8 h, 69.4 and 71.5 µg/ml at 12 h,
and
38.1 and 38.2 µg/ml at 24 h. Statistical analysis (by paired
t test) of the individual
Cmax,
t1/2, and AUC values for plasma
revealed no
significant differences (
P > 0.05) between oral and
i.v. administration. The
Cmax in blister fluid
was lower than
that in plasma (
P < 0.01). The
t1/2 in blister fluid was significantly
greater
than that in plasma (
P = 0.004).
One volunteer, scheduled to receive his first dose by the I.V. route
experienced severe phlebitis at the site of i.v. administration
following 30 ml of drug infusion. At the same time, a maculopapular
rash developed over the volunteer's trunk and arms. Vital signs
showed
a tachycardia but no bronchospasms. An ECG was immediately
performed;
the corrected cardiac interval was not prolonged; 100
mg of
hydrocortisone was administered i.v., and the phlebitis
and rash
disappeared within 35 min. This volunteer who had a hypersensitivity
reaction typical of those reported for this group of drugs
(
4)
was withdrawn from the study and hence did not receive
the second
dose by the oral route. Five volunteers experienced
headaches
4 to 12 h postdose, all resolving spontaneously (for
four of five
volunteers) or following administration of 1 g of
paracetamol
(for one of five volunteers). Physical examination revealed
no
abnormalities attributable to moxifloxacin administration. The
biochemical, hematological, and ECG parameters studied revealed
no
abnormalities.
There is limited published information on the pharmacokinetics of
moxifloxacin (
5,
6). Our results are in good agreement
with
these earlier findings in terms of the AUC data. We noted
the
Cmax to be greater at doses of about 5 µg/ml
(when given by
either route), while the earlier reports found the value
to be
2.5 to 3.0 µg/ml when given by mouth. The two earlier reports
also suggested a longer
t1/2 from plasma at 11 to 14 h (depending
on whether two-compartment or noncompartmental
analysis, respectively,
was performed). Our data suggest a lower value
of ca. 8
h.
Moxifloxacin appears to penetrate rapidly and completely into the
inflammatory exudate. The MIC of moxifloxacin at which 90%
of the
common respiratory tract pathogens (such as
S. pneumoniae,
Moraxella catarrhalis, and
Haemophilus
influenzae) are inhibited
is
0.25 µg/ml. This concentration is
exceeded in both plasma
and inflammatory fluid for at least 24 h.
In addition, an AUC-to-MIC
ratio (AUIC) of >125 is deemed to predict
efficacy; in selected
respiratory tract infections (
3), the
AUIC of moxifloxacin
for these pathogens is ca. 180. Both these facts
suggest that
moxifloxacin in a dose of 400 mg per day, given either
orally
or by i.v. administration, should be efficacious in the
treatment
of respiratory and other infections caused by susceptible
pathogens.
The high bioavailability and great similarity of
pharmacokinetics
following either route of administration suggest that
a switch
from i.v. to oral use should be
straightforward.
| |
ACKNOWLEDGMENTS |
We thank A. Dalhoff of Bayer AG for advice and financial support.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medical Microbiology, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH, United Kingdom. Phone: 44 121 507 4255. Fax: 44 121 551 7763. E-mail: R.Wise{at}bham.ac.uk.
| |
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Antimicrobial Agents and Chemotherapy, June 1999, p. 1508-1510, Vol. 43, No. 6
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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