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Antimicrobial Agents and Chemotherapy, June 2000, p. 1674-1679, Vol. 44, No. 6
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Pharmacokinetics of Ciprofloxacin in the Human Eye:
a Clinical Study and Population Pharmacokinetic Analysis
Nigel
Morlet,1,*
Garry G.
Graham,2
Barrie
Gatus,3
Andrew J.
McLachlan,4
Chris
Salonikas,5
Daya
Naidoo,5
Ivan
Goldberg,1 and
Chi Man
Lam1
Departments of
Ophthalmology,1
Microbiology,3 and Clinical
Biochemistry,5 Prince of Wales Hospital,
School of Physiology and Pharmacology, University of New South
Wales,2 and Faculty of Pharmacy,
University of Sydney,4 Sydney, New South Wales,
Australia
Received 11 May 1999/Returned for modification 7 November
1999/Accepted 28 January 2000
 |
ABSTRACT |
Ciprofloxacin, a fluoroquinolone antibiotic active against a wide
variety of bacteria, is one of a few antibiotics which enters the human
eye after oral administration. However, little is known about its
pharmacokinetics in the human eye. One or two oral doses of 750 mg of
ciprofloxacin (at a 12-h interval) were administered to 48 patients at
various times prior to ocular surgery. Clotted blood, aqueous, and
vitreous were collected at surgery, and the concentrations of
ciprofloxacin were assayed by high-performance liquid chromatography.
Our data were combined with those of others, and a population
pharmacokinetic analysis was conducted. The concentrations of
ciprofloxacin in both aqueous and vitreous were lower than those in
serum and peaked at a later time. The pharmacokinetics of ciprofloxacin
in aqueous and vitreous were fitted to a compartmental model in which
the antibiotic was transferred into and out of the two compartments
(aqueous and vitreous) by first-order processes. Population
pharmacokinetic software, P-Pharm, was used to calculate the mean
half-lives of the loss of ciprofloxacin from aqueous and vitreous,
which were 3.5 and 5.3 h, respectively. At steady state, the mean
ratios of then concentrations in aqueous and vitreous to the
concentrations in serum were 23 and 17%, respectively. After the
administration of one or two doses of 750 mg of ciprofloxacin, the
concentrations in both aqueous and vitreous in a number of patients
were lower than the MICs at which 90% of isolates are inhibited (0.5 mg/liter) for common intraocular bacterial pathogens. Simulations of
concentrations in the eye after the administration of higher doses
(1,500 mg of ciprofloxacin as a single dose, two doses of 750 mg 2 h apart, and 750 mg every 6 h) indicated that in approximately
20% of patients the concentrations would still be below 0.5 mg/liter.
Although oral ciprofloxacin may be a beneficial adjunctive therapy, the
use of oral ciprofloxacin alone may not be adequate for perioperative
prophylaxis or for treatment of bacterial endophthalmitis.
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INTRODUCTION |
Ciprofloxacin, a fluoroquinolone
antibiotic, is active against a wide variety of bacteria. It is
potentially a very useful antibiotic in ophthalmology because it is one
of only a few antibiotics which enters the human eye after oral
administration. Reported concentrations of ciprofloxacin varied from
0.1 to 0.65 mg/liter in aqueous and from 0.17 to 0.51 mg/liter in
vitreous after the oral administration of various doses of the
antibiotic to humans (4, 10, 11, 16, 17, 20, 21, 24, 28).
However, few have provided an analysis of the pharmacokinetics of
ciprofloxacin in the human eye.
In normal clinical practice, it is not possible to obtain a full
concentration-time profile of a drug in the eye because of limited
opportunities to sample ocular fluids. However, a population pharmacokinetic approach (1, 31) allows sparse observation data to be analyzed, so that even one observation can be used (2). Drusano et al. (8) used a population
approach to examine the kinetics of ciprofloxacin using multiple plasma
samples and single samples of vitreous from rabbits. An important
aspect of the pharmacokinetics of any drug is understanding the
interpatient variability in the pharmacokinetic parameters, and a
feature of the population approach is that it allows the determination
of the variability in the pharmacokinetic parameters from very limited data for each patient.
In the present study, the concentrations of ciprofloxacin in serum,
aqueous, and vitreous were measured simultaneously after its oral
administration to 48 patients who underwent intraocular surgery. The
combination of our data together with those obtained from the
literature (4, 10, 11, 16, 17, 20, 21, 24, 28) provided a
substantial amount of information which enabled a population
pharmacokinetic study of ciprofloxacin in the human eye. We were able
not only to determine the interpatient variation in the pharmacokinetic
parameters but also to use these differences to predict the extent of
variation in the predicted time course of concentrations of
ciprofloxacin in the two compartments of the eye. The kinetic
parameters also permitted the prediction of the intraocular
concentrations with various dosage schedules other than those used in
the present study, thus allowing practical application of our
pharmacokinetic analysis.
(This study was presented in part at the American Academy of
Ophthalmology Meeting, San Francisco, Calif., November 1994.)
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MATERIALS AND METHODS |
Patients.
Following approval from the Ethics Committee of
the Eastern Sydney Area Health Service, informed consent was obtained
from 48 patients. A single dose of 750 mg of ciprofloxacin was
administered to 19 patients at various times prior to cataract or
glaucoma surgery, and 29 patients received two oral doses of 750 mg of ciprofloxacin, 12 h apart, at various times prior to vitrectomy or
surgery for retinal detachment. Patients with ocular inflammation or
with a clinically disturbed blood aqueous barrier (seen as an aqueous
flare on the slit lamp) were excluded from the study. Ciprofloxacin was
administered to fasting patients in the absence of any other agents,
such as antacids, which may have interfered with the absorption of the
antibiotic. There were 28 males and 20 females whose ages ranged from
15 to 83 years. None had significant impairment of renal function.
Samples of clotted blood (10 ml), aqueous (0.1 ml), and, wherever
possible, vitreous (0.1 ml) were taken simultaneously from each patient
at the commencement of surgery. All samples were protected from light
and were stored at 
80°C until the concentrations of ciprofloxacin
were measured.
Measurement of the concentrations of ciprofloxacin.
The
concentrations of ciprofloxacin were measured by high-performance
liquid chromatography (HPLC) with a C18 4µ Nova-Pak cartridge and a column (8 by 100 mm; Waters Millipore) (25). Ciprofloxacin was quantitated with a fluorescence detector, with the
wavelengths of excitation and emission being 279 and 440 nm, respectively. The concentrations of ciprofloxacin were determined by
comparing the peak areas for the samples with those for three standard
preparations of the antibiotic which encompassed the expected range of
measurement. The mobile phase consisted of 81% phosphate buffer (20 mM
KH2PO4, 2 mM tetrabutylammonium hydroxide, 6 mM
H3PO4 [pH 3.0]) with 5% acetonitrile and
14% methanol at a flow rate of 2.5 ml/min. The ciprofloxacin
concentration in each sample of serum was determined after a 500-µl
aliquot was added to 25 µl of perchloric acid and the mixture was
vortexed for 30 s and centrifuged (Biofuge 13; Heraeus Sepatech)
at 3,000 rpm for 30 min. A 25-µl aliquot of the supernatant was then
injected into the column. The ciprofloxacin concentrations in aqueous
and vitreous were determined after a 50-µl aliquot of each specimen was diluted with 200 µl of the mobile phase and centrifuged (Biofuge 13; Heraeus Sepatech) at 3,000 rpm for 10 min and 50 µl of the supernatant was injected into the column. There was an 8% analytical coefficient of variation over the range measured.
Population analysis.
A comprehensive search of the
literature found several studies (10, 11, 17, 20, 21, 24,
28) in which the concentrations of ciprofloxacin were measured in
samples of serum, aqueous, and vitreous which were collected
simultaneously at various times after the oral administration of one or
two doses of the antibiotic. In most cases ciprofloxacin was
administered at doses of 750 mg. However, doses of 500, 1,000, and
1,500 mg were administered in two studies (11, 28) so 46 concentrations in serum and aqueous were normalized to a dose of 750 mg. These data were combined with our data for 48 samples of serum, 44 aqueous samples, and 23 vitreous samples (samples of both aqueous and
vitreous were collected from some patients, but only one ocular humor
sample was collected from the others). This produced a total of 161 serum samples, 108 samples of aqueous, and 66 vitreous samples. With the exception of the study by El Baba et al. (10), in which a microbiological assay was used, all other studies used HPLC to
determine the concentrations of ciprofloxacin. In addition, four
studies (4, 16, 21, 24) were found which included a total of
17 measurements of ciprofloxacin in the aqueous after intravenous
administration of the antibiotic.
Pharmacokinetic modeling.
The time courses of the
concentrations of ciprofloxacin in the various compartments (Fig.
1) were fitted by the general
polyexponential equations of time assuming first-order transfer
processes (see the Appendix).
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FIG. 1.
Pharmacokinetic model used to describe the
pharmacokinetics of ciprofloxacin in aqueous and vitreous. It was
assumed that ciprofloxacin was transferred between plasma and aqueous
or vitreous as separate compartments by first-order processes.
Vc, Va, and
Vvit are the volumes of the central, aqueous,
and vitreous compartments, respectively. The rate constants
kpa and kap and the rate
constants kpv and kvp are
the rate constants of absorption and loss for the aqueous and vitreous,
respectively. In the final population analysis, the concentrations in
aqueous humor and plasma (or serum) were fitted simultaneously by the
model. The concentrations in vitreous and plasma were also fitted
simultaneously but separately from the data for aqueous and plasma.
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In general, the complex constant
kpa ·
Vc/Va (where
kpa is the first-order rate constant of transfer
from the central compartment
to the aqueous,
Vc
is the volume of the central compartment, and
Va
is the volume of the aqueous compartment) directly determines
the
concentrations at any time in the aqueous. If this complex
constant is
small (i.e., the corresponding half-life is long),
then the
concentrations in aqueous will tend to be low. By contrast,
the rate
constant of loss from aqueous (
kap) determines
the time
taken to achieve the peak concentration in this compartment of
the eye. If this constant is small, the peak concentration occurs
later
than in plasma but the concentrations in aqueous are more
sustained.
These considerations are analogous for the rate constants
in
vitreous.
The ratio of the mean concentration of ciprofloxacin in aqueous or
vitreous to the mean concentration in serum can also be
determined
(
15) (see the
Appendix). The concentration ratio
K (described previously as "the penetration" into
aqueous [
8])
is given by the ratio of the rate
constants.
Population pharmacokinetic analysis.
The data analysis was
conducted in two stages. (i) The concentrations in serum, aqueous, and
vitreous were pooled for all subjects and were fitted by the model
equations by using the nonlinear regression program Minim (R. D. Purves, University of Otago, Dunedin, New Zealand). This procedure is
termed "naive pooling."
(ii) By using the starting estimates of the pharmacokinetic parameters
from naive pooling, the time courses of the concentrations
in serum and
aqueous were fitted simultaneously by a nonlinear
mixed effect model
with the P-Pharm program (version 1.3) (
5,
12,
23). The
pharmacokinetic parameters in serum and vitreous
were similarly
determined simultaneously but in a separate computation
because the
P-Pharm program does not readily allow the simultaneous
estimation of
the parameters in three fluids. The P-Pharm program
uses an iterative
process that involves computation of the maximum-likelihood
estimates
(EM-like algorithm) of the population parameters and
their variability
(
12). Preliminary analysis of the pattern
of residuals and
reduction in the standard deviation of the estimates
of the population
parameters indicated that interpatient variability
in the transfer rate
constants
kpa,
kap,
kpv, and
kvp (where
kpa,
kap,
kpv, and
kvp are
first-order rate constants of transfer from
the central compartment to
aqueous, aqueous to central compartment,
central compartment to
vitreous, and vitreous to central compartment,
respectively) was best
described by a log-normal distribution,
while interpatient variability
in the remaining parameters (volume
of distribution [
V],
absorption rate constant [
ka], and elimination
rate constant [
kel]) was described best by a
normal distribution.
Two error models available in P-Pharm were
evaluated. These were
a heteroscedastic error model, in which the
residual error was
inversely proportional to the squared value of the
predicted value,
and a homoscedastic error model, in which the residual
error was
constant. In the simultaneous analysis of the concentrations
in
serum and vitreous, the error with the heteroscedastic model was
smaller (0.28 mg/liter) than that found with the homoscedastic
model,
with which the error was 0.47 mg/liter. The heteroscedastic
model was
also used in the analysis of the pharmacokinetics in
the aqueous.
Following the determination of the mean population
pharmacokinetic
parameters, the parameters that describe the pharmacokinetics
in serum
and in either aqueous or vitreous were subsequently obtained
for each
patient by using the population parameters and individual
posterior
Bayesian estimates based upon one ciprofloxacin concentration
in each
fluid.
Simulation study.
The concentration-time profiles of
ciprofloxacin in aqueous and vitreous after different dose regimens
were simulated by using the population means and standard deviations of
the pharmacokinetic parameters described in Table
1. Pharmacokinetic parameters for 2,500 patients were generated by the procedure described by Upton (29). These parameters were used to calculate the mean and
the upper and lower 68% confidence interval (±1 standard deviation) concentration-time profile following the administration of 1,500 mg of
ciprofloxacin as a single dose, the administration of two doses of 750 mg ciprofloxacin given 2 h apart, or continuous dosing of 750 mg
of ciprofloxacin every 6 h.
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TABLE 1.
Pharmacokinetic parameters describing the time course of
concentrations of ciprofloxacin in plasma and compartments of
the eyea
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RESULTS |
Profile of concentrations in serum, aqueous, and vitreous over
time.
The concentrations of ciprofloxacin in serum showed
considerable interpatient variation. The concentrations in serum
reached a peak at approximately 1 to 2 h after administration of
the initial dose of 750 mg of ciprofloxacin (Fig.
2). Concentrations in serum declined
thereafter, until the second dose was administered 12 h after
administration of the first dose. There was no significant accumulation
of the antibiotic in serum, and the concentrations after administration
of the second dose were very similar to the concentrations after
administration of the first dose (Fig. 2).
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FIG. 2.
Time courses of concentrations of ciprofloxacin in
serum, aqueous, and vitreous after administration of one and two oral
doses (750 mg) at 12-h intervals. In the modeling, the total
concentrations after administration of the second dose were assumed to
result from a second dose alone added to the concentrations remaining
from the first dose. The curves are drawn from the mean population
pharmacokinetic parameters (Table 1). Experimental values come from our
data for 48 samples of serum, 44 samples of aqueous, and 23 vitreous
samples, together with published data (10, 11, 17, 20, 21, 24,
28).
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The concentrations of ciprofloxacin in aqueous and vitreous showed a
pattern different from those in serum, and although variable,
they were
relatively constant from 4 h after administration of
the first
dose until 12 h after administration of the second dose
(Fig.
2).
In both compartments of the eye the concentrations were
lower, but more
sustained, than those in serum throughout the
24 h of the study.
It is evident that ciprofloxacin is transferred
slowly between serum
and both compartments of the
eye.
Pharmacokinetic modeling.
Although the time courses of the
concentrations of ciprofloxacin in serum, aqueous, and vitreous were
scattered (Fig. 2), the assumption of first-order absorption and
elimination of ciprofloxacin together with first-order transfer into
and out of the eye provided an adequate description of the
concentration-time courses in the eye. The equations fitted to the data
allowed the determination of the rate constants of the processes of
ciprofloxacin distribution in the eye; however, the population analysis
indicated that there was considerable interpatient variation in the
kinetic parameters. The mean population kel was
0.135 h
1, which corresponded to a serum half-life of
5.1 h, which was in good agreement with the half-life (4 h)
recorded in several previous studies (9, 13, 14). The
smallest coefficient observed was V.
The mean pharmacokinetic parameters found by the population analysis
were generally similar to the initial values found by
the naive pooling
method. Although naive pooling does not provide
good estimates of the
variability of any parameter, the only parameter
which was altered to a
large extent was
kvp. For this parameter,
the
mean value from the population analysis was considerably smaller
than
the initial estimate from naive
pooling.
One advantage of the population approach is that the model can be used
to predict the individual concentration-time profile
expected in the
plasma and the eye for any patient. By using one
concentration in
plasma and in a compartment of the eye, the population
method allows
the Bayesian estimate of the pharmacokinetic parameters
for that
individual. The predicted time course of concentrations
can then be
calculated from these parameters. An example is shown
in Fig.
3.
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FIG. 3.
Time course of concentrations of ciprofloxacin in serum,
aqueous, and vitreous in one patient after administration of two doses
of 750 mg of ciprofloxacin orally. Samples were collected at 19 h
after administration of the first dose (7 h after administration of the
second dose). The ciprofloxacin concentrations measured in aqueous and
vitreous were both 0.4 mg/liter ( ), and that measured in serum was
2.3 mg/liter ( ). For this patient, the estimated pharmacokinetic
parameters were as follows: Vc, 174.5 liters;
ka, 2.05 h1;
kel, 0.134 h1;
kap, 0.233 h1;
kpa · Vc/Va, 0.039 h1;
kvp, 0.131 h1;
kpv · Vc/Vvit, 0.021 h1.
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The rate constants of transfer of ciprofloxacin into and out of the
compartments of the eye (
kpa,
kap,
kpv,
kvp) were of the
same order or longer than the
rate constants of absorption and
elimination from serum
(
ka,
kel) determined from
the time course
of concentrations in serum (Table
1). The mean rate
constants
of elimination from aqueous (
kap) and
vitreous (
kvp) were 0.20
and 0.13 h
1, respectively, corresponding to half-lives of 3.5 and
5.3 h,
respectively. The predicted result from equations 1 and 5 in the
Appendix is that the changes in the concentrations in both
compartments
of the eye lag behind the concentrations in serum, as was
observed
(Fig.
2 and
3).
The systemic pharmacokinetic parameters of ciprofloxacin were
determined twice by the use of the P-Pharm program. The naive
pooling
method allows the simultaneous fitting to the concentrations
in the
three fluids, serum, aqueous, and vitreous, but P-Pharm
allows only
pair-wise simultaneous analysis. However, the systemic
pharmacokinetic
parameters (
V,
kel, and
ka) fitted to serum and
aqueous were very
similar to those estimated from serum and vitreous
(Table
1). For
example, the mean half-lives of elimination from
serum were 5.3 and
4.9 h from the aqueous and vitreous analyses,
respectively. The
similar systemic parameters produced by the
two analyses support the
validity of the pharmacokinetic
modeling.
The rate constant of transfer of the drug into vitreous
(
kpv) was smaller than the rate constant of
transfer into aqueous
(
kpa), this difference
being consistent with the lower initial
concentrations in vitreous.
However at steady state, the mean
concentration ratios (
K;
also termed "the penetration") in the
two compartments of the eye
were similar (Table
1).
It is possible to make an estimate of the expected contribution of the
eye in the distribution of ciprofloxacin in the eye
from
K
(see equation 6 in the
Appendix), the volumes of aqueous
(
Va) and vitreous (
Vv)
humors, and
V. For example, the fractions
of ciprofloxacin
in the aqueous and vitreous humors are estimated
by
Ka · Va/V and
Kv · Vv/V, respectively.
Va and
Vv are
approximately
0.22 and 4 ml, respectively, making these factors
approximately
0.0003 and 0.004, respectively. These small fractions are
consistent
with the assumption in the derivation of equation 5 in the
Appendix,
namely, that the amounts of ciprofloxacin in both aqueous and
vitreous humors are small and do not influence the kinetics of
the drug
in
plasma.
The mean kinetic parameters of transfer of ciprofloxacin into and out
of aqueous were tested by using published data of the
concentrations of
the drug in aqueous following intravenous administration
of the drug
(
4,
16,
20,
22). The ciprofloxacin time course
in aqueous
was predicted by using published kinetic parameters
for serum (
9,
13,
14) and the parameters determined in
the present study.
Although there was scatter of the ciprofloxacin
concentrations in
aqueous, these were close to the predicted pattern,
providing some
validation of our calculated mean rate constants
of transfer of
ciprofloxacin into and out of aqueous (Fig.
4).
After 3 h, the concentrations in
aqueous were similar to the predicted
concentrations; however, the
concentrations at prior times were
higher than those predicted.
Compared with oral administration,
the smaller intravenous dose
produced an earlier peak concentration,
but this was not sustained and
resulted in a lower concentration
in aqueous.
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FIG. 4.
Time course of predicted concentrations of ciprofloxacin
in serum and aqueous following cessation of an intravenous infusion
(200 mg over 30 min). The time course of concentrations in serum were
modeled from the mean kinetic constants after intravenous
administration (distribution phase constant = 2.9 h1, elimination phase constant = 0.179 h1) (9, 13, 14). The concentrations in aqueous
were predicted by using these kinetic constants and the mean rate
constants of transfer of ciprofloxacin into and out of aqueous
determined in the present study. The datum points represent the actual
concentration in previous studies after intravenous administration
(4, 16, 21, 24).
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DISCUSSION |
The small number of previous pharmacokinetic studies of
ciprofloxacin or related compounds in the eye were conducted mainly with rabbits (8, 22). However, one study with rabbits
successfully demonstrated the use of a population modeling program to
describe the pharmacokinetics with a limited amount of data
(8). This rabbit model may be useful when examining the
potential antibacterial activity of ciprofloxacin in the eye because
the mean concentration in aqueous/concentration in plasma ratio for the
rabbit was approximately 30% (22), which was similar to the
mean ratio of 22.5% found in the present study for the human eye.
However, the concentration in vitreous/concentration in plasma ratios
for the rabbit were lower than those found in our study (mean values,
0.029 [9] and 0.065 [22] compared
with 0.17 in the present study). A better penetration of ciprofloxacin
into the vitreous of inflamed eyes was demonstrated in both the rabbit
and the swine models (3). The higher ratio in the human eye
in the present study may possibly reflect an abnormal blood-retina
barrier due to disease in patients undergoing vitrectomy. However,
patients with inflamed eyes and other clinical evidence of a grossly
deficient blood-retina barrier were excluded from our study and from
the other studies used in our analysis.
The modeling yields pharmacokinetic parameters that describe the
handling of the drug in the body as a whole. V and the
half-life of ciprofloxacin were very similar to those found previously, in which the V of ciprofloxacin ranged from means of 2.7 to
4.7 liters/kg (9, 13, 14, 30). In the present study the mean V's of 171 and 174 liters (Table 1) were approximately
equivalent to the lower limit of the published range (30).
Similarly, the mean values for half-life of elimination (4.9 and
5.3 h; Table 1) were within the published range of mean values (3 to 6.6 h) (9, 13, 14, 30).
The pharmacokinetic parameters of ciprofloxacin were calculated by
assuming nonsaturable transfer between compartments. Saturation of any
ciprofloxacin carrier-mediated processes may be possible, but the
interpatient variation in the pharmacokinetics of the drug appear to be
too great for our analyses to detect any saturation of significant
systemic processes or any saturation of transfer of ciprofloxacin into
or out of the eye.
While the concentrations of ciprofloxacin in the eye were relatively
stable for at least 12 h after the administration of a second oral
dose of 750 mg, the concentrations do not appear to be satisfactory for
all patients. In 20% of patients who used this regimen, the
intraocular concentrations of the antibiotic were lower than 0.5 mg/liter, which is below the MIC at which 90% of isolates are
inhibited for commonly occurring intraocular pathogens (18).
Consequently, we conducted simulations of the expected time courses of
concentrations in both aqueous and vitreous using several other dosing schedules.
The first was the simulation of the concentrations in both compartments
following administration of a single large oral dose of 1,500 mg of
ciprofloxacin. The mean peak concentration in aqueous was above 0.5 mg/liter, but in approximately 20% of patients the peak was still
below this level (Fig. 5). Although the
peak predicted concentration in vitreous was less variable, it was
lower (0.54 mg/liter) and in 16% of the patients it was still below
0.42 mg/liter. In view of the possible intolerance of such a large
single dose of ciprofloxacin, the concentrations in the eye were
simulated after administration of two oral 750-mg doses 2 h apart
(data not shown). The concentrations in both compartments of the eye were similar to the concentrations after administration of a single oral dose of 1,500 mg.
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FIG. 5.
Time courses of predicted concentrations in aqueous and
vitreous following administration of 750 mg of ciprofloxacin every
6 h (A) and a single dose of 1,500 mg of ciprofloxacin (B). The
mean ± 1 standard deviation is shown. Thus, 16% of all patients
should have concentrations above the range shown and 16% should have
concentrations below the range shown.
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The remaining simulation was 750 mg every 6 h (Fig. 5). With this
dose schedule, there was considerable accumulation of ciprofloxacin in
both aqueous and vitreous. After 2 days the predicted mean concentration of ciprofloxacin in vitreous was approximately 1.0 mg/liter (±0.45 mg/liter). Despite the accumulation in the aqueous and
vitreous, in approximately 15% of patients the concentrations were
still below 0.5 mg/liter even after administration of several doses.
However, it is possible that this proportion would be less in patients
with inflamed eyes (3). It should also be noted that this
dose is above that presently recommended and has not been evaluated for safety.
Topical application of ciprofloxacin appears to offer no advantage. Two
studies found that application of 0.3% ciprofloxacin drops was
insufficient to achieve a concentration in aqueous above 0.5 mg/liter
(7, 19).
The aim of the present study was to examine the clinical utility of
different doses of oral ciprofloxacin for ocular treatment and
prophylaxis. Although there was a relatively constant concentration of
ciprofloxacin in both compartments (particularly the vitreous) from
about 5 h after administration of the first 750-mg dose, a stable
concentration was best achieved after administration of an equivalent
second dose. The model predicts some accumulation after administration
of the second dose (Fig. 5), and furthermore, the absorption phase is
less significant after administration of the second dose. If
ciprofloxacin is used for ocular surgical prophylaxis, we recommend
administration of at least two 750-mg tablets 12 h preoperatively.
Surgery could commence at any time within 12 h after
administration of the second dose.
In general, systemic ciprofloxacin should not be relied upon as a sole
prophylactic agent before ocular surgery or in the treatment of
suspected intraocular infections, especially as one study found that
for 27% of the organisms isolated the MIC of ciprofloxacin at which
90% of isolates are inhibited was >0.5 mg/liter (18).
However, the results from the present study indicate that an
appropriate oral dose of ciprofloxacin may still be a useful adjunct
for ocular therapy and prophylaxis.
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APPENDIX |
The time (t) course of concentrations (C)
in plasma was fitted to polyexponential equations of the general form
|
(1)
|
where
Ci and
ki are
concentration and disposition rate constants,
respectively.
In the present study, the time courses of concentrations in plasma
after oral and intravenous dosing were described by biexponential equations 2 and 4, respectively:
|
(2)
|
where
kel and
ka
are the rate constants of elimination and absorption, respectively, and
A is a complex concentration constant:
|
(3)
|
|
(4)
|
where
C1 and
C2 are
concentration constants,
k1 and
k2 are rate constants of disposition, and
D is the
dose.
Assuming that ciprofloxacin is transferred between plasma and aqueous
or vitreous by first-order processes and that the amounts transferred
do not alter significantly the concentrations in plasma (6,
26), then the concentrations in these fluids should follow the
general equation
![C<SUB>1</SUB>=k<SUB><UP>pa</UP></SUB> · V<SUB>c</SUB>/V<SUB>a</SUB><LIM><OP>∑</OP></LIM><SUB>i</SUB>[(e<SUP>−k<SUB>i</SUB>t</SUP>−e<SUP>−k<SUB>ap</SUB>t</SUP>)/(k<SUB><UP>ap</UP></SUB>−k<SUB>i</SUB>)]](/content/vol44/issue6/fulltext/1674/img005.gif)
|
(5)
|
where
kpa is the first-order rate constant
of transfer from the central compartment to the aqueous, while
Vc and
Va are the
volumes
of the central compartment and aqueous, respectively.
The rate constant
of loss from aqueous is
kap (Fig.
1).
The constants A, kel, and
ka were determined from the plasma ciprofloxacin
concentrations (equation 2); the rate constant kpa and the complex constant
kpa · Vc/Va were then determined by
fitting equation 5 to the time course of concentrations in the aqueous.
The model equations 1 to 5 are applicable after administration of a
single dose. After administration of the second dose, it was assumed
that the principle of superposition was followed. Thus, the
concentrations in plasma and aqueous were the sums of those remaining
from the first dose and those produced from the second dose.
An equation analogous to equation 5 can be written for the time course
of concentrations in vitreous, and the rate constants of transfer can
be determined.
The concentration ratio K (described previously
[8] as "the penetration" into aqueous) is given by
the ratio of the rate constants. Thus:
|
(6)
|
A similar equation can be written for the ratio of the mean
concentration in vitreous and
plasma.
| |
ACKNOWLEDGMENT |
The assistance of M. R. Lesk, who supplied details of his
results, is gratefully acknowledged.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: 592 Stirling
Highway, Mosman Park, WA, 6012, Australia. Phone: 64 8 9385 6665. Fax: 64 8 9385 6669. E-mail: n-morlet{at}q-net.net.au.
| |
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Antimicrobial Agents and Chemotherapy, June 2000, p. 1674-1679, Vol. 44, No. 6
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Abstract
Introduction
