International Journal of Antimicrobial Agents 15 (2000) 283 289

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Original article
The effect of ferrous sulphate and sucralfate on the bioavailability
of oral gemifloxacin in healthy volunteers
A. Allen a,*, E. Bygate b, H. Faessel a, L. Isaac b, A. Lewis c
a
Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts AL6 9AR, UK
b
Clinical Pharmacology Unit, SmithKline Beecham Pharmaceuticals, Harlow, Essex, UK
c
Clinical Pharmacology Statistics Department, Harlow, Essex, UK
Received 11 January 2000; accepted 17 March 2000

Abstract

Sucralfate is a cytoprotectant with antacid properties and ferrous sulphate is commonly prescribed for iron-deficiency anaemia.
This open, randomized, single-dose, five-way crossover study investigated the effect of sucralfate and ferrous sulphate on the
bioavailability of gemifloxacin, a novel fluoroquinolone antimicrobial. Twenty-seven healthy male volunteers received
gemifloxacin, 320 mg p.o., alone, 3 h after sucralfate (2 g) or ferrous sulphate (325 mg), or 2 h before sucralfate or ferrous
sulphate. Each subject received all five dosing regimens in random order with at least 6 days between regimens. Plasma samples
collected up to 48 h after dosing with gemifloxacin, were assayed for gemifloxacin to determine pharmacokinetic parameters.
Administration of gemifloxacin 3 h after sucralfate produced a marked decrease of 53% in the area under the plasma
concentrationtime curve from time zero extrapolated to infinity (AUC0 ), and a decrease of 69% in the maximal plasma
concentration (Cmax). Administration of gemifloxacin 3 h after ferrous sulphate resulted in only a modest reduction of 11% in
AUC0  and of 20% in Cmax, which was not considered to be clinically significant. In contrast, at the doses used neither sucralfate
nor ferrous sulphate altered gemifloxacin bioavailability when it was administered 2 h before either of these agents. Gemifloxacin
was well tolerated in all the regimens. The results of this study support the dosing recommendation that gemifloxacin can be safely
administered at least 2 h before sucralfate or ferrous sulphate, or at least 3 h after ferrous sulphate. 2000 Elsevier Science B.V.
and International Society of Chemotherapy. All rights reserved.

Keywords: Gemifloxacin; Fluoroquinolone; Pharmacokinetics; Sucralfate; Ferrous sulphate; Drug interactions

1. Introduction ical microorganisms [57]. Furthermore, in studies of

Gemifloxacin is a novel, synthetic fluoroquinolone
antibacterial agent with a broad spectrum of activity
against both Gram-negative and Gram-positive organ-
isms [13]. In vitro studies have shown that
gemifloxacin is 4- to 64-fold more active than reference
quinolones against Gram-positive cocci [4]. Its spec-
trum of activity covers all the major respiratory tract
pathogens including Streptococcus pneumoniae,
Haemophilus influenzae, Moraxella catarrhalis and atyp-
* Corresponding author. Tel.: +44-1438-782598; fax: +44-1438-
782600.
E-mail address: Ann Allen@sbphrd.com (A. Allen).
its activity in vitro against clinical isolates, gemifloxacin
was highly active against various Enterobacteriaceae
including those implicated in urinary tract infections
(Escherichia coli, Klebsiella pneumoniae and Proteus
mirabilis), 90% of which were inhibited at gemifloxacin
concentrations of B 0.5 mg/l [2,8].
Gemifloxacin is rapidly absorbed with a time to
maximum plasma concentration (Tmax) of 0.5 2 h in
healthy subjects and displays linear pharmacokinetics
over the dose range studied (20800 mg), with an
apparent plasma terminal half-life (t1/2) after single or
repeated administration of about 8 h [9,10]. A mini-
mum of 2030% of the oral dose is excreted unchanged
in the urine. Plasma protein binding of gemifloxacin is

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284 A. Allen et al. / International Journal of Antimicrobial Agents 15 (2000) 283289
low (about 70%) [9,10]. Following repeated once-daily
administration, there is negligible accumulation of
gemifloxacin at doses up to 640 mg [10].
Sucralfate is an aluminium containing cytoprotectant
with antacid properties used for patients with duodenal
or gastric ulcer or with gastritis. Ferrous sulphate or
other iron salts are commonly given as a dietary supple-
ment for the treatment of iron-deficiency anaemia.
Many patients using either sucralfate or iron salts will
also be prescribed antimicrobials at some time. How-
ever as a class, oral quinolones interact with antacids
containing di or trivalent ions (magnesium, aluminium
and calcium), with sucralfate [11 18] and with iron
[19,20], probably as a result of the formation of poorly
absorbed chelates [21]. If these agents are administered
concomitantly with a quinolone, a significant reduction
in plasma concentrations of antimicrobial may result
with a consequent loss of efficacy. It is therefore impor-
tant to define a therapeutic time window within which
a quinolone antimicrobial can be co-administered with
sucralfate or iron. This study was designed to investi-
gate the effect of sucralfate and of ferrous sulphate on
the bioavailability of oral gemifloxacin, when adminis-
tered either 3 h before or 2 h after gemifloxacin.
2. Materials and methods
2.1. Study design
This open, randomized, single-dose, five-way,
crossover study in healthy male volunteers was con-
ducted in accordance with Good Clinical Practice
Guidelines and the amended Declaration of Helsinki.
All participants gave written informed consent before
any study procedures were performed.
2.2. Subjects
Male subjects aged 18 60 years were eligible if they
were within 15% of ideal body weight for height, frame
and age and provided they exhibited no clinically sig-
nificant abnormalities on clinical examination, clinical
chemistry, haematology or urinalysis. They were also
required to have a normal 12-lead electrocardiograph
(ECG), a negative urine drug screen and a negative
hepatitis B surface antigen result. The exclusion criteria
were: use of antacids, sucralfate, medications contain-
ing di- and trivalent cations (e.g. iron, zinc or calcium),
zinc-containing multivitamins, or over-the-counter
medications within 48 h before the first dosing day of
each study session; use of prescribed medications within
14 days of the study start; a history of allergy to
quinolones; a history of any condition known to inter-
fere with the pharmacokinetics or pharmacodynamics
of drugs; a definite or suspected history of adverse
reactions or hypersensitivity to the study drug or drugs
with a similar chemical structure; participation in any
drug trial within the previous 4 months or in more than
three clinical trials with different new drugs within the
previous 12 months. Subjects who smoked were re-
stricted to ten cigarettes a day during the study and
were asked to refrain from smoking during residential
periods in the study. Subjects were also asked to refrain
from strenuous physical activity from 48 h before until
48 h after each dosing day and from sunbathing or
using sun-beds from 24 h before until 48 h after dosing
on each dosing day.
2.3. Protocol
A total of 31 subjects entered the study. Subjects
were to receive each of five dosing regimens separated
by a washout period of at least 6 days. The order of
regimens was randomized for each subject. The five
regimens were: sucralfate, 2 g, administered 3 h before
gemifloxacin; sucralfate, 2 g, administered 2 h after
gemifloxacin; ferrous sulphate, 325 mg, administered 3
h before gemifloxacin; ferrous sulphate, 325 mg, admin-
istered 2 h after gemifloxacin; a single dose of
gemifloxacin. In each case a single oral dose of 320 mg
gemifloxacin was administered. All study medication
was swallowed without chewing with 200 ml of water.
Subjects fasted from midnight the night prior to each
dosing session and food was restricted until 3 h after
dosing with gemifloxacin when a light standard meal
was provided. Dinner was provided 910 h after dosing
with gemifloxacin. Drinking of mineral water only was
permitted until 7 h after dosing, after which fluid intake
was unrestricted. Subjects abstained from alcohol, caf-
feine-containing drinks and grapefruit juice from 24 h
prior to the study start until 48 h after dosing on each
dosing day. Subjects were also asked to fast from
midnight the night before collection of blood and urine
samples for safety evaluation at 24 h after dosing.
2.4. Screening and safety e6aluation
All subjects who received at least one dose of study
medication were included in the safety evaluation.
Pulse, semi-supine blood pressure and 12-lead ECG
were measured before the study, before dosing, and at
2 h and 12 h after dosing on each dosing day, and at
follow-up. Clinical laboratory assessments (haematol-
ogy, clinical chemistry and urinalysis) were made before
the study, before dosing, 24 h after dosing on each
study day, and at follow-up. In addition, a urine drug
screen was performed before the study and at random
before dosing; each subject underwent a urine drug
screen on at least one occasion during the study. Ad-
verse experiences were recorded before dosing, at 2, 12,
and 24 h after dosing on each dosing day and at
 A. Allen et al. / International Journal of Antimicrobial Agents 15 (2000) 283289
follow-up. Spontaneous reports of adverse experiences
were also recorded. Adverse experiences were graded
for severity and relationship to the study drug by the
investigator. The follow-up assessments were made be-
tween 7 and 15 days of the final dosing day.
2.5. Blood sampling and assay methods
On each dosing day, venous blood samples of :3 ml
were obtained via indwelling cannula from each subject
before dosing and at 15, 30, 45, 60 and 90 min, then at
2, 3, 4, 6, 8, 12, 24, 36 and 48 h after each single-dose
administration of gemifloxacin. Samples were cen-
trifuged at approximately +4C and the resulting
plasma was transferred to plain tubes, frozen and
stored at approximately 20C until analysis. Plasma
samples were assayed for gemifloxacin using a method
based on protein precipitation with acetonitrile, fol-
lowed by high-pressure liquid chromatographic and
mass spectrometric analysis using positive-ion spray
ionization (SmithKline Beecham, unpublished data).
The calibration curve of the assay was linear over a
plasma range of 0.01 0.5 mg/l (correlation coefficient,
0.9980), and the intra-assay and inter-assay coefficients
of variation (CVs) over this range were B 10%. The
lower limit of quantification for gemifloxacin was 0.01
mg/l using a 0.05 ml aliquot of human plasma.
2.6. Pharmacokinetic analysis
Gemifloxacin plasma concentration time data were
analysed by non-compartmental methods using Win-
Nonlin Professional (version 1.5; Pharsight, Cary, NC,
USA). The first occurrence of maximal plasma concen-
tration (Cmax) and the time to Cmax (Tmax) were
recorded. The area under the concentration time curve
from time zero to the last quantifiable plasma concen-
tration (AUC0 t) was calculated using the linear trape-
zoidal rule for each incremental trapezoid and the log
trapezoidal rule for each trapezoid after Cmax [22].
285
2.7. Statistical analysis
Assuming maximal within-subject CVs of 35% for
AUC and Cmax (from previous studies with
gemifloxacin), it was calculated that 27 evaluable sub-
jects would be required to provide at least 90% power
to detect a difference of 30% (true ratio 0.70 or 1.43) in
AUC and Cmax. Adjustments were made for the four
multiple comparisons using Dunnetts procedure to en-
sure the overall type I error rate was maintained at 5%
[23]. Thirty subjects were recruited with the aim of
obtaining evaluable data from at least 27 subjects.
The primary endpoints were AUC and Cmax and
these were loge-transformed and compared by analysis
of variance (ANOVA) fitting terms for sequence, sub-
ject within sequence, period and dosing regimen. The
point estimates and adjusted 95% confidence intervals
(CIs) for the difference between the regimens (sucralfate
3 h before:gemifloxacin alone; sucralfate 2 h af-
ter:gemifloxacin alone; ferrous sulphate 3 h be-
fore:gemifloxacin alone; ferrous sulphate 2 h
after:gemifloxacin alone) were constructed using the
residual variance from the model. The ANOVA indi-
cated that the homogeneity of variance assumption
might have been violated due to higher variation on
regimen giving sucralfate 3 h before gemifloxacin rela-
tive to the other regimens.
In order to address this regimen for sucralfate 3 h
before gemifloxacin was removed from the ANOVA
and revised point estimates and adjusted 95% confi-
dence intervals for the difference between the regimens
(sucralfate 2 h after:gemifloxacin alone; ferrous sul-
phate 3 h before:gemifloxacin alone; ferrous sulphate 2
h after:gemifloxacin alone) were constructed using the
residual variance from the model and making the ap-
propriate adjustments for the four multiple compari-
sons using Dunnetts procedure. A paired t-test was
constructed for the comparison of sucralfate 3 h before
gemifloxacin with gemifloxacin alone, which does not
assume equal variances between regimens. Appropriate
adjustments were made for the four multiple compari-
sons using Dunnetts procedure.
AUC extrapolated to infinity (AUC0 ) was calculated
as the sum of the AUC0 t and C(t)/lz, where C(t) was
the predicted concentration from the log linear regres- 3. Results
sion analysis at the last quantifiable time point and lz
was the elimination rate constant. The percentage of 3.1. Patient demographics
AUC0  that was extrapolated was calculated as the
ratio of (AUC0  AUC0 t) to AUC0 . The appar-
ent terminal elimination rate constant (lz) was derived
from the log linear disposition phase of the concentra-
tion time curve using least-squares regression with vi-
sual inspection of the data to determine the appropriate
number of terminal points to calculate lz. The appar-
ent terminal-phase elimination half-life (t1/2) was calcu-
lated as ln(2)/lz.
A total of 31 healthy, male subjects entered the study
and received study medication, of whom 28 received all
five treatment regimens and 27 completed the study.
Twenty-nine subjects contributed to at least one com-
parison of interest and were included in statistical
analyses. Two subjects were withdrawn due to adverse
experiences and one subject who received all five dosing
regimens was lost to follow-up. Another patient was
286 A. Allen et al. / International Journal of Antimicrobial Agents 15 (2000) 283289

was 79.69 12.3 kg. Twenty-eight subjects (90%) were

white people.

3.2. Pharmacokinetics

The concentrationtime profiles for gemifloxacin

were similar in most subjects following oral adminis-
tration of gemifloxacin, 320 mg alone, with
gemifloxacin present in plasma within 1 h and gener-
ally remaining quantifiable for 30 h. The mean Cmax
of 1.05 mg/l was reached at 0.52 h, and
gemifloxacin plasma concentrations subsequently de-
creased bi-exponentially, with a mean t1/2 of 8.09 h.
Administration of sucralfate 3 h before gemifloxacin
considerably reduced Cmax for gemifloxacin (Fig. 1)
but there was large variability between subjects in the
concentrationtime profiles. Administration of ferrous
sulphate 3 h before gemifloxacin slightly lowered Cmax
for gemifloxacin, but administration of either sucral-
fate or ferrous sulphate 2 h after gemifloxacin had
negligible effect on Cmax for gemifloxacin.
Administration of sucralfate 3 h before dosing with
gemifloxacin significantly reduced the bioavailability
of gemifloxacin (mean decrease of 53% in AUC0 
and of 69% in Cmax) compared with gemifloxacin
given alone (Tables 1 and 2). Administration of fer-
rous sulphate 3 h before dosing with gemifloxacin
only moderately decreased the bioavailability of
Fig. 1. Mean plasma concentrations of gemifloxacin following a
single oral dose of gemifloxacin, 320 mg, alone, or given 2 h before or
3 h after sucralfate (2 g) or ferrous sulphate (325 mg).
gemifloxacin (mean decrease of 11% in AUC0  and
of 20% in Cmax). The bioavailability of gemifloxacin
was not notably altered by administration of either
sucralfate or ferrous sulphate 2 h after gemifloxacin
withdrawn before the final dosing session because the
required number of evaluable patients had been
reached. For the 31 subjects who received at least one
dose of study medication, the mean ( 9 SD) age was
34 9 10.7 years (range, 19 60 years), mean height was
1.809 0.06 m (range, 1.66 1.94 m) and mean weight
dosing (mean decrease of 810% in AUC0  and of
24% in Cmax).
Administration of sucralfate or ferrous sulphate be-
fore or after gemifloxacin dosing did not alter the
elimination phase and estimates of t1/2 were similar
for all five dosing regimens (Table 1) with an overall
mean of : 8 h.

Table 1
Pharmacokinetic parameters for gemifloxacin following a single oral dose of 320 mg given alone or at various times relative to administration of
sucralfate (2 g) or ferrous sulphate (325 mg)a

Parameter Sucralfate 3 h Sucralfate 2 h after Ferrous sulphate 3 h Ferrous sulphate 2 h after Gemifloxacin
before gemifloxacin gemifloxacin before gemifloxacin gemifloxacinb alone

Cmax (mg/l) 0.5119 0.385 1.0609 0.488 0.843 9 0.320 1.020 90.375 1.050 9 0.409
AUC0 (mg 3.559 2.12c 5.519 1.78b 5.33 91.98 5.37 91.53 5.97 9 1.92
h/l)
Tmax (h)d 1.50 (0.754.00) 1.00 (0.521.93) 1.02 (0.753.03) 1.00 (0.501.92) 1.00 (0.501.98)
t1/2 (h) 8.169 2.18c 8.31 9 1.78b 7.48 9 1.29 8.12 9 1.92 8.09 91.64

a
Values given are arithmetic means 9 standard deviation (29 subjects).
b
28 subjects.
c
27 subjects.
d
Median value (range).
 A. Allen et al. / International Journal of Antimicrobial Agents 15 (2000) 283289 287

Table 2
Comparison of pharmacokinetic parameters of gemifloxacin following a single oral dose of 320 mg given alone or at various times relative to
administration of sucralfate (2 g) of ferrous sulphate (325 mg)

Parameter Comparison versus gemifloxacin alone Point estimate 95% CIa Within-subject CV

AUC0 Sucralfate 3 h before gemifloxacin 0.47 (0.29, 0.74) 78.3

Sucralfate 2 h after gemifloxacin 0.92 (0.77, 1.10) 27.6
Ferrous sulphate 3 h before gemifloxacin 0.89 (0.74, 1.06) 27.6
Ferrous sulphate 2 h after gemifloxacin 0.90 (0.75, 1.07) 27.6
Cmax Sucralfate 3 h before gemifloxacin 0.31 (0.17, 0.53) 104.2
Sucralfate 2 h after gemifloxacin 0.98 (0.79, 1.21) 33.2
Ferrous sulphate 3 h before gemifloxacin 0.80 (0.65, 0.99) 33.2
Ferrous sulphate 2 h after gemifloxacin 0.96 (0.77, 1.19) 33.2

a
Adjustments made for four multiple comparisons using Dunnetts procedure.

3.3. Safety and may result in therapeutic failure [26]. Consistent

with this, in the present study, administration of sucral-
No deaths or serious adverse experiences occurred fate before dosing with oral gemifloxacin resulted in a
during the study. The number of adverse experiences significant reduction in bioavailability of gemifloxacin
and the number of subjects with adverse experiences
were similar across all five treatment regimens. Two
subjects were withdrawn because of mild adverse expe-
riences (mild hyperbilirubinaemia and a mild rash). In
all, 49 adverse experiences were reported by 22 subjects
but none were considered to be probably related to
study medication. Most adverse experiences were con-
sidered to be not related or unlikely to be related to
study medication, but five were suspected with reason-
able possibility to be related to study medication. The
most common adverse experience was headache (11
headaches in eight subjects), followed by contact der-
(mean decrease of 53% for AUC0  and 69% for Cmax).
This reduction in bioavailability was similar in magni-
tude to that reported for other fluoroquinolones given
orally with sucralfate, e.g. concomitant oral administra-
tion of sucralfate with norfloxacin [15], ciprofloxacin
[27], ofloxacin [28], enoxacin [29], sparfloxacin [30] and
moxifloxacin [31] led to reductions in bioavailability of
44100%.
The relative timing of administration may determine
the effect of sucralfate on the pharmacokinetics of
fluoroquinolones. In the present study, administration
of sucralfate 2 h after dosing with gemifloxacin had
matitis, diarrhoea and abdominal pain. All the reports
of contact dermatitis were related to application of
ECG electrodes or occurred at the cannulation site and
were not considered related to study medication. Three
subjects developed a mild rash during the study, which
resolved spontaneously. One case of rash was suspected
with reasonable possibility to be related to study medi-
cation and this patient was withdrawn. One subject
suffered a severe headache which was considered un-
likely to be related to study medication and which
resolved with appropriate therapy. All other adverse
experiences were of mild or moderate intensity.
There were no clinically important changes in blood
pressure, pulse rate, ECG parameters or clinical labora-
tory parameters during the study. The hyperbiliru-
binaemia that led to withdrawal of one subject was not
only a small effect on AUC0  (decrease of 8%) or
Cmax (decrease of 2%), and similar results have been
reported with ciprofloxacin [32], enoxacin [29] and
levofloxacin [33]. The lack of effect of sucralfate on
gemifloxacin pharmacokinetics when it is administered
2 h after gemifloxacin dosing reflects the relatively rapid
absorption of gemifloxacin (median Tmax about 1 h
after a single dose in healthy volunteers) [9], which
ensures that absorption would be complete by this time.
Conversely, administration of sucralfate 2 h before
norfloxacin [15] or enoxacin [29] reduced
fluoroquinolone bioavailability by 43 and 46%, respec-
tively, compared with decreases of 98 and 87% when
the two types of agent were administered concomi-
tantly. The present study, which found a decrease of
considered to be related to study medication.
4. Discussion
As reviewed by several authors, the interaction of
quinolone antimicrobials with metallic di- and trivalent
cation-containing agents is a class effect [21,24,25]
which greatly reduces the bioavailability of these agents
53% in AUC0  and of 69% in Cmax when sucralfate
was given 3 h before gemifloxacin, is consistent with
these findings. The pharmacokinetic parameters of
gemifloxacin given alone in the present study were
similar to those determined in previous studies [9,34
36].
The effect of ferrous sulphate has been investigated
with various fluoroquinolones. Thus, the bioavailabili-
ties of norfloxacin, ciprofloxacin, ofloxacin and
levofloxacin are decreased by 2573% when they are
288 A. Allen et al. / International Journal of Antimicrobial Agents 15 (2000) 283289
administered concurrently with ferrous sulphate [19,20].
No data are available so far on the influence of the
timing of administration of ferrous sulphate on
fluoroquinolone absorption. In the present study, ad-
ministration of ferrous sulphate, 325 mg, 3 h before
dosing with gemifloxacin, 320 mg resulted in only a
small decrease in bioavailability of gemifloxacin (de-
[6] Critchley IA, Broskey J, Coleman K. SB-265805 (LB20304a):
In-vitro Activity, Intracellular Accumulation and Killing of Le-
gionella pneumophila in Human Macrophages. San Diego, CA:
38th Interscience Conference on Antimicrobial Agents and
Chemotherapy, 1998 [Poster F-100].
[7] Felmingham D, Robbins MJ, Dencer C, Salman H, Mathias I,
Ridgway GL. In vitro activity of gemifloxacin against S. pneu-
moniae, H. influenzae, M. catarrhalis, L. pneumophila and
Chlamydia spp. [Abstract P408]. J Antimicrob Chemother
crease of 11% in AUC0  and of 20% in Cmax), which
is not considered clinically significant. Similarly, admin-
istration of ferrous sulphate 2 h after gemifloxacin had
only a small effect on enteral absorption of
gemifloxacin (decreases of 10 and 4%, respectively).
The most commonly used dose of sucralfate is 4
g/day divided into two or four doses. In the UK, the
most common dose of ferrous sulphate for iron-defi-
ciency anaemia is 200 mg three times daily but in the
USA the unit dose may be as high as 325 mg. The doses
of sucralfate and ferrous sulphate used in the present
study were based on the highest doses likely to be
administered on a single occasion. Smaller doses would
reasonably be expected to have less of an effect on
absorption of gemifloxacin.
Gemifloxacin was well tolerated when administered
alone or with sucralfate or ferrous sulphate. All the
adverse events reported were similar in nature and
frequency to those observed in previous single-dose
studies in healthy volunteers [34]. In conclusion, this
study supports the dosing recommendation that
gemifloxacin can be safely administered at least 2 h
before sucralfate or ferrous sulphate, and at least 3 h
after ferrous sulphate. Further studies are needed to
determine the minimum interval after sucralfate admin-
istration for dosing with gemifloxacin.
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