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research-article2015
TAR0010.1177/1753465815620338Therapeutic Advances in Respiratory DiseaseOhno et al

Therapeutic Advances in Respiratory Disease Original Research

Pharmacokinetics of consecutive oral

Ther Adv Respir Dis

2016, Vol. 10(1) 34­–42

moxifloxacin (400 mg/day) in patients with DOI: 10.1177/

1753465815620338

respiratory tract infection

© The Author(s), 2015.
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Fumitaka Ito, Yasushi Ohno, Sayaka Toyoshi, Daizo Kaito, Yanase Koumei, Junki Endo,
Fumihiko Kamamiya, Hidenori Mori, Masahiro Mori, Megumi Morishita,
Norihiko Funaguchi and Shinya Minatoguchi

Abstract:  A population pharmacokinetic analysis was performed to investigate the

pharmacokinetics of moxifloxacin (400 mg) following a once-daily oral administration in 28
patients with respiratory tract infection disease. The maximum plasma concentration and
the area under the plasma concentration–time curve were 3.97 µg/ml and 51.74 µg·h/ml,
respectively; these values were nearly equivalent to those of healthy adult men. Two adverse
drug reactions (nausea, vomiting) occurred, but both reactions were mild and nonserious
and the patients recovered without treatment. The pharmacokinetic profile of moxifloxacin in
Japanese patients with respiratory tract infection and an underlying disease should thus be
considered safe and comparable with that in healthy adult men, and adjustment of dose may
do not need for age, sex, body weight, or renal function.

Keywords:  moxifloxacin, pharmacokinetics, respiratory tract infection

Introduction agent (FQ) with a once-daily oral administration Correspondence to:

Yasushi Ohno, PhD
Acute respiratory tract infection is one of the most of 400 mg to have the same dosage and adminis- Second Department of
problematic infections induced by major causa- tration regimen in Japan as in Europe and the US, Internal Medicine, Gifu
University Graduate School
tive bacteria, such as Streptococcus pneumoniae and based on the pharmacokinetics/pharmacodynam- of Medicine, 1-1 Yanagido,
Haemophilus influenzae, or by organisms casing ics (PK-PD) profile of the drug. The clinical effi- Gifu 501-1194, Japan
yasusi@gifu-u.ac.jp
atypical pneumonia, such as mycoplasma [Ishida cacy and safety of this drug has been confirmed Fumitaka Ito, MD
et al. 2004; Higashiyama et al. 2008]. both within and outside of Japan [Welte et  al. Sayaka Toyoshi, MD
Daizo Kaito, MD
2005; Fogarty et  al. 2005; Anzueto et  al. 2006; Yanase Koumei, MD
High-dose penicillin antibiotics are the first choice Torres et  al. 2008; Ott et  al. 2008; Kobayashi Junki Endo, PhD
Fumihiko Kamamiya, MD
for the treatment of bacterial pneumonia, but cur- et al. 2005; Liu et al. 2014] based on its favorable Hidenori Mori, PhD
rent increases in the isolation rates of bacteria antibacterial activity [Nishino and Otsuki, 2005; Masahiro Mori, MD
Megumi Morishita, MD
showing resistance to penicillin antibiotics, such as Inoue et  al. 2005; Niki et  al. 2011] and PK-PD Norihiko Funaguchi, PhD
penicillin-resistant S. pneumoniae (PRSP) or profile [Jacobs, 2001; Onishi, 2005], and MXF is Shinya Minatoguchi, PhD
β-lactamase nonproducing ampicillin-resistant expected to be highly useful for the treatment Second Department of
Internal Medicine, Gifu
(BLNAR) H. influenzae, often make treatment dif- of outpatients with 0–2 points CURB-65 of University Graduate School
of Medicine, Gifu, Japan
ficult. Consequently, respiratory quinolones are community-acquired pneumonia and secondary
now favored among antibacterial agents for the infections arising from chronic respiratory
treatment of respiratory tract infections based on diseases.
their strong antibacterial activity against causative
bacteria (such as S. pneumoniae), a favorable distri- Given that dose adjustments are not necessary for
bution in the lungs, and a high degree of safety. MXF, even for patients with impaired renal func-
tion [Stass, 2002; Mishina, 2010; Tanaka and
Moxifloxacin (MXF), a respiratory quinolone Watanabe, 2005], and that MXF exhibits a rela-
developed by Bayer Germany and Bayer Inter- tively high antibacterial activity against anaerobic
national is the first fluoroquinolone antibacterial bacteria (compared with other FQs) [Tanaka and

34 http://tar.sagepub.com

Watanabe, 2005], MXF is also highly useful for
patients with recurrent respiratory tract infec-
tions, such as elderly patients with underlying dis-
eases. While some reports on its pharmacokinetics
in patients with infection have been published
outside of Japan [Simon et  al. 2003; Noreddin
et  al. 2007], the pharmacokinetics of MXF in
Japanese patients with infection have not been
sufficiently reported, and no report has been pub-
lished so far concerning the measurement of drug
concentrations in a population pharmacokinetic
analysis of patients with respiratory tract infection
and an underlying disease or complication.
Reported here are the results of our population
pharmacokinetic analysis in Japanese patients
with respiratory tract infection and an underlying
disease or complications.
Patients and methods
Patients
Patients aged 20 years or older who visited the
study site from 2008 through 2011, were diag-
nosed as having to acute exacerbation of COPD
or respiratory infection in patients with previously
diagnosed respiratory diseases or pneumonia, and
voluntarily provided written consent were
enrolled in this study. The following three inclu-
sion criteria were applied to study subjects with a
secondary infection in addition to a chronic res-
piratory infection:
1. body temperature above 37°C and presen-
tation with clinical symptoms characteristic
of respiratory infection, such as coughing,
sputum, chest pain, and dyspnea;
2. white blood cell (WBC) count of 8000/
mm3 or higher and a C-reactive protein
(CRP) level of 0.7 mg/dl or higher; and
3. acute and new onset of an infiltration
shadow on a chest X-ray image in addition
to criteria 1 and 2 above for patients with
pneumonia.
The subjects enrolled in this study were patients
with an infection score of 0–2 using CURB-65
who had been previously treated with an antibac-
terial agent prior to the start of this study and
whose symptoms had not improved despite treat-
ment for 3 days or longer, in principle. Patient
exclusion criteria for this study were serious cases
with a CURB-65 score of more than three points
http://tar.sagepub.com 35
F Ito, Y Ohno et al.
or serious complications. Patients who cannot
evaluate the effectiveness of the drug were also
excluded. In addition, patients with impaired
serious liver function, patients with the cerebro-
vascular disease, patients allergic to the quinolone
medicine, patients with an extension of QTc, and
pregnant patients were excluded from this study
Administration method
An oral dose of MXF (Avelox® Tablets, 400 mg;
Bayer Yakuhin, Ltd) was consecutively adminis-
tered once daily for 7 days, in principle.
For this study, patients less than 40 kg in weight
and 65 years or older received treatment with the
same dose as a physically unimpaired person. The
treatment period was to be shortened when the
treatment purpose was achieved or when discon-
tinuation was unavoidable because of the onset of
adverse drug reactions.
Contraindicated drugs and concomitant drugs/
therapies
The use of other antibacterial agents that could
influence the efficacy evaluation of MXF was
prohibited during treatment with this drug.
However, the use of oral antibiotic and long-term
and small doses of macrolide antibacterial agents
that had been continued from before the initia-
tion of this study were permitted, provided that
the dosage and administration schedule remained
unchanged. The use of an antipyretic/analgesic
agent was permitted only on an as-needed basis.
The concomitant use of steroids (such as predo-
nine) was permitted, provided that the dosage
and administration schedule remained unchanged
during the treatment period. When another drug
was used, the drug name and duration of admin-
istration were recorded.
Observation items and timing
Plasma drug concentration. Blood specimens
were collected at two or three time points (at
approximately 1–2 hours, 10 hours, and 24 hours)
after the third administration of the study drug.
The specimens were centrifuged, and the plasma
blood concentration of MXF was determined
using high-performance liquid chromatography
(HPLC). HPLC is a kind of column chromatog-
raphy and is a method using a high-pressure liq-
uid as a mobile phase.
Therapeutic Advances in Respiratory Disease 10(1)
Table 1. Demographic factors.
A population pharmacokinetic analysis using a
nonlinear mixed effect model was performed for
the obtained plasma drug concentration data.
NONMEM VI (version 2.0, FOCE INTER) was
used for the analysis. A relative error model was
used, after assuming that the individual variation
(η) and the intra-individual variation (ε) would
follow a log-normal distribution. Covariates were
explored for age, weight (WT), creatinine clear-
ance (CrCL), WBC count, CRP, aspartate
transaminase (AST), alanine transaminase
(ALT), sex, and severity of renal impairment.
The level of significance for the likelihood ratio
test was p = 0.01 (when the F value was 1, the
change in the corresponding objective function
[OBJ] was ⊿OBJ = 6.63).
Safety. The onset of adverse events was observed
throughout the study period. A clinical laboratory
test and chest X-ray examination were performed
at baseline, 3 days after the initiation of treatment
(whenever possible), and 7 days after the initiation
of treatment or at treatment completion (discon-
tinuation). When adverse events or abnormal vari-
ations in the clinical laboratory data were observed,
the symptom, date of onset, severity, causal rela-
tionship with the drug, action and course, and out-
come were investigated. The criteria for judging
36 http://tar.sagepub.com
the seriousness of the adverse event and the causal
relationship with MXF were determined prior to
the initiation of this study, and these parameters
were evaluated as ‘serious or nonserious’ and
‘related or not related’, respectively.
Results
Evaluated patients
Of the 34 patients who were enrolled in this study
and received MXF, 28 patients were included in
the analyses of efficacy and pharmacokinetics
after excluding six subjects for whom data regard-
ing body weight, timing of the blood sampling, or
CrCL were missing. The patient demographics of
the 28 patients included in the pharmacokinetic
analysis were as follows: 22 men and six women,
mean age of 71.2 years, mean weight of 50.7 kg,
and mean CrCL of 67.7 ml/min (Table 1). The
diagnoses were pneumonia in 16 patients, exacer-
bation of the chronic respiratory tract infectious
disease in eight patients, and bronchitis in four
patients (Table 2). The underlying diseases were
COPD in eight patients, lung cancer in seven
patients, second infectious disease in tuberculosis
aftereffects in four patients, bronchiectasis in
three patients, bronchial asthma in two patients,

Table 2. Disease names and underlying diseases.
and pleural mesothelioma, and bronchitis in
one patient each (Table 2). The safety analysis
included all of the patients who were treated with
MXF (34 patients).
Administration state
The mean MXF treatment period was 7.6 days
(3–15 days), and 28 patients were treated for 7
days or longer.
Plasma pharmacokinetic parameters
Figure 1 shows the plasma drug concentration
obtained from blood samples collected at 56 time
points for the 28 patients who were included in the
pharmacokinetic evaluation, and Tables 3 and 4
show the estimated pharmacokinetic parameters of
the final pharmacokinetic model and the pharma-
cokinetic parameters of each patient, respectively.
The maximum plasma concentration at up to 24
hours after administration (Cmax, ss) and the area
under the concentration-time curve (AUC0–24, ss)
at steady state were calculated using a post-hoc
estimation of the variation in the plasma drug con-
centration in each patient based on the obtained
pharmacokinetic parameters. WT was included in
the final pharmacokinetic model as a covariant of
clearance (CL). The inter-patient variations in the
http://tar.sagepub.com 37
F Ito, Y Ohno et al.
absorption rate constant (Ka), CL, and distribu-
tion volume (V) were not included. The intra-
individual variation (ε) was 40.1% (CV). Figure 2
shows the GOF (goodness of fit) plot that was
used for model validation. Figure 3 shows the esti-
mated changes in the plasma drug concentration
and the measured values for each patient. The final
model was favorably applied to the measured
plasma concentration data.
Safety
Adverse events consisting of nausea and vomiting
and for which a causal relationship with MXF
could not be denied (adverse drug reactions)
occurred in one patient each, but both events
were mild and nonserious and both patients
recovered without treatment.
Discussion
In vitro and in vivo studies have recently been
actively performed to elucidate the PK-PD pro-
file of various antibacterial agents, and close
relationships between the pharmacokinetics
and efficacy and prevention of drug resistance
have been disclosed. FQs show a concentra-
tion-dependent bactericidal action, and the
AUC/minimal inhibitory concentration (MIC)
Therapeutic Advances in Respiratory Disease 10(1)

Figure 1.  Plasma concentration after the oral administration of moxifloxacin (400 mg) (left graph: linear scale,
right graph: semilog scale). The open circles show the observed moxifloxacin concentrations at steady state
after multiple doses of moxifloxacin (400 mg) administered once daily.

Table 3. Pharmacokinetic parameters includes in final model.

ratio showed the highest correlation with the
therapeutic effect among PK-PD parameters
[Craig, 1998, 2001; Lacy et  al. 1999; Andes
and Craig, 2002], indicating the necessity of a
sufficient drug concentration for the prevention
of drug resistance. Repeated respiratory tract
infections are often experienced particularly in
the elderly and in patients with an underlying
disease, resulting in the repeated prescription
of antibacterial agents and increasing the risk of
drug resistance.
The pharmacokinetic parameters obtained in this
study were compared with the results of a phase I
repeated oral-dose study of MXF in healthy
Japanese adult subjects at steady state (Cmax, ss,

38 http://tar.sagepub.com

Table 4. Estimated pharmacokinetic parameters in each subject.
4.08 µg/ml; AUC0–24, ss, 46.67 µg·h/ml; t1/2, ss, 14
hours [arithmetic mean]) [Onishi, 2005], and sim-
ilar results were obtained for Cmax, ss and AUC0–24, ss.
The difference in t1/2, ss that was observed was con-
sidered to be attributable to a difference in the
compartment model. Because multiple blood sam-
ples can be difficult to collect in clinical settings,
blood samples were collected two or three times
under steady-state conditions in the present study.
The results of a previous phase I clinical study had
showed that a two-compartment model was appli-
cable to evaluating the pharmacokinetics in the
present study; however, a one-compartment model
was used for the analysis in this study because the
data obtained from the patients with respiratory
tract infections were insufficient to enable an anal-
ysis using a two-compartment model.
The mean age of the 28 subjects enrolled in this
study was 70 years, and the underlying diseases
included lung cancer in 7 patients, chronic
obstructive pulmonary disease (COPD) in 7,
tuberculosis in 4, and bronchial asthma in 2
(including some patients with more than one
http://tar.sagepub.com 39
F Ito, Y Ohno et al.
underlying disease). Clinically, FQs are fre-
quently administered to elderly patients with rela-
tively serious underlying diseases who develop
recurrent infections. Given that MFLX, in par-
ticular, is expected to show a superior usefulness
in patients with impaired renal function or aspira-
tion pneumonia based on its drug profile [Stass,
2002; Hori, 2010; Mishina, 2010], compared
with other FQs, MXF is likely to be frequently
used in these patients. However, few studies have
investigated the pharmacokinetic profile in
patients with respiratory tract infections. Some
reports have been published outside of Japan
[Simon et al. 2003; Noreddin et al. 2007], but the
measurement of drug concentrations in Japanese
patients with infections in a population pharma-
cokinetic analysis has not been reported to date,
and no study has been performed in Japan or else-
where in patients with respiratory tract infections
and an underlying disease.
The results of our population pharmacokinetic
analysis showed that the plasma MXF concentra-
tion in Japanese elderly patients with respiratory
Therapeutic Advances in Respiratory Disease 10(1)

Figure 2.  GOF (goodness of fit) plot of the final model. The mean estimates (PRED) and individual post hoc
estimates (IPRED) of the moxifloxacin concentrations derived from the pharmokinetics final model versus
the observed moxifloxacin concentrations produced an identical dashed line (upper left and right graphs,
respectively). In the graphs plotting the weighted residual (WRES) versus the PRED and the individual weighted
residual (IWRES) versus the IPRED (lower left and right graphs, respectively), the solid lines show a spline
curve. WRES and IWRES were defined using the equations WRES = (observed – PRED)/W and IWRES =
(observed – IPRED)/W, where W = IPRED.

Figure 3.  Estimated changes in plasma drug concentration and measured values in each subject.

tract infections and underlying diseases had a MXF is therefore considered to be a useful thera-
pharmacokinetic profile that was similar to that of peutic agent for respiratory tract infection that
healthy adult men. can be safely administered using a dosage and

40 http://tar.sagepub.com

administration schedule of 400 mg once daily
(which is the dame dosage and administration
schedule used outside of Japan) for Japanese
patients with infections and underlying diseases.
Acknowledgements
The authors would like to offer their special
thanks to William Goldman for English revision.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The authors declare that they have no competing
interests.
References
Andes, D. and Craig, W. (2002) Animal model
pharmacokinetics and pharmacodynamics: a critical
review. Int J Antimicrob Agents 19: 261–268.
Anzueto, A., Niederman, M., Pearle, J., Restrepo, M.,
Heyder, A. and Choudhri, S. (2006) Community-
acquired pneumonia recovery in the elderly
(CAPRIE): efficacy and safety of moxifloxacin therapy
versus that of levofloxacin therapy. Clin Infect Dis 42:
73–81.
Craig, W. (1998) Pharmacokinetic/pharmacodynamic
parameters: rationale for antibacterial dosing of mice
and men. Clin Infect Dis 26: 1–12.
Craig, W. (2001) Does dose matter? Clin Infect Dis
33(Suppl. 3): S233–S237.
Fogarty, C., Torres, A., Choudhri, S., Haverstock,
D., Herrington, J. and Ambler, J. (2005) Efficacy of
moxifloxacin for treatment of penicillin-, macrolide-
and multidrug-resistant Streptococcus pneumoniae in
community- acquired pneumonia. Int J Clin Pract 59:
1253–1259.
Higashiyama, Y., Watanabe, A., Aoki, N., Niki,
Y. and Kohno, S. (2008) Clinical evaluation
of levofloxacin versus oral β-lactams for acute
exacerbation of COPD. Jpn J Chemother 56: 33–48.
Hori, S. (2010) Pharmacokinetics–pharmacodynamics
based antimicrobial chemotherapy. Antibiotics
Chemother 26(Suppl. 1): 953–961.
Inoue, M., Sato, Y. and Okamoto, R. (2005) In vitro
antibacterial activity of moxifloxacin. Jpn J Chemother
53(Suppl. 3): 16–20.
Ishida, T., Hashimoto, T., Arita, M., Tojo, Y.,
Tachibana, H. and Jinnai, M. (2004) A 3-year
http://tar.sagepub.com 41
F Ito, Y Ohno et al.
prospective study of a urinary antigen-detection test
for Streptococcus pneumoniae in community-acquired
pneumonia: utility and clinical impact on the reported
etiology. J Infect Chemother 10: 359–363.
Jacobs, M. (2001) Optimisation of antimicrobial
therapy using pharmacokinetic and pharmacodynamic
parameters. Clin Microbiol Infect 7: 589–596.
Kobayashi, H., Aoki, N., Niki, Y., Watanabe,
A., Kawai, S. and Odagiri, S. (2005a) Phase III
double-blind comparative study of BAY 12-8039
(moxifloxacin) versus levofloxacin in patients with
community-acquired pneumonia (in Japanese;
abstract in English). Jpn J Chemother 53(Suppl. 3):
27–46.
Kobayashi, H., Aoki, N., Niki, Y., Watanabe, A.,
Kawai, S., Odagiri, S. et al. (2005b) Phase III clinical
study of BAY 12-8039 (moxifloxacin) for respiratory
tract infections (in Japanese; abstract in English). Jpn
J Chemother 53(Suppl. 3): 47–59.
Lacy, M., Lu, W., Xu, X., Tessier, P., Nicolau,
D. and Quintiliani, R. (1999) Pharmacodynamic
comparisons of levofloxacin, ciprofloxacin, and
ampicillin against Streptococcus pneumoniae in an in
vitro model of infection. Antimicrob Agents Chemother
43: 672–677.
Liu, K., Xu, B., Wang, J., Zhang, J., Ding, H., Ariani,
F. et al. (2014) Efficacy and safety of moxifloxacin in
acute exacerbations of chronic bronchitis and COPD:
a systematic review and meta-analysis. J Thorac Dis.
(2014) 6: 221–229.
Mishina, K. (2010) Pharmacokinetics of moxifloxacin
in the patients with respiratory infection. Antibiotics
Chemother 12: 2452–2459.
Niki, Y., Hanaki, H., Matsumoto, T., Yagisawa,
M., Kohno, S., Aoki, N. et al. (2011) Nationwide
surveillance of bacterial respiratory pathogens
conducted by the Japanese Society of Chemotherapy
in 2008: general view of the pathogens’ antibacterial
susceptibility. J Infect Chemother 17: 510–523.
Nishino, T. and Otsuki, M. (2005) In vitro and in
vivo antibacterial activity of moxifloxacin, a novel
quinolone antibacterial agent. Jpn J Chemother
53(Suppl. 3): 1–15.
Noreddin, A., Reese, A., Ostroski, M., Hoban, D. and
Zhanel, G. (2007) Comparative pharmacodynamics
of garenoxacin, gemifloxacin, and moxifloxacin
in community-acquired pneumonia caused by
Streptococcus pneumoniae: a Monte Carlo simulation
analysis. Clin Ther 29: 2685–2689.
Onishi, A. (2005) Safety, pharmacokinetics and
influence on the intestinal flora of BAY 12-8039
(moxifloxacin hydrochloride) after oral administration
in healthy male subjects. Jpn Pharmacol Ther 33:
1029–1045.
Therapeutic Advances in Respiratory Disease 10(1)
Ott, S., Allewelt, M., Lorenz, J., Reimnitz, P. and
Lode, H. for The German Lung Abscess Study
Group (2008) Moxifloxacin vs. ampicillin/sulbactam
in aspiration pneumonia and primary lung abscess.
Infection 36: 23–30.
Simon, N., Sapol, E., Albanesa, J., Martin,
C., Arvis, P. and Urien, S. (2003) Population
pharmacokinetics of moxifloxacin in plasma
and bronchial secretions in patients with severe
bronchopneumonia. Clin Pharmacol Ther 74:
353–363.
Stass, H. (2002) Pharmacokinetics of moxifloxacin,
a novel 8-methoxy-quinolone, in patients with renal
dysfunction. Br J Clin Pharmacol 53: 232–237.
Visit SAGE journals online
http://tar.sagepub.com
Tanaka, K. and Watanabe, K. (2005) In vitro
SAGE journals antibacterial activity of moxifloxacin against anaerobic
42 http://tar.sagepub.com
and facultative bacteria. Jpn J Chemother 52(Suppl. 3):
21–26.
Torres, A., Garau, J., Arvis, P., Carlet, J., Choudhri,
S., Kureishi, A. et al. for the MOTIV (Moxifloxacin
Treatment IV) Study Group (2008) Moxifloxacin
monotherapy is effective in hospitalized patients
with community-acquired pneumonia: The MOTIV
study – a randomized clinical trial. Clin Infect Dis
46:1499–1509.
Welte, T., Petermann, W., Schuermann, D., Bauer,
T. and Reimnitz, P. for the MOXIRAPID Study
Group (2005) Treatment with sequential intravenous
or oral moxifloxacin was associated with faster
clinical improvement than was standard therapy
for hospitalized patients with community-acquired
pneumonia who received initial parenteral therapy.
Clin Infect Dis 41: 1697–1705.