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141（ 1 ）Pharmacokinetic study of garenoxacin
in severe renal failure patients
YUKA YAMAGISHI1, 2, MAO HAGIHARA2, YUKIHIRO HAMADA2,YUKIHIRO KIMURA3, HIROKAZU IMAI3 and HIROSHIGE MIKAMO1, 2
1

Department of Clinical Infectious Diseases, Aichi Medical University,
Nagakute, Aichi 480–1195, Japan2
Department of Infection Control and Prevention, Aichi Medical University,
Nagakute, Aichi 480–1195, Japan
3
Division of Nephrology and Rheumatology, Department of Internal Medicine,
Aichi Medical University, Nagakute, Aichi 480–1195, Japan(Received for publication May 28, 2014)

Garenoxacin is a type of ﬂuoroquinolone antibacterial agents. Previous studies have suggested that garenoxacin 400 mg once daily dose is appropriate for patients with normal to moderate renal disfunction against common bacteria of respiratory infections. However, limited information has been obtained in terms of treatment for severe renal failure patients, such as
hemodialysis patients, with this drug. Twenty severe renal failure patients with respiratory infection received single garenoxacin dose (200 mg and 400 mg). By measuring blood concentration of
garenoxacin, pharmacodynamics parameters, such as the peak plasma concentration (Cmax) andthe area under the concentration curve (AUC), were calculated with NONMEM®. After single
dose of garenoxacin, Cmax at the 200 and 400 mg doses were within the range of 2.9±0.6 and 6.0±1.0 μg/mL, respectively. The corresponding values for AUC at the 200 and 400 mg doses were
within the ranges of 62.3±11.9 and 128.0±12.5 μg･hr/mL, respectively. The mean half-life (T1/2)
for garenoxacin appeared to be independent of dose (13.9±2.2 hr and 13.7±1.9 hr at the 200 and
400 mg dose). There were no serious adverse events suspected to be related with garenoxacin.
Consequently, for severe renal failure patients, the 400 mg once daily garenoxacin dose was expected to be effective against common bacteria of respiratory infections.

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Introduction
Garenoxacin, is a type of ﬂuoroquinolone antibacterial agents, has been shown to be effective in vitro against a wide range of clinically important Gram-positive and Gram-negative aerobes and anaerobes including some multidrug-resistant pathogen, such as Streptococcus pneumoniae, β-lactamase-producing Moraxella catarrhalis and ampicillin-resistant Haemophilus
inﬂuenzae (BLNAR)1〜8). This antibacterial agent is approved for the treatment of pneumonia,
secondary infection of chronic respiratory disease, acute bronchitis, sinusitis, otitis media, laryngopharyngitis and tonsillitis in Japan.
Several studies have revealed that oral dose of garenoxacin is completely absorbed and its
pharmacokinetics (PK) is proportional to dose9〜11). Additionally, renal clearance of garenoxacin
is the major elimination pathway for patients with normal renal function, while excretion of
garenoxacin involves non-renal pathways due to metabolism via phase two enzymes9, 12, 13). Accordingly, relevant decrease in total body clearance of garenoxacin is expected in patients with
impaired renal function.
In terms of the antibacterial action of ﬂuoroquinolones, a number of recent studies haveclearly shown that the area under the concentration-time curve (AUC) divided by the minimum
inhibitory concentration (MIC) (AUC/MIC ratio) is the most important predictive value of clinical and microbiological response14, 15). Previous studies have suggested that garenoxacin 400 mg
once daily dose is appropriate for patients with normal to moderate renal dysfunction from thepharmacokinetics-pharmacodynamics (PK-PD) stand point9, 13, 16).
However, few studies exist on the PK proﬁle of garenoxacin in infected patients with endstage renal disease. Hence, we investigated the PK of garenoxacin to understand safety and efﬁcacy of the treatment for severe renal failure patients with respiratory infection.

Material and Methods
Subjects
This randomized, open-label, single-dose study was conducted at Aichi Medical University
hospital in Aichi Japan. All patients were diagnosed as respiratory infection and had been on aregular thrice-weekly 4 hr hemodialysis regimen (blood and dialysate ﬂow rates were ﬁxed at 200
and 500 mL/min, respectively). All patients were required to give informed, written consent prior
to the initiation of any study-speciﬁc procedures, this study was performed in accordance with
protocol reviewed and approved by local institution committee.
Any of the following excluded a patient from the study: a history of a serious hypersensitivity reaction to any ﬂuoroquinolones and abnormal electrocardiographic, current clinically signiﬁcant hepatic disease (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]June 2015

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143（ 3 ）and/or total bilirubin levels greater than or equal to three times the upper limit of normal), malabsorption syndromes or other gastrointestinal disturbances affecting drug absorption, and pregnancy and/or breast feeding.
Dosing procedures
Each subject was given single oral garenoxacin dose of either 200 or 400 mg in non-hemodialysis day. Patients randomized to 200 mg and 400 mg regimen of garenoxacin. The patients wererequired to fast (nothing to eat or drink except water) for at least 2 hr prior to 2 hr after dose andwere prohibited from receiving cation-containing compounds.
Sample collection and assay
Two to four blood samples for measurement of garenoxacin concentrations were taken(around 2 hr and 24 hr after dose). The blood samples were collected into vials containing EDTA
as an anticoagulant and were centrifuged to obtain plasma. Plasma samples were stored at -80ºCprior to subsequent analysis.
The plasma concentration of garenoxacin was determined by high-performance liquid chromatography (HPLC) (LC-20AD pump, SIL-20A auto-sampler, CTO-20A column oven, DGU20A3 degasser, CBM-20A system controller, SHIMADZU, Kyoto, Japan) according to themethod previously published12). In brief, the compound was processed by solid extraction method(Oasis HLB, Waters), then injected on to the column (Develosil ODS-HG-5, 4.6 mm I.D.×15 cm,
nomura science). The isocratic mobile phase consisted of acetonitrile, citrate buffer solution(pH 3.5), and distilled water (280 : 150 : 570, v/v/v). The ﬂow rate was set to 1.0 mL/min, and thedetection wavelength was 280 nm. The limits of quantiﬁcation based on garenoxacin standard
curves ranged from 0.03 to 10 μg/mL, with the coefﬁcient for each calibration curve was >0.999.
The intra- and inter-day coefﬁcients of variation (%CV) were 0.6 to 9.7% for plasma sample.
Calculation of pharmacokinetic parameters
Analyses are performed the ﬁrst order conditional estimation with interaction (FOCE-I) algorithm using by using NONMEM® software (version Ⅵ , double precision, level 1.0)17).
These parameters; clearance (CL), volume of distribution (Vd) and ﬁrst-order absorption rate
constant (Ka) were calculated by Bayesian estimation (ʻMAXEVAL=0ʼ and ʻPosthocʼ in the $ESTIMATION step) using current concentrations and previously reported model13). This model included creatinine clearance (Ccr), was ﬁxed 5 mL/min18), and serum creatinine (Scr) which was assessed at screening conducted within a week prior to garenoxacin dose, and body weight (WT) as
variation factors of CL, and WT and gender as Vd. In addition, the area under the curve (AUC),
peak plasma concentration (Cmax), elimination rate constant (Ke) and half-life (T1/2) were calculated based on an open one-compartment model.

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SafetyThe evaluation of drug safety included a review of treatment-emergent clinical adverse
events, clinical laboratory ﬁndings, and vital signs. Treatment-emergent clinical adverse eventswere deﬁned as illness, signs, or symptoms, independent of causality, which appeared or worsened after garenoxacin dose. Laboratory adverse events were deﬁned as results deemed clinicallysigniﬁcant by the investigator.
Statistical analysis
Statistical analysis was performed using JMP software (version 10; SAS Institute). The univariate relation between each independent variable and garenoxacin dosage was evaluated using at test for continuous variables. Pearsonʼs χ2 test for categorical variables was used to analyze categorized variables. Signiﬁcance was deﬁned as p<0.05.

Results
Subject demographics and baseline characteristics
Twenty subjects were enrolled and completed the study (Table 1). Ten patients were received
single 200 mg of garenoxacin dose and other 10 patients were received single 400 mg of garenoxacin dose. All subjectsʼ age ranged from 35 to 82 years, with an average of 68 years; their weights
ranged from 37.0 to 91.0 kg, with an average of 56.4 kg; 60% (n=12) were men and 40% (n=8)
were women. Based on the data of serum creatinine ranged from 3.46 to 13.50 mg/dL with the average 8.55 mg/dL. The demographic characteristics of the patients were similar across the different dosage groups. All subjects were evaluable for PK and safety analysis, with no subjects withdrawing from the study for any reason.
Pharmacokinetics
Observed garenoxacin concentrations versus the time following an oral dose of 200 and
400 mg, were presented in Figure 1. The ﬁnal data consisted of 60 plasma garenoxacin concentraTable 1. Background of patients enrolled in the study

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145（ 5 ）Fig. 1. Observed garenoxacin concentrations versus the time since administration of the single
dose of 200 mg (1A) and 400 mg (1B) of garenoxacin
Plotted symbols show the observed concentration data, and the line shows the results ofvisual predictive checks.

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Table 2. Pharmacokinetic parameters of garenoxacin

tions derived from 20 patients. All patients were taken 2 to 4 samples in 24 hr after garenoxacin
dose. Some predicted PK parameters are summarized in Table 2. There was no signiﬁcant difference in parameters, except AUC and Cmax, across the different dosage groups.
After single garenoxacin dosing, Cmax at the 200 and 400 mg doses were proportionally increased and were within the range of 2.9±0.6 and 6.0±1.0 μg/mL: p<0.001, respectively. The
corresponding values for AUC in plasma at the 200 and 400 mg doses showed similar tendency
and were within the ranges of 62.3±11.9 and 128.0±12.5 μg･hr/mL: p<0.001, respectively. The
mean half-life (T1/2) for garenoxacin appeared to be independent of dose (13.9±2.2 hr and 13.7±
1.9 hr after 200 and 400 mg dose: p=0.84) (Table 2).
SafetyThere were no serious adverse events, suspected to be related with garenoxacin. Oral dose of
garenoxacin (200 and 400 mg) were well tolerated.

Discussion
Garenoxacin is an oral ﬂuoroquinolone with potent antibacterial activity against common respiratory pathogens, including resistant strains, such as multidrug-resistant S. pneumoniae,
β-lactamase-producing M. catarrhalis, and BLNAR1〜8). As for quinolone antibacterial agents, thedrug AUC/MIC ratio is the PD measurement that generally has the strongest correlation with outcome in non-clinical infection models and infected patients19, 20). While the PD goal of therapy
differs for Gram-positive and Gram-negative microorganisms, the probability for attainment of
the target free AUC/MIC ratio estimated by Monte Carlo simulation was consistent with the actual efﬁcacy of the phase III study for each strain in Japan11, 13). And, previous studies have revealed that 400 mg once daily dose of garenoxacin for patients with normal to moderate renal

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147（ 7 ）dysfunction has favorable PK proﬁles to show adequate antibacterial activity against common
bacteria of respiratory infections10, 21, 22).
Garenoxacin PK analysis have showed that WT, Ccr, gender and age were associated withstatistically signiﬁcant effects on its clearance and volume of distribution11); approximately 20 to
50% of an administrated garenoxacin dose was excreted unchanged in the urine9). Additionally, invivo animal studies have revealed that excretion of garenoxacin and its metabolites involves not
only renal but also biliary pathways, while some studies have revealed that renal elimination is
the major pathway9, 12). Accordingly, there is a potential that PK of garenoxacin could be alteredin subjects with severe renal impairment. However, no PK proﬁle of garenoxacin in severe renal
failure patients has evaluated.
In current PK analysis, when stratiﬁed by two dosages (200 and 400 mg), Cmax and AUC
were proportionally increased to garenoxacin dose (Table 1). Additionally, compared to Japanese
healthy adult patients, both dose-level cohorts showed a decrease in mean Cmax (200 mg; 2.9 versus 4.9 μg/mL, 400 mg; 6.0 versus 7.4 μg/mL), while mean AUC increased in both hemodialysis
cohorts (200 mg; 62.3 versus 48.9 μg･hr/mL, 400 mg; 128.0 versus 100.7 μg･hr/mL)23). Garenoxacin AUC and Cmax were increased by 27% and lowered by 19%, respectively, in subjects withsever renal failure, compared with healthy volunteers. Mean CL of severe renal failure patientswas lower than that of patients with normal renal function. Hence, severe renal failure patientsdemonstrated an increase in AUC compared to those with normal renal function. On the otherhands, mean Vd of severe renal failure patients was bigger than that of patients with normal renal
function. The increased Vd of garenoxacin, might derive from decreasing of protein binding andenhancement of permeability into some tissue, leaded a decreasing of Cmax in severe renal failure
patients. The T1/2 for garenoxacin appeared to be independent of dose in our study (Table 2). And
the T1/2 was prolonged in subjects with sever renal impairment compared with healthy volunteers(13.7 versus 12.4 hr at 400 mg dose, respectively)23). These data indicated that a possible requirement for dose modiﬁcation with multiple dose.
Additionally, this study found that AUC after single oral garenoxacin dose (400 mg) for severe renal failure patients was approximately comparable with the AUC of healthy volunteers
after administrated 600 mg once daily dose23). GAJJAR, et al.9) also showed garenoxacin to be welltolerated when administered at doses up to 1200 mg for 14 days in healthy subjects. In subjects
who were given 1200 mg, the mean AUC values for garenoxacin ranged from 205 to 471 μg･hr/
mL. In the multiple dose study of garenoxacin, with a single exception, all adverse events, suchas headache, pharyngitis and dizziness, were mild or moderate in intensity and all were resolved
without treatment; there did not appear to be any relationship between the garenoxacin dose andeither the type or the frequency of adverse events, including abnormal clinical laboratory values.
The average AUC observed in our study did not exceed values previously shown to be well tolerated9). Hence, changes in garenoxacin exposure for patients with severe renal failure do not ap-

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pear to be clinically signiﬁcant.
Moreover, ﬂuoroquinolones have been reported that resistant mutants are selected exclusively within a concentration range (mutant selection window) between the mutant prevention
concentration (MPC) and MIC24, 25). To restrict resistant mutants, the optimal dose needs to be selected in view of the maintenance of a trough concentration above the MPC of common bacteria,such as S. pneumoniae, Staphylococcus aureus and H. inﬂuenzae, is <1 μg/mL, the probability of
having a trough concentration >1 μg/mL was computed at several doses13). In the mixed groups ofhealthy volunteers and moderate impair renal function, the probability for a trough garenoxacin
concentration above the MPC (1 μg/mL) base on the plasma concentration of garenoxacin above
the MPC is expected to exceed the MPC during the 400 mg treatment13). Our data also revealed
that garenoxacin concentrations at 24 hr after dose were higher than 1 μg/mL in subjects who
were given 400 mg (Fig. 1). Accordingly, patients with severe renal failure are also expected to
exceed the MPC with same dosage.
The limitations to our current study are that individual PK parameters were predicted basedon the existed PK model based on the Phase I to III data conducted in Japan13). However, themodel had been subjected to a bootstrap analysis; the result of mean parameter estimates obtained
from the bootstrap process (with 1,000 runs) were not statistically signiﬁcantly different from theestimates previously obtained with the original data set. Another limitation is that garenoxacin
was administrated as a single dose; thus, concentrations may not reﬂect those achieved with multiple dosing. However, previous study showed garenoxacin to be well tolerated when administered at doses up to 1200 mg for 14 days in healthy subjects9), while a decreased CL in sever renal
failure patients still suggested a possible requirement for dose modiﬁcation with multiple dose.
Finally, we did not evaluate the effects of hemodialysis on garenoxacin PK proﬁle. However, previous study suggested that, in subjects receiving dialysis, removal of garenoxacin from systemic
circulation was relatively insufﬁcient (1.5% to 11.5%). And no need for a supplemental dose of
garenoxacin after dialysis26), although it may be better to dose after hemodialysis for renal failure
patients. Hence, over all these PK analysis support the 400 mg once daily garenoxacin regimen as
effective treatment of respiratory tract infections, while the drug can exhibits modest an accumulation with multiple dosing that is consistent with its T1/2.
In summary, this is the ﬁrst study identiﬁed optimal garenoxacin dosing for severe renal failure patients receiving thrice-weekly hemodialysis. The PK of garenoxacin in the patients demonstrated a decrease in Cmax and an increase in AUC compared to patients with normal renal function. While a prolonged T1/2 in hemodialysis patients indicates a necessity for careful drug
administration and suggests a possible requirement for dose modiﬁcation when considering repetitive administration, 400 mg once-daily dose of garenoxacin, not 200 mg once-daily dose, was expected to be effective for severe renal failure patients infected with common bacteria of respiratory tract infections, as well as to prevent the emergence of resistant strain.

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149（ 9 ）Acknowledgement
We thank all clinicians assisted with the provision of data for this project.
Declaration of interest
This study is not funded any grants.

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