Introduction
Sitafloxacin, ((−)-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(
1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid), is a fluoroquinolone antimicrobial agent developed by Daiichi Sankyo Co., Ltd. in Japan. Sitafloxacin has a broad-spectrum antimicrobial activity against aerobic, anaerobic, gram-positive, and gram-negative bacteria, as well as
Mycoplasma spp. and
Chlamydia spp. It also has a higher antimicrobial activity than other quinolones against many pathogenic organisms [
1,
2].
According to several clinical pharmacology studies that have been already reported [
3‐
6], sitafloxacin was rapidly absorbed after oral administration and has a high bioavailability (89 %). The serum concentration of sitafloxacin increased in a dose-proportional manner between 25 and 200 mg in Japanese healthy male subjects. The cumulative urinary excretion of unchanged sitafloxacin within 48 h after administration is approximately 70 % of the dose in Japanese subjects. The renal clearance of sitafloxacin was approximately 200 ml/min, which indicates both glomerular filtration and tubular secretion are involved in the urinary elimination of sitafloxacin [
7].
Recently, evidence of a correlation between the pharmacokinetics (PK) and the pharmacodynamics (PD) of antimicrobial agents has been accumulating [
8‐
10]. These studies have reported that a clinical outcome might be predicted by the parameter indicated by the correlation between a drug concentration in the plasma/serum and the minimum inhibitory concentration (MIC) of the drug against a pathogen. Indices based on PK and PD characteristics often differ according to antimicrobial class. For example, fluoroquinolones are known as concentration-dependent agents, and bacterial eradication can be obtained by fluoroquinolones when the ratio of the area under the plasma/serum concentration–time curve (AUC) to the MIC is around 25–30 for gram-positive bacteria and around 100–125 for gram-negative bacteria [
8,
11‐
14].
We conducted the clinical PK–PD study as phase III, and the clinical efficacy and safety of sitafloxacin have been previously reported [
15]. As a result of a rough PK–PD analysis in the report, both the clinical and bacteriological efficacy of sitafloxacin for the treatment of respiratory tract infections (RTIs) were shown to be more than 90 % when either of the following target values was achieved, AUC
0–24h/MIC ≥ 100 or
C
max/MIC ≥ 5. In the present report, we constructed a population PK (PPK) model of sitafloxacin using the data of RTI patients in the clinical PK–PD study and of non-patients in five clinical pharmacology studies. The PK parameters in individual patients were determined using the Bayesian method. In addition, the correlation between clinical dose regimens and the bacteriological efficacy of sitafloxacin was examined using a PK–PD analysis.
All the clinical studies described in this report were conducted in compliance with the ethical principles originating in the Declaration of Helsinki, and in compliance with the Ethics Committees of each participating hospital or institute, informed consent regulations, and the ICH Good Clinical Practices Guideline. In addition, these protocols were approved by the health authority and the institutional review board or ethics committee.
Discussion
In the present study, we conducted a PPK analysis of sitafloxacin in patients with RTIs before an exposure–response analysis. We determined the serum concentrations of sitafloxacin in patients with RTIs enrolled in a clinical PK–PD study and analyzed these data together with data from non-patients including healthy subjects, renal-impaired subjects, and elderly subjects. The results suggested that CL
cr, body weight, age, disease status, and fasting status influenced the PK of sitafloxacin. The CL
cr considerably affected the serum concentration of sitafloxacin, whereas other factors, such as body weight, age, and fasting status, had only slight effects on
C
max and
T
max. This finding is consistent with the fact that the cumulative urinary excretion of unchanged drug after oral administration amounts to approximately 70 % in Japanese subjects [
4]. Levofloxacin is primarily eliminated through the kidneys, similar to sitafloxacin, and patients with renal impairment are known to have increased serum concentration levels of these drugs [
18,
19]. Therefore, a reduction in the dose or frequency of administration is recommended in renal-impaired patients.
After the repeated oral administration of sitafloxacin at a dose of 50 or 100 mg twice daily in patients with RTIs, the
C
max was 0.57 and 1.17 mg/l, respectively, and the AUC
0–24h was 9.38 and 17.16 mg·h/l, respectively. The
C
max and AUC
0–inf in healthy Japanese individuals treated with a 50 mg single dose of sitafloxacin were 0.51 ± 0.14 mg/l and 2.62 ± 0.53 mg·h/l, respectively [
4]. The AUC
0–24h value that was calculated in this study was two times higher than the AUC value per dosing interval (AUC
0–tau). However, taking this into consideration, the AUC of patients with RTIs was higher than that of healthy individuals. Renal function and creatinine clearance are known to decline with age [
20]. Therefore, the elimination of drugs by renal excretion is often delayed and, consequently, an increase in the serum level is observed in elderly patients. Many elderly patients with declined renal function were enrolled in the clinical PK–PD study. Thus, the results for these subjects might have led to the higher serum concentrations of sitafloxacin compared with the results in healthy individuals.
For fluoroquinolones,
fC
max/MIC and
fAUC/MIC are used to predict an antibacterial effect and the emergence of antibacterial resistance [
21,
22]. We previously reported the PK–PD parameters in patients with RTIs receiving 50 or 100 mg of sitafloxacin twice daily [
15]. In this previous study, the eradication rate of causative organisms increased when the
C
max/MIC was more than 5 and/or the AUC
0–24h/MIC was more than 100. In the present study, we evaluated the PK–PD target value and the attainment rate of this target when 50 or 100 mg of sitafloxacin was simulated twice daily based on the results of the clinical PK–PD study. A
fC
max/MIC value ≥ 2 and/or a
fAUC
0–24h/MIC value ≥ 30 were suggested to be necessary to eradicate causative organisms in patients with RTIs. When threshold values of
C
max/MIC (5) and AUC
0–24h/MIC (100) are converted to
fC
max/MIC and
fAUC
0–24h/MIC using unbound fraction of serum protein binding (0.388) of sitafloxacin, the threshold
fC
max/MIC and
fAUC
0–24h/MIC values are calculated as 2 and 39, respectively. These values are consistent with the present results for the target values of
fC
max/MIC (2) and
fAUC
0–24h/MIC (30). Actually, the 50 mg twice-daily regimen was effective for the treatment of mild to moderate community-acquired RTIs, in addition to the 100 mg twice-daily regimen. Furthermore, a 100 mg once-daily regimen of sitafloxacin was also suggested to have an efficacy similar to that of the 50 mg twice-daily regimen, based on the PK–PD simulation results.
Sitafloxacin has strong antimicrobial activity against a broad range of gram-positive and gram-negative bacteria including anaerobic bacteria, as well as against atypical pathogens. The MIC
90 of sitafloxacin against
S. pneumoniae,
H. influenzae, and
Moraxella catarrhalis, which are major pathogens in respiratory tract infections, are < 0.06, < 0.01, and < 0.01 mg/l, respectively [
2]. Furthermore, sitafloxacin inhibits the activity of both the DNA gyrase and the topoisomerase IV enzymes. The inhibitory activity against these enzymes was greater than that of comparative fluoroquinolones [
23]. Therefore, we consider that sitafloxacin administered orally at a dose of even 50 mg twice daily is likely to be adequately effective against major pathogens causing RTIs.
In conclusion, we conducted PPK and PK–PD analyses to estimate PK–PD parameters of sitafloxacin in patients with RTIs. The required PK–PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC0–24h/MIC ≥ 30 and fC
max/MIC ≥ 2. The PK–PD parameters with 50 or 100 mg twice daily in major pathogens of RTIs reached these PK–PD target values for Staphylococcus aureus, Streptococcus pneumoniae, M. catarrhalis, H. influenzae, and partially for Klebsiella pneumoniae and Pseudomonas aeruginosa. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy because this regimen also reached the target values based upon the PK–PD simulations.
Acknowledgments
The PK–PD advisory committee organized the phase III clinical study. The committee members were Atsushi Saito (Sasebo Dojin-kai Hospital, Nagasaki, Japan), Mitsuo Kaku (Tohoku University Graduate School of Medicine, Sendai, Japan), Kyoichi Totsuka (Tokyo Women’s Medical University, Tokyo, Japan), and Yusuke Tanigawara (Keio University School of Medicine, Tokyo, Japan). We wish to acknowledge the following investigators who enrolled patients in the clinical PK–PD study: Yasuhiro Yamazaki, Masafumi Kamachi, Masumi Tomizawa, Mitsuhide Ohmichi, Hiroyuki Sugawara, Bine Uchiyama, Kazuo Sato, Hideki Ikeda, Kazuo Oshimi, Yoshitaka Nakamori, Megumi Hiida, Hideaki Nagai, Yuji Watanuki, Hiroshi Takahashi, Yasuo Arai, Shigeki Odagiri, Teruaki Yoshioka, Hiroshi Hayakaawa, Kingo Chida, Hidenori Nakamura, Atsushi Kawabata, Naoki Fujimura, Hirotaka Yasuba, Niro Okimoto, Hirohide Yoneyama, Hiroki Hara, Kohichiro Yoshida, Masayoshi Kawanishi, Masao Kuwabara, Hiroyuki Nakamura, Sadako Sueyasu, Takeharu Koga, Takashi Mitsui, Shinichiro Hayashi, Katsunori Yanagihara, Takashi Shinzato, Masao Tateyama, Tomohiko Ishimine, and Masato Tohyama. This paper was presented in part at the 21st European Congress of Clinical Microbiology and Infectious Diseases/27th International Congress of Chemotherapy and Infection, Milano, Italy, 2011. We thank Daiichi Sankyo Co., Ltd., Tokyo, Japan, for providing editorial assistance. This work was sponsored by Daiichi Sankyo Co., Ltd, Tokyo, Japan.