Limits...
Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections.

Tanigawara Y, Kaku M, Totsuka K, Tsuge H, Saito A - J. Infect. Chemother. (2013)

Bottom Line: As a result of the univariate logistic regression analysis, the larger the value of fAUC(0-24h)/MIC or fC max/MIC becomes, the higher the bacteriological efficacies.The eradication rates for fAUC(0-24h)/MIC ≥ 30 and for fC max/MIC ≥ 2 were 96.4% and 96.3%, respectively.Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK-PD simulations.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan, tanigawara-yusuke@umin.ac.jp.

ABSTRACT
An optimal dosage regimen of sitafloxacin was considered based on a pharmacokinetics and pharmacodynamics (PK-PD) analysis in patients with community-acquired respiratory tract infections (RTI). A population pharmacokinetic analysis of sitafloxacin was conducted using clinical data of five clinical pharmacology studies and one clinical PK-PD study in patients with RTIs. The pharmacokinetic parameters in individual patients were estimated by the Bayesian method to examine any correlation between pharmacokinetics and bacteriological efficacy. Efficacy data were obtained from the clinical PK-PD study, in which 50 or 100 mg sitafloxacin was administered twice daily for 7 days. In addition, an efficacy was simulated for a hypothetical dose regimen of 100 mg once daily. The fAUC(0-24h)/MIC and the fC max/MIC of sitafloxacin at a dose of 50 mg twice daily were 117.5 ± 78.0 and 7.3 ± 4.7 (mean ± SD), respectively. As a result of the univariate logistic regression analysis, the larger the value of fAUC(0-24h)/MIC or fC max/MIC becomes, the higher the bacteriological efficacies. The eradication rates for fAUC(0-24h)/MIC ≥ 30 and for fC max/MIC ≥ 2 were 96.4% and 96.3%, respectively. The PK-PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC(0-24h)/MIC ≥ 30 and fC max/MIC ≥ 2. The PK-PD parameters at the regimen of 50 or 100 mg twice daily in patients with RTIs reached the target values. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK-PD simulations.

Show MeSH

Related in: MedlinePlus

Serum concentration–time profiles of sitafloxacin in patients with respiratory tract infection (RTI) (left:open circles 100 mg, n = 28; filled circles 50 mg, n = 109; total 137 patients) and in subjects participating in clinical pharmacology studies (right: 25, 50, 100, or 200 mg; total 75 subjects)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3824208&req=5

Fig1: Serum concentration–time profiles of sitafloxacin in patients with respiratory tract infection (RTI) (left:open circles 100 mg, n = 28; filled circles 50 mg, n = 109; total 137 patients) and in subjects participating in clinical pharmacology studies (right: 25, 50, 100, or 200 mg; total 75 subjects)

Mentions: A total of 1,497 serum concentration data points from 212 subjects/patients were used for the PPK analysis. The serum concentration–time profiles after the last dose are shown in Fig. 1. In the forward selection step, the CLcr and disease status had a statistically significant effect on CLt/F, body weight and age on Vd/F, and age and fasting status on ka. All the selected covariates were confirmed to be statistically significant in the backward elimination step. However, the results of a bootstrap calculation showed that the effect of age on ka was not statistically significant, and the effect was removed from the final model. The PPK parameters for the final model, and the mean and 95 % CI of the parameters estimated using the bootstrap calculation, are shown in Table 2. The correlations between individual PK parameters estimated using the Bayesian method and covariates were examined. CLt/F appeared to be proportional to CLcr with the population mean ratio of 2.58 and was 1.27 times higher in healthy volunteers than patients with RTIs. Vd/F was correlated with body weight in a proportional manner, and the slope for the elderly patients differed from that for nonelderly patients. The ka values after fasting were higher than those after feeding.Fig. 1


Population pharmacokinetics and pharmacodynamics of sitafloxacin in patients with community-acquired respiratory tract infections.

Tanigawara Y, Kaku M, Totsuka K, Tsuge H, Saito A - J. Infect. Chemother. (2013)

Serum concentration–time profiles of sitafloxacin in patients with respiratory tract infection (RTI) (left:open circles 100 mg, n = 28; filled circles 50 mg, n = 109; total 137 patients) and in subjects participating in clinical pharmacology studies (right: 25, 50, 100, or 200 mg; total 75 subjects)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824208&req=5

Fig1: Serum concentration–time profiles of sitafloxacin in patients with respiratory tract infection (RTI) (left:open circles 100 mg, n = 28; filled circles 50 mg, n = 109; total 137 patients) and in subjects participating in clinical pharmacology studies (right: 25, 50, 100, or 200 mg; total 75 subjects)
Mentions: A total of 1,497 serum concentration data points from 212 subjects/patients were used for the PPK analysis. The serum concentration–time profiles after the last dose are shown in Fig. 1. In the forward selection step, the CLcr and disease status had a statistically significant effect on CLt/F, body weight and age on Vd/F, and age and fasting status on ka. All the selected covariates were confirmed to be statistically significant in the backward elimination step. However, the results of a bootstrap calculation showed that the effect of age on ka was not statistically significant, and the effect was removed from the final model. The PPK parameters for the final model, and the mean and 95 % CI of the parameters estimated using the bootstrap calculation, are shown in Table 2. The correlations between individual PK parameters estimated using the Bayesian method and covariates were examined. CLt/F appeared to be proportional to CLcr with the population mean ratio of 2.58 and was 1.27 times higher in healthy volunteers than patients with RTIs. Vd/F was correlated with body weight in a proportional manner, and the slope for the elderly patients differed from that for nonelderly patients. The ka values after fasting were higher than those after feeding.Fig. 1

Bottom Line: As a result of the univariate logistic regression analysis, the larger the value of fAUC(0-24h)/MIC or fC max/MIC becomes, the higher the bacteriological efficacies.The eradication rates for fAUC(0-24h)/MIC ≥ 30 and for fC max/MIC ≥ 2 were 96.4% and 96.3%, respectively.Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK-PD simulations.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan, tanigawara-yusuke@umin.ac.jp.

ABSTRACT
An optimal dosage regimen of sitafloxacin was considered based on a pharmacokinetics and pharmacodynamics (PK-PD) analysis in patients with community-acquired respiratory tract infections (RTI). A population pharmacokinetic analysis of sitafloxacin was conducted using clinical data of five clinical pharmacology studies and one clinical PK-PD study in patients with RTIs. The pharmacokinetic parameters in individual patients were estimated by the Bayesian method to examine any correlation between pharmacokinetics and bacteriological efficacy. Efficacy data were obtained from the clinical PK-PD study, in which 50 or 100 mg sitafloxacin was administered twice daily for 7 days. In addition, an efficacy was simulated for a hypothetical dose regimen of 100 mg once daily. The fAUC(0-24h)/MIC and the fC max/MIC of sitafloxacin at a dose of 50 mg twice daily were 117.5 ± 78.0 and 7.3 ± 4.7 (mean ± SD), respectively. As a result of the univariate logistic regression analysis, the larger the value of fAUC(0-24h)/MIC or fC max/MIC becomes, the higher the bacteriological efficacies. The eradication rates for fAUC(0-24h)/MIC ≥ 30 and for fC max/MIC ≥ 2 were 96.4% and 96.3%, respectively. The PK-PD target values of sitafloxacin for the treatment of mild to moderate RTIs were considered to be fAUC(0-24h)/MIC ≥ 30 and fC max/MIC ≥ 2. The PK-PD parameters at the regimen of 50 or 100 mg twice daily in patients with RTIs reached the target values. Furthermore, a 100 mg once-daily regimen was expected to show similar efficacy based on the PK-PD simulations.

Show MeSH
Related in: MedlinePlus