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Population pharmacokinetics of oral levofloxacin 500 mg once-daily dosage in community-acquired lower respiratory tract infections: results of a prospective multicenter study in China.
J Infect Chemother. 2009 Oct; 15(5):293-300.JI

Abstract

This study aimed to explore the pharmacokinetic features of levofloxacin (LVFX) in Chinese patients with infections and to confirm oral LVFX 500 mg once daily as an optimal treatment regimen based on pharmacokinetic-pharmacodynamic (PK-PD) analysis. A total of 1052 plasma samples from 164 Chinese adult patients with community acquired lower respiratory tract infections (CALRTIs) and 18 healthy volunteers were used for population PK analysis. LVFX 500-mg tablets were given once daily. A nonlinear mixed effects model (NONMEM) program was used for population PK model-building and a two-compartment model with first-order absorption process was established. Creatinine clearance (CL(cr)) and body weight were identified as intrinsic factors which significantly affected oral clearance (CL(t)/F) and the apparent volume of distribution of the central compartment (V1/F), respectively. The final model is described as follows: CL(t)/F (l/h) = (8.97 + 0.917 x (CL(cr) (ml/min)-100.92) x 60/1000) x exp (eta(CLt/F)). V1/F (l) = (85.3 + 1.22 x (weight (kg)-60.75)) x exp (eta(V1/F)). Q/F (l/h) = 0.351. V2/F (l) = 6.81. k(a) (h(-1)) = 1.44 x exp(eta(ka)). Based on the population PK model, mean C(max) and AUC(0-24h) in CALRTI patients were estimated as 5.13 microg/ml and 58.98 microg.h/ml, respectively. A subgroup analysis showed that patients with mild renal dysfunction (50 ml/min < or = CL(cr) < 80 ml/min) had 34% higher AUC(0-24h) values compared to patients with normal renal function (CL(cr) > or = 80 ml/min). Postmodeling simulation using final population PK estimates also showed that C(max) and AUC(0-24h) increased markedly in patients with severe renal dysfunction. The results indicate that LVFX dosage adjustment should be individualized on the basis of the CL(cr), especially in those with CL(cr) less than 50 ml/min. None of the PK parameters had any correlation with the occurrence of adverse events. PK-PD analysis indicated that, in patients treated with LVFX 500 mg once daily, the AUC(0-24h)/MIC ratio exceeded the target for those major CALRTI pathogens isolated. In addition, the C(max)/MIC ratio reached 5 for Streptococcus pneumoniae, indicating that the emergence of LVFX-resistant S. pneumoniae could be prevented during the therapy with this dosage regimen. These results demonstrate that oral LVFX 500 mg once daily has favorable PK parameters and PK-PD features in patients with CALRTIs, and the results strongly support this dosage regimen for the treatment of CALRTI.

Authors+Show Affiliations

Institute of Antibiotics, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Lu, Shanghai 200040, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19856067

Citation

Zhang, Jing, et al. "Population Pharmacokinetics of Oral Levofloxacin 500 Mg Once-daily Dosage in Community-acquired Lower Respiratory Tract Infections: Results of a Prospective Multicenter Study in China." Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy, vol. 15, no. 5, 2009, pp. 293-300.
Zhang J, Xu JF, Liu YB, et al. Population pharmacokinetics of oral levofloxacin 500 mg once-daily dosage in community-acquired lower respiratory tract infections: results of a prospective multicenter study in China. J Infect Chemother. 2009;15(5):293-300.
Zhang, J., Xu, J. F., Liu, Y. B., Xiao, Z. K., Huang, J. A., Si, B., Sun, S. H., Xia, Q. M., Wu, X. J., Cao, G. Y., Shi, Y. G., & Zhang, Y. Y. (2009). Population pharmacokinetics of oral levofloxacin 500 mg once-daily dosage in community-acquired lower respiratory tract infections: results of a prospective multicenter study in China. Journal of Infection and Chemotherapy : Official Journal of the Japan Society of Chemotherapy, 15(5), 293-300. https://doi.org/10.1007/s10156-009-0714-8
Zhang J, et al. Population Pharmacokinetics of Oral Levofloxacin 500 Mg Once-daily Dosage in Community-acquired Lower Respiratory Tract Infections: Results of a Prospective Multicenter Study in China. J Infect Chemother. 2009;15(5):293-300. PubMed PMID: 19856067.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Population pharmacokinetics of oral levofloxacin 500 mg once-daily dosage in community-acquired lower respiratory tract infections: results of a prospective multicenter study in China. AU - Zhang,Jing, AU - Xu,Jun-Fang, AU - Liu,Yan-Bin, AU - Xiao,Zu-Ke, AU - Huang,Jian-An, AU - Si,Bin, AU - Sun,Sheng-Hua, AU - Xia,Qian-Ming, AU - Wu,Xiao-Jie, AU - Cao,Guo-Ying, AU - Shi,Yao-Guo, AU - Zhang,Ying-Yuan, Y1 - 2009/10/24/ PY - 2009/04/28/received PY - 2009/07/07/accepted PY - 2009/10/27/entrez PY - 2009/10/27/pubmed PY - 2010/1/15/medline SP - 293 EP - 300 JF - Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy JO - J Infect Chemother VL - 15 IS - 5 N2 - This study aimed to explore the pharmacokinetic features of levofloxacin (LVFX) in Chinese patients with infections and to confirm oral LVFX 500 mg once daily as an optimal treatment regimen based on pharmacokinetic-pharmacodynamic (PK-PD) analysis. A total of 1052 plasma samples from 164 Chinese adult patients with community acquired lower respiratory tract infections (CALRTIs) and 18 healthy volunteers were used for population PK analysis. LVFX 500-mg tablets were given once daily. A nonlinear mixed effects model (NONMEM) program was used for population PK model-building and a two-compartment model with first-order absorption process was established. Creatinine clearance (CL(cr)) and body weight were identified as intrinsic factors which significantly affected oral clearance (CL(t)/F) and the apparent volume of distribution of the central compartment (V1/F), respectively. The final model is described as follows: CL(t)/F (l/h) = (8.97 + 0.917 x (CL(cr) (ml/min)-100.92) x 60/1000) x exp (eta(CLt/F)). V1/F (l) = (85.3 + 1.22 x (weight (kg)-60.75)) x exp (eta(V1/F)). Q/F (l/h) = 0.351. V2/F (l) = 6.81. k(a) (h(-1)) = 1.44 x exp(eta(ka)). Based on the population PK model, mean C(max) and AUC(0-24h) in CALRTI patients were estimated as 5.13 microg/ml and 58.98 microg.h/ml, respectively. A subgroup analysis showed that patients with mild renal dysfunction (50 ml/min < or = CL(cr) < 80 ml/min) had 34% higher AUC(0-24h) values compared to patients with normal renal function (CL(cr) > or = 80 ml/min). Postmodeling simulation using final population PK estimates also showed that C(max) and AUC(0-24h) increased markedly in patients with severe renal dysfunction. The results indicate that LVFX dosage adjustment should be individualized on the basis of the CL(cr), especially in those with CL(cr) less than 50 ml/min. None of the PK parameters had any correlation with the occurrence of adverse events. PK-PD analysis indicated that, in patients treated with LVFX 500 mg once daily, the AUC(0-24h)/MIC ratio exceeded the target for those major CALRTI pathogens isolated. In addition, the C(max)/MIC ratio reached 5 for Streptococcus pneumoniae, indicating that the emergence of LVFX-resistant S. pneumoniae could be prevented during the therapy with this dosage regimen. These results demonstrate that oral LVFX 500 mg once daily has favorable PK parameters and PK-PD features in patients with CALRTIs, and the results strongly support this dosage regimen for the treatment of CALRTI. SN - 1437-7780 UR - https://www.unboundmedicine.com/medline/citation/19856067/Population_pharmacokinetics_of_oral_levofloxacin_500_mg_once_daily_dosage_in_community_acquired_lower_respiratory_tract_infections:_results_of_a_prospective_multicenter_study_in_China_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1341-321X(09)70662-2 DB - PRIME DP - Unbound Medicine ER -