Pharmacokinetics and pharmacodynamics of multiple-dose intravenous nemonoxacin in healthy Chinese volunteers.

This study evaluated the safety and pharmacokinetic/pharmacodynamic profiles of nemonoxacin in healthy Chinese volunteers following multiple-dose intravenous infusion once daily for 10 consecutive days. The study was composed of two stages. In the open-label stage, 500 mg or 750 mg of nemonoxacin (n = 12 each) was administered at an infusion rate of 5.56 mg/min. In the second stage, with a randomized double-blind placebo-controlled design, 500, 650, or 750 mg of nemonoxacin (n = 16 in each cohort; 12 subjects received the drug and the other 4 subjects received the placebo) was given at an infusion rate of 4.17 mg/min. The results showed that, in the first stage, the maximal nemonoxacin concentrations (mean ± SD) at steady state (Cmax_ss) were 9.60 ± 1.84 and 11.04 ± 2.18 µg/ml in the 500-mg and 750-mg cohorts, respectively; the areas under the concentration-time curve at steady state (AUC0-24_ss) were 44.03 ± 8.62 and 65.82 ± 10.78 µg · h/ml in the 500-mg and 750-mg cohorts, respectively. In the second stage, the nemonoxacin Cmax_ss values were 7.13 ± 1.47, 8.17 ± 1.76, and 9.96 ± 2.23 µg/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively; the AUC0-24_ss values were 40.46 ± 9.52, 54.17 ± 12.10, and 71.34 ± 17.79 µg · h/ml in the 500-mg, 650-mg, and 750-mg cohorts, respectively. No accumulation was found after the 10-day infusion with any regimen. The drug was well tolerated. A Monte Carlo simulation indicated that the cumulative fraction of response of any dosing regimen was nearly 100% against Streptococcus pneumoniae. The probability of target attainment of nemonoxacin therapy was >98% when the MIC of nemonoxacin against S. pneumoniae was ≤1 mg/liter. It is suggested that all of the studied intravenous nemonoxacin dosing regimens should have favorable clinical and microbiological efficacies in future clinical studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

Safety, tolerability, and pharmacokinetics of intravenous nemonoxacin in healthy chinese volunteers.

Nemonoxacin (TG-873870) is a novel nonfluorinated quinolone with potent broad-spectrum activity against Gram-positive, Gram-negative, and atypical pathogens, including vancomycin-nonsusceptible methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant MRSA, quinolone-resistant Streptococcus pneumoniae, penicillin-resistant S. pneumoniae, and erythromycin-resistant S. pneumoniae. This first-in-human study was aimed at assessing the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin in healthy Chinese volunteers. The study comprised a randomized, double-blind, placebo-controlled, dose escalating safety and tolerability study in 92 subjects and a randomized, single-dose, open-label, 3-period Latin-square crossover pharmacokinetic study in 12 subjects. The study revealed that nemonoxacin infusion was well tolerated up to the maximum dose of 1,250 mg, and the acceptable infusion rates ranged from 0.42 to 5.56 mg/min. Drug-related adverse events (AEs) were mild, transient, and confined to local irritation at the injection site. The pharmacokinetic study revealed that after the administration of 250, 500, and 750 mg of intravenous nemonoxacin, the maximum plasma drug concentration (Cmax) values were 4.826 µg/ml, 7.152 µg/ml, and 11.029 µg/ml, respectively. The corresponding values for the area under the concentration-time curve from 0 to 72 hours (AUC0-72 h) were 17.05 µg · h/ml, 39.30 µg · h/ml, and 61.98 µg · h/ml. The mean elimination half-life (t1/2) was 11 h, and the mean cumulative drug excretion rate within 72 h ranged from 64.93% to 77.17%. Volunteers treated with 250 to 750 mg nemonoxacin exhibited a linear dose-response relationship between the AUC0-72 h and AUC0-∞. These findings provide further support for the safety, tolerability, and pharmacokinetic properties of intravenous nemonoxacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01944774.).

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.

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.

Pharmacokinetics of colistin methanesulfonate (CMS) in healthy Chinese subjects after single and multiple intravenous doses.

The high prevalence of extensively drug-resistant Gram-negative pathogens has forced clinicians to use colistin as a last-line therapy. Knowledge on the pharmacokinetics of colistin methanesulfonate (CMS), an inactive prodrug, and colistin has increased substantially; however, the pharmacokinetics in the Chinese population is still unknown due to lack of a CMS product in China. This study aimed to evaluate the pharmacokinetics of a new CMS product developed in China in order to optimise dosing regimens. A total of 24 healthy subjects (12 female, 12 male) were enrolled in single- and multiple-dose pharmacokinetic (PK) studies. Concentrations of CMS and formed colistin in plasma and urine were measured, and PK analysis was conducted using a non-compartmental approach. Following a single CMS dose [2.36 mg colistin base activity (CBA) per kg, 1 h infusion], peak concentrations (Cmax) of CMS and formed colistin were 18.0 mg/L and 0.661 mg/L, respectively. The estimated half-life (t1/2) of CMS and colistin were 1.38 h and 4.49 h, respectively. Approximately 62.5% of the CMS dose was excreted via urine within 24 h after dosing, whilst only 1.28% was present in the form of colistin. Following multiple CMS doses, colistin reached steady-state within 24 h; there was no accumulation of CMS, but colistin accumulated slightly (RAUC = 1.33). This study provides the first PK data in the Chinese population and is essential for designing CMS dosing regimens for use in Chinese hospitals. The urinary PK data strongly support the use of intravenous CMS for serious urinary tract infections.

Selective method for the determination of cefdinir in human plasma using liquid chromatography electrospray ionization tandam mass spectrometry.

A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of cefdinir in human plasma. After a simple protein precipitation using trichloracetic acid, the post-treatment samples were applied to a prepacked RP18 Waters SymmetryShield column interfaced with a triple quadrupole tandem mass spectrometer. Positive electrospray ionization was employed as the ionization source. The mobile phase consisted of methanol-water-formic acid (25:75:0.075, v/v/v). The analyte and I.S. cefaclor were both detected by the use of selected reaction monitoring mode. The method was linear in the concentration range of 5-2,000 ng/ml. The lower limit of quantification was 5 ng/ml. The intra- and inter-day relative standard deviation across three validation runs over the entire concentration range was less than 4.3%. The accuracy determined at three concentrations (36, 360 and 1,800 ng/ml for cefdinir) ranged from 99.6 to 106.7% in terms of recovery. The chromatographic run time for each plasma sample was less than 3 min. The method herein described was successfully applied for the evaluation of pharmacokinetic profiles of cefdinir capsule in 12 healthy volunteers.

[Study of pharmacokinetics/pharmacodynamics of levofloxacin].

OBJECTIVE: To evaluate the dosing regimens of levofloxacin. METHODS: The drug concentrations in serum and urine were assayed by HPLC method and the pharmacokinetic parameters were calculated after intravenous infusion of a single dose of 200 mg, 300 mg and 500 mg levofloxacin to healthy volunteers. The in vitro activity MIC of levofloxacin against 823 clinical isolates were determined and compared with other antimicrobial agents. Based on the above results, the PK/PD parameters C(max)/MIC and AUC/MIC were calculated and the dosing regimens of levofloxacin were proposed for infections caused by different pathogens. RESULTS: The results of clinical pharmacokinetic study showed that the C(max) of levofloxacin was 3.4 mg/L +/- 0.8 mg/L, 4.8 mg/L +/- 1.4 mg/L and 7.6 mg/L +/- 1.1 mg/L respectively, AUC(0-infinity) was 14.4 mg.h/L +/- 2.5 mg.h/L, 21.9 mg.h/L +/- 4.5 mg.h/L and 38.3 mg.h/L +/- 4.9 mg.h/L respectively, T(1)/2 beta was 6.2 h +/- 0.4 h, 6.4 h +/- 0.9 h and 6.5 h +/- 0.6 h respectively, and 69% +/- 5%, 69% +/- 6%, and 65% +/- 4% of the doses were excreted in urine within 24 h after intravenous infusion of a single dose of levofloxacin 200 mg, 300 mg and 500 mg. The in vitro pharmacodynamic study showed that levofloxacin was highly active against Hemolytic streptococcus and Moraxella catarrhalis. It was active against Streptococcus pneumoniae (including penicillin nonsusceptible strains), Hemophilus influenzae, methicillin-sensitive Staphylococcus aureus (MSSA), Klebsiella pneumoniae and Stenotrophomonas maltophilia. Levofloxacin also had good activity against Pseudomonas aeruginosa and K.pneumoniae. However, most of isolates of enterococcal spp. were resistant to levofloxacin. Above 50% of Escherichia coli isolates were resistant to levofloxacin. Based on the results of PK/PD parameters, the adequate dosing regimens of levofloxacin should be once daily 200 mg once daily of levofloxacin was expected to be effective for the treatment of infections caused by M. catarrhalis. The regimen of 300 mg once daily could be effective for the treatment of infections caused by Hemolytic streptococcus. 500 mg once daily of levofloxacin was expected to be effective for the treatment of respiratory tract infections caused by S. pneumoniae or H. influenzae. For treatment of respiratory tract infections and urinary tract infections caused by levofloxacin-susceptible organisms including K. pneumoniae, E. coli, P. aeruginosa, and S.maltophilia, 500 mg once daily of levofloxacin was needed to obtain good clinical efficacy. But PK/PD parameters predicted that 500 mg daily of levofloxacin was not effective for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and Enterococci. CONCLUSION: The proposed dosing regimens of levofloxacin based on PK/PD concepts are expected to provide good efficacy in clinical practice.

Establishment of norvancomycin fluorescence polarization immunoassay for therapeutic drug monitoring.

To establish a rapid and simple fluorescence polarization immunoassay method for determination of norvancomycin serum concentration, we collected 300 serum samples from the patients receiving norvancomycin in the hospitals localized in Shanghai, China. The drug concentrations were measured by the established HPLC method and FPIA with vancomycin kit. A FPIA algorithm for the determination of norvancomycin concentration was established according to the correlation between the FPIA and HPLC results. The methods and algorithm were validated in another 70 clinical samples. HPLC determination showed a good linear correlation within the range of 0.5-100 mg l(-1) of norvancomycin concentrations. The method was validated via extraction recovery, intra- and inter-day methodological recovery and stability of norvancomycin in serum. Correlation analysis between the measurements of HPLC and FPIA in 300 serum samples gave the linear regression equation: (concentration by HPLC)=0.760 × (concentration by FPIA)-0.577 (P<0.001, R(2)=0.982). An algorithm was derived from this correlation for measuring the serum norvancomycin concentrations with FPIA. When it was validated in additional 70 serum samples from patients, 'FPIA algorithm' showed good accuracy versus HPLC: 'FPIA algorithm'=0.93 (HPLC)+0.63, R(2)=0.962, and 94.3% of the results from FPIA algorithm fell within the range of -20%/+20% of HPLC. This algorithm developed in this study can be easily used for determination of norvancomycin using TDx analyzer with vancomycin kit indirectly. It may also be useful for norvancomycin therapeutic drug monitoring.

Permeability and concentration of levofloxacin in epithelial lining fluid in patients with lower respiratory tract infections.

The purpose of the study was to assess the bactericidal effects of a single oral dose of levofloxacin (LVFX) by examining the concentration of LVFX in alveolar epithelial lining fluid (ELF) from patients with lower respiratory tract infections (LRTI). Forty patients with LRTI took 500 mg of LVFX and then received a fiberoptic bronchoscopic procedure randomly 1, 4, 8, 12, or 24 hours following dosing. Bronchoalveolar lavage fluid and blood were collected at the time of the bronchopulmonary procedure, and the LVFX concentration was determined. The mean peak concentrations of LVFX in plasma and ELF were achieved at 1.5 hours (4.07 mg/L) and 1 hour (3.44 mg/L), respectively. The AUC(24h) samples were 50.12 mg . h/L and 34.51 mg . h/L, respectively. The permeability of LVFX, which was estimated based on the ratio of LVFX concentration in tissue fluids to that in plasma, was 0.78 on average across all time points. After a single dose of LVFX in patients with LRTI, the drug rapidly distributed into bronchopulmonary tissue, thereby suggesting this dose is capable of achieving the concentration in target organs required for bactericidal efficacy.