Beining Guo

Safety and clinical pharmacokinetics of nemonoxacin, a novel non-fluorinated quinolone, in healthy Chinese volunteers following single and multiple oral doses.

AbstractBackground: Nemonoxacin, a novel C-8-methoxy non-fluorinated quinolone, is currently being developed in oral and intravenous formulations. It exhibits potent antibacterial activities against Gram-positive, Gram-negative and atypical pathogens, especially methicillin-resistant Staphylococcus aureus. The first-in-human study of a nemonoxacin capsule was conducted in a Western population. This current study was the first investigation on the clinical pharmacokinetics (PK) of nemonoxacin in a Chinese population, and was designed to determine PK data in a Chinese population and investigate the dose regimen for future clinical use. Objective: The objective of this study was to evaluate the PK profile of nemonoxacin as well as its safety and tolerability in healthy Chinese volunteers following single and multiple oral doses. Methods: The first part of the study was a double-blind, placebo-controlled, sequential ascending single-dose safety and tolerability study. In each cohort, two subjects received a placebo and six received single oral doses of nemonoxacin 125, 250, 500, 750 or 1000 mg. In the second part, the single-dose PK study, three dose levels (250, 500 and 750 mg) of nemonoxacin were administered orally to 12 healthy Chinese volunteers (male: female = 1:1) under fasting conditions in a crossover manner. The same volunteers received orally an additional dose of 500 mg under fed conditions after a 7-day washout. In the third part, the multiple-dose PK study, 24 subjects received 500 or 750 mg of nemonoxacin orally once daily for 10 consecutive days. Within each cohort, 12 subjects (male: female = 1:1) received the same dose level of nemonoxacin under fasting conditions. The PK profiles, safety and tolerability, and food and sex effects were evaluated. Results: No severe or serious adverse events (AEs) occurred in this study, and no clinically significant abnormalities were noted in the vital signs or on physical examination. Notable AEs, mainly nausea and rash with or without pruritus, were mild and resolved spontaneously. Most laboratory AEs were mild and transient and the subjects recovered without treatment. Nemonoxacin was found to be rapidly absorbed, with peak plasma concentrations (Cmax) attained 1–2 hours after administration. The Cmax and area under the concentration-time curve from time zero to infinity (AUC∞) were dose-proportional after single oral doses. The elimination half-life was 10–12 hours. Nemonoxacin was excreted primarily in urine, with a recovery of intact nemonoxacin of 60–70% of the dose over 72 hours. Food had a significant effect on the rate and extent of absorption (p<0.001), increasing the time to reach Cmax from 1.14 to 3.64 hours and reducing Cmax by 34% and AUC∞ by 18%, while a sex effect was not found. Cmax and AUC∞ were similar between the single-dose and multiple-dose PK studies. The multiple-dose PK data suggested no drug accumulation in healthy subjects. Conclusion: Nemonoxacin exhibited a linear PK profile in the 250–750 mg dose range with moderate food effects. There was no accumulation following consecutive administration for 10 days. The PK and safety profiles of nemonoxacin in Chinese subjects support evaluation of once-daily dosing in the future development of this agent.

Pathogenic Implication of a Fibrinogen-Binding Protein of Staphylococcus epidermidis in a Rat Model of Intravascular-Catheter-Associated Infection

ABSTRACT The involvement of Fbe, a fibrinogen-binding protein of Staphylococcus epidermidis, in the pathogenesis of catheter-associated infection was investigated. An fbe (gene encoding Fbe protein) mutant was constructed by allelic replacement, wherein an erythromycin resistance gene replaced a portion of the A region of fbe. Meanwhile, a rat central venous catheter (CVC) infection model was established to assess the importance of Fbe in the pathogenesis of CVC-associated infection due to S. epidermidis. Fbe-positive S. epidermidis strain HB was significantly more likely to cause a CVC-associated infection resulting in bacteremia and metastatic disease than its isogenic Fbe-deficient mutant (100% versus 20%, P < 0.01). These results confirm the importance of adherence associated with Fbe in the pathogenesis of CVC-associated infection caused by S. epidermidis.

Liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of cefoperazone and sulbactam in plasma and its application to a pharmacokinetic study

A rapid and highly sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for simultaneous determination of cefoperazone sodium and sulbactam sodium in human plasma was developed. The analytes and internal standard (IS), cefuroxime sodium, were extracted from human plasma via liquid-liquid extraction with ethyl acetate and separated on a Waters Xterra C18 column within 3.5 min. Quantitation was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique, operating in selected reaction monitoring (SRM) and negative ion mode. The precursor to product ion transitions monitored for cefoperazone, sulbactam and IS were m/z 644.1→528.0, 232.1→140.0, and 423.0→362.0, respectively. The assay was validated in the linear range of 0.1-20 μg/mL for cefoperazone and 0.02-4 μg/mL for sulbactam. The intra- and inter-day precisions (CV%) were within 8.39% for each analyte. The recoveries were greater than 87.3% for cefoperazone and 87.2% for sulbactam. Each analyte was found to be stable during all sample storage, preparation and analytical procedures. The method was successfully applied in a pharmacokinetic study of Sulperazon injection in six hospital-acquired pneumonia (HAP) patients.

A liquid chromatography–tandem mass spectrometry assay for the determination of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, in human plasma and urine and its application to a single-dose pharmacokinetic study in healthy Chinese volunteers

Nemonoxacin (TG-873870) is a novel C-8-methoxy nonfluorinated quinolone with higher activity than ciprofloxacin, levofloxacin and moxifloxacin against Gram-positive pathogens including methicillin-susceptible or methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae with various resistant phenotypes. A rapid, sensitive and selective liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated to determine the concentration of nemonoxacin in human plasma and urine. Protein precipitation and liquid-liquid extraction were employed for plasma and urine sample preparations, respectively, and extract was then injected into the system. Separation was performed on a C(18) reversed-phase column using acetonitrile-0.1% formic acid as a mobile phase. Both analyte and internal standard (gatifloxacin) were determined using electrospray ionization and the MS data acquisition via the selected reaction monitoring in positive-ion mode. The lower limit of quantification was 5 ng/mL and the calibration curves were linear in the concentration range of 5-1000 ng/mL. The accuracy, precision, selectivity, linearity, recovery, matrix effect and stability were validated for TG-873870 in human plasma and urine. The method was successfully applied to a pharmacokinetic study enrolling 12 healthy Chinese volunteers administered nemonoxacin malate capsules.

Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization

The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen.

Quantification of levornidazole and its metabolites in human plasma and urine by ultra-performance liquid chromatography–mass spectrometry

We developed and validated an ultra-performance liquid chromatographic (UPLC) method coupled with atmospheric pressure chemical ionization (APCI) mass spectrometry for simultaneous determination of levornidazole and its first-pass metabolites, l-chloro-3-(2-hydroxymethyl-5-nitro-l-imidazolyl)-2-propanol (Ml), 2-methyl-5-nitroimidazole (M2) and 3-(2-methyl-5-nitro-1-imidazolyl)-1,2-propanediol (M4), in human plasma and urine. The biological samples were pretreated by protein precipitation and liquid-liquid extraction and analyzed using an ACQUITY UPLC CSH C18 column (2.1×50 mm, 1.7 μm) and a QTRAP mass spectrometer in multiple reaction monitoring mode via APCI. Acetonitrile and 0.1% formic acid in water was used as the mobile phase in gradient elution at a flow rate of 0.6 mL/min. The lower limit of quantification of this method was 0.0100, 0.00500, 0.0200 and 0.00250 μg/mL for levornidazole, M1, M2 and M4, respectively. The linear calibration curves were obtained for levornidazole, M1, M2, and M4 over the range of 0.0100-5.00, 0.00500-2.50, 0.0200-10.0 and 0.00250-1.25 μg/mL, respectively. The intra- and inter-batch precision was less than 12.2% in plasma and less than 10.8% in urine. The intra- and inter-batch accuracy was 87.8-105.7% in plasma and 92.8-109.2% in urine. The mean recovery of levornidazole, M1, M2 and M4 was 91.1-105.1%, 95.8-103.8%, 87.8-96.8%, 96.8-100.6% from plasma and 96.0-100.9%, 96.9-107.9%, 95.1-102.7%, 103.7-105.9% from urine respectively. This method was validated under various conditions, including room temperature, freeze-thaw cycles, long-term storage at -40 ± 5°C, after pretreatment in the autosampler (at 10°C), and 10- and 100-fold dilution. This newly established analytical method was successfully applied in a pharmacokinetic study following single intravenous infusion of levornidazole in 24 healthy Chinese subjects.

Improved pharmacokinetic profile of levornidazole following intravenous infusion of 750 mg every 24 h compared with 500 mg every 12 h in healthy Chinese volunteers

Levornidazole is the levo-isomer of ornidazole with similar anti-anaerobic activity and lower central neurotoxicity compared with ornidazole. This open-label, parallel, randomised, multidose trial was conducted to compare the pharmacokinetics and safety of levornidazole following intravenous (i.v.) infusion 750mg every 24h (q24h) (test group, 12 subjects) versus 500mg every 12h (q12h) (reference group, 12 subjects) for 7 days in healthy Chinese volunteers. Following i.v. infusion for 7 days, the test group showed a 33.8% lower accumulation ratio (AR) and a 45.0% higher volume of distribution of levornidazole than the reference group. The cumulative urinary excretion rate of levornidazole during the 0-72h period (Ae0-72) was 16.6±20.9% in the test group and 24.2±5.7% in the reference group. The metabolite M1/parent and M4/parent ratios were, respectively, 2.18±0.77% and 2.94±0.37% in test group and 3.15±1.09% and 3.18±0.34% in the reference group. The Ae0-72 of M1, M2 and M4 were all <10% in both groups. Both regimens were well tolerated. Drug-related adverse events were generally transient and were mild or moderate in severity. These findings support the recommendation of i.v. infusion of levornidazole 750mg q24h in clinical practice, which shows a lower AR and similar safety compared with the conventional 500mg q12h regimen. [Chinese Clinical Trial Registry identifier: ChiCTR-IPR-14005574.].

Safety, Tolerability, and Pharmacokinetics of Intravenous Nemonoxacin in Healthy Chinese Volunteers

ABSTRACT 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.)

Development of an Liquid Chromatography–Tandem Mass Spectrometry Method for the Determination of Amoxicillin in Broth Medium and its Application to an In Vitro Pharmacokinetic and Pharmacodynamic Model

A simple, rapid and highly sensitive liquid chromatographic-tandem mass spectrometry (LC-MS-MS) method has been developed and validated for the quantification of amoxicillin in broth-a liquid bacterial culture medium. After appropriate dilution with ultrapure water, broth samples containing amoxicillin and an internal standard (IS) were extracted by acetonitrile and dichloromethane. The extract was injected into the system. The analyte and the IS were separated by a prepacked Atlantis C18 column using acetonitrile-0.1% formic acid as a mobile phase and detected by selected reaction monitoring in electrospray ionization positive ion mode. The calibration curve of amoxicillin was linear over the concentration range of 0.05-20.00 µg/mL. The mean recovery of amoxicillin from broth was 71.7%, and the intra- and interday precision and accuracies of the assay were within 10%. Amoxicillin was stable in broth for 12 h at room temperature (24°C), for 6.5 months at -80°C and for 24 h after preparation in an autosampler at room temperature. It has been successfully applied to an in vitro pharmacokinetic (PK) and pharmacodynamic (PD) model in which the broth is used for bacterial growth. The method provides high-throughput biological analysis to facilitate the in vitro PK and PD model of amoxicillin.

Population Pharmacokinetics Study of Morinidazole in Patients with Moderate Hepatic Impairment

Objective Morinidazole is a novel third generation 5-nitroimidazole antimicrobial drug which has demonstrated substantial antibacterial activity against clinical isolates of anaerobe. The aim of this study was to build population pharmacokinetic (PPK) model of morinidazole among patients with hepatic impairment and to provide dosage adjustment strategy for morinidazole in patients with hepatic impairment and/or renal dysfunction. Methods The nonlinear mixed effects modeling tool NONMEM (version7.3, ICON Development Solutions) was used to develop the PPK model of morinidazole. Results One-compartment model was conducted to establish the morinidazole PPK model. Disease condition was the significant covariate for CL and weight was the significant covariate for V. The AUC0-∞ was 120.44±37.05 (79.25-207.20) μg×h/mL in hepatic impairment group and was 79.46±23.71 (42.94-116.75) μg×h/mL in control group. The AUC0-∞ was 164.9±44.8 μg×h/mL and 77.2±23.1 μg×h/mLin in the 3 subjects with both hepatic impairment and mild renal impairment and in the 3 matched healthy subjects, respectively. Conclusion It is not necessary to adjust morinidazole dosage for patients with moderate hepatic impairment without confirmed renal dysfunction. For patient with moderate hepatic and mild renal impairment, morinidazole regimen should be considered as 500mg every 24 hours. When used in patients with moderate/severe hepatic impairment combined with renal dysfunction, both dosage and interval adjustment of morinidazole should be considered.