Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae

Li, Xin; Chen, Yuancheng; Xu, Xiaoyong; Li, Yang; Fan, Yaxin; Liu, Xiaofen; Bian, Xingchen; Wu, Haijiang; Xu, Zu-De; Feng, Meiqing; Guo, Beining; Zhang, Jing

doi:10.3389/fphar.2021.658558

Cited by 4 publications

(1 citation statement)

References 37 publications

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“…The inclusion of multiple bacterial isolates with various susceptibility should be considered in animal PK/PD experiment design to obtain a robust PK/PD target. 16 , 17 In our study, totally 69 strains of Staphylococcus aureus were used for MIC test in vitro, and one of them, STRAIN 18-W27-73 (STRAIN MIC 50 ), was used for murine infection and death protection test. Two clinical strains 18-W26-14 (STRAIN MIC 90 ) and 18-W27-73 (STRAIN MIC 50 ) were used in subsequent PK/PD study.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of a Novel Vancomycin Derivative LYSC98 in a Murine Thigh Infection Model Against Staphylococcus aureus

He¹,

Li²,

Guo³

et al. 2023

IDR

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Introduction LYSC98 is a novel vancomycin derivative used for gram-positive bacterial infections. Here we compared the antibacterial activity of LYSC98 with vancomycin and linezolid in vitro and in vivo. Besides, we also reported the pharmacokinetic/pharmacodynamic (PK/PD) index and efficacy-target values of LYSC98. Methods The MIC values of LYSC98 were identified through broth microdilution method. A mice sepsis model was established to investigate the protective effect of LYSC98 in vivo. Single-dose pharmacokinetics of LYSC98 was studied in thigh-infected mice and liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was used to determine LYSC98 concentration in plasma. Dose fractionation studies were performed to evaluate different PK/PD indices. Two methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used in the dose ranging studies to determine the efficacy-target values. Results LYSC98 showed a universal antibacterial effect in Staphylococcus aureus with a MIC range of 2–4 µg/mL. In vivo, LYSC98 demonstrated distinctive mortality protection in mice sepsis model with an ED 50 value of 0.41–1.86 mg/kg. The pharmacokinetics results displayed maximum plasma concentration (C max ) 11,466.67−48,866.67 ng/mL, area under the concentration–time curve from 0 to 24 h (AUC 0–24 ) 14,788.42−91,885.93 ng/mL·h, and elimination half-life (T 1/2 ) 1.70–2.64 h, respectively. C max /MIC ( R 2 0.8941) was proved to be the most suitable PK/PD index for LYSC98 to predict its antibacterial efficacy. The magnitude of LYSC98 C max /MIC associated with net stasis, 1, 2, 3 and 4 - log 10 kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively. Conclusion Our study demonstrates that LYSC98 is more effective than vancomycin either in killing vancomycin-resistant Staphylococcus aureus (VRSA) in vitro or treating S. aureus infections in vivo, making it a novel and promising antibiotic. The PK/PD analysis will also contribute to the LYSC98 Phase I dose design.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of a Novel Vancomycin Derivative LYSC98 in a Murine Thigh Infection Model Against Staphylococcus aureus

He¹,

Li²,

Guo³

et al. 2023

IDR

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Pharmacokinetics and Pharmacodynamics of Vancomycin derivative LYSC98 in a Murine Thigh Infection Model against Staphylococcus aureus

Guo

et al. 2021

Preprint

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LYSC98 is a vancomycin derivative used for gram-positive bacterial infections therapy. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of LYSC98 against Staphylococcus aureus using a murine thigh infection model. Three Staphylococcus aureus strains were utilized. Single-dose plasma pharmacokinetics of LYSC98 were determined in infected mice after the tail vein injection of 2, 4, and 8mg/kg. The results showed maximum plasma concentration (Cmax) 11466.67 - 48866.67 ng/mL, area under the concentration-time curve from 0 to 24 h(AUC0-24) 14788.42 -91885.93 ng/mL·h, and elimination half-life(T1/2) 1.70-2.64 h, respectively. The Cmax (R2 0.9994) and AUC0-24 (R2 0.981) were positively correlated with the dose of LYSC98 in the range of 2-8 mg/kg.Dose fractionation studies using total doses of 2 to 8 mg/kg administered with q6h, q8h, q12h, and q24h were performed to evaluate the correlation of different PK/PD indices with efficacy. Sigmoid model analysis showed Cmax/MIC (R2 0.8941) was the best PK/PD index to predict the efficacy of LYSC98. In the dose ranging studies, two Methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used to infect the mice and 2-fold-increasing doses (1 to 16 mg/kg) of LYSC98 were administered. The magnitude of LYSC98 Cmax/MIC associated with net stasis, 1, 2, 3 and 4 - log10 kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively. The results of this study showed LYSC98 a promising antibiotic with in vivo potency against MRSA, and will help in the dose design of phase one study for LYSC98.

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Integrative population pharmacokinetic/pharmacodynamic analysis of nemonoxacin capsule in Chinese patients with community-acquired pneumonia

Chen

Wu²,

Tsai³

et al. 2023

Front. Pharmacol.

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Introduction: Nemonoxacin is an innovative quinolone antibiotic for treatment of community-acquired pneumonia (CAP). As more data are available from clinical studies, it is necessary to perform an integrative pharmacokinetic/pharmacodynamic (PK/PD) analysis to support and justify the optimal dosing regimen of nemonoxacin in clinical practice.Methods and Results: We developed a population PK model using non-linear mixed effect model based on the data of 195 Chinese subjects receiving nemonoxacin in phase I to III clinical trials. The base model was a standard two-compartment PK model defined by clearance (12 L/h) and central volume of distribution (86 L). Covariates included creatinine clearance (CLcr), body weight (BW), sex, disease status and food. Compared to the subject with BW 60 kg, Cmax and AUC0‐24, ss reduced by 24% and 19% in the subject with BW 80 kg, respectively. Compared to the subject with CLcr 150 ml/min, AUC0‐24, ss and T1/2 increased by 28% and 24%, respectively in the subject with CLcr 30 ml/min. Compared to the fasted status, Tmax of nemonoxacin increased by 1.2 h in the subject with fed status. Effects of sex and disease status on PK parameters were small (change of PK parameters ≤19%). AUC0–24/MIC and %T > MIC were identified as the optimal PK/PD indices for predicting clinical efficacy. The AUC0-24/MIC target was 63.3, 97.8, and 115.7 against Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, respectively. The %T > MIC target was 7.96% against Klebsiella pneumoniae. Monte Carlo simulation showed that treatment with nemonoxacin 500 mg q24 h could attain a PK/PD cutoff value higher than the MIC90 against S. pneumoniae and S. aureus. The corresponding cumulative fraction of response (CFR) was greater than 93%, while nemonoxacin 750 mg q24 h would provide higher PK/PD cutoff value against Haemophilus parainfluenzae, and higher CFR (83%) than 500 mg q24 h.Conclusion: Integrative PK/PD analysis justifies the reliable clinical and microbiological efficacy of nemonoxacin 500 mg q24 h in treating CAP caused by S. pneumoniae, S. aureus, and K. pneumoniae, irrespective of patient sex, mild renal impairment, empty stomach or not. However, nemonoxacin 750 mg q24 h would provide better efficacy than 500 mg q24 h for the CAP caused by H. parainfluenzae in terms of CFR.

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Pharmacokinetics and Pharmacodynamics of Nemonoxacin in a Neutropenic Murine Lung Infection Model Against Streptococcus Pneumoniae

Cited by 4 publications

References 37 publications

Pharmacokinetics and Pharmacodynamics of a Novel Vancomycin Derivative LYSC98 in a Murine Thigh Infection Model Against Staphylococcus aureus

Pharmacokinetics and Pharmacodynamics of a Novel Vancomycin Derivative LYSC98 in a Murine Thigh Infection Model Against Staphylococcus aureus

Pharmacokinetics and Pharmacodynamics of Vancomycin derivative LYSC98 in a Murine Thigh Infection Model against Staphylococcus aureus

Integrative population pharmacokinetic/pharmacodynamic analysis of nemonoxacin capsule in Chinese patients with community-acquired pneumonia

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