Effects of Nemonoxacin on Thorough ECG QT/QTc Interval: A Randomized, Placebo- and Positive-controlled Crossover Study in Healthy Chinese Adults

Zhao, Caiyun; Lv, Yuan; Li, Xiangyan; Hou, Fanfan; Ma, Xiaoli; Wei, Min-Ji; Kang, Zisheng; Cui, Lanqing; Xia, Yueyuan; Liu, Yan; Tian, Jihong

doi:10.1016/j.clinthera.2018.04.014

Cited by 7 publications

(7 citation statements)

References 15 publications

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“…All of the AEs were mild or moderate, including loss of appetite, nausea, vomiting and stomach discomfort, and were tolerable to patients ( Liu et al, 2017 ). A thorough QT clinical study suggested that nemonoxacin 500 mg oral dose had no risk of QTc prolongation (ΔΔQTc 8.1 s) and 750 mg had a potential risk of prolongation (ΔΔQTc 10.4 s) ( Zhao et al, 2018 ). Considering the incidence of adverse reactions in phase II clinical trial and the risk of QTc prolongation, 500 mg was selected as the phase III clinical trial dose, the incidence of drug-related AEs was 19.4% ( Yuan et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

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

Chen

et al. 2021

Front. Pharmacol.

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Nemonoxacin, a novel nonfluorinated quinolone for the treatment of community-acquired pneumonia. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets and PK/PD breakpoints of nemonoxacin against Streptococcus pneumoniae using a neutropenic murine lung infection model. Single-dose PK analysis after subcutaneous administration of nemonoxacin at doses from 2.5 to 80 mg/kg showed maximum plasma concentration (Cmax) 0.56–7.32 mg/L, area under the concentration-time curve from 0 to 24 h (AUC0-24) 0.67–26.10 mg·h/L, and elimination half-life (T1/2) 0.8–1.4 h. The epithelial lining fluid (ELF) penetration ratio of total drug was 1.40. Dose fractionation (1.25–80 mg/kg/day, every 24, 12, 8, and 6 h) and dose escalation studies (1.25–160 mg/kg, every 24 h) were conducted. The sigmoid Emax Hill equation was used to describe the dose-response data. The free-drug plasma fAUC0-24/MIC ratio was considered the PK/PD index most closely associated with efficacy (R2 0.9268). Median fAUC0-24/MIC associated with static, 1-log10 and 2-log10 CFU reduction from baseline were 8.6, 23.2 and 44.4, respectively. Monte Carlo simulation showed 500 mg qd and 750 mg qd oral doses of nemonoxacin were able to achieve 90% probability of target attainment (PTA) against bacteria with MIC of 0.5 mg/L and 1 mg/L. We recommended susceptibility (S) ≤ 0.5 mg/L, intermediate (I) = 1 mg/L and resistant (R) ≥ 2 mg/L as the PK/PD breakpoints for nemonoxacin against S. pneumoniae.

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Section: Discussionmentioning

confidence: 99%

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

Chen

et al. 2021

Front. Pharmacol.

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“…seems to increase in a dose-dependent manner. 13 Compared with the standard dosage (0.5 g q24h), the dosing regimen (0.5 g q48h) is…”

Section: Discussionmentioning

confidence: 99%

“…The cardiac repolarization characteristics at therapeutic dose (0.5 g q24h) are acceptable, while a supratherapeutic dose (0.75 g q24h) should raise more concerns. 13 Therefore, dose adjustment appears necessary for nemonoxacin in patients with renal impairment.…”

Section: Introductionmentioning

confidence: 99%

Nemonoxacin dosage adjustment in patients with severe renal impairment based on population pharmacokinetic and pharmacodynamic analysis

Kang

et al. 2021

Brit J Clinical Pharma

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Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic (PPK)/pharmacodynamic analysis. Methods:The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of a 0.5-g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 72 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment and the cumulative fraction of response against Streptococcus pneumoniae and Staphylococcus aureus was calculated by Monte Carlo simulation. Results:The data best fitted a 2-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L) and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4 ± 6.5% in severe renal impairment patients and 66.1 ± 16.8% in healthy controls. PPK/pharmacodynamic modelling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g every 48 hours (q48h) was the optimal dosing regimen in severe renal impairment patients, evidenced by higher probability of target attainment (92.7%) and cumulative fraction of response (>99%) at nemonoxacin minimum inhibitory concentration ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if minimum inhibitory concentration = 1 mg/L. Conclusion:An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

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“…However, the use of a crossover design in this study, coupled with the need to achieve supratherapeutic levels by escalating doses to steady state, necessitated a lengthy washout period (≥2 weeks) between successive treatment periods. A multiple‐dose, TQTc study of indacaterol (half‐life, 45.5‐126 hours) used a parallel‐group design, whereas several other previous TQTc studies for medications with long half‐lives have used a crossover design with 7‐ to 28‐day washout periods . These crossover design studies were single‐dose trials; steady‐state concentrations were not achieved.…”

Section: Discussionmentioning

confidence: 99%

“…A multiple-dose, TQTc study of indacaterol (half-life, 45.5-126 hours) used a parallel-group design, 35 whereas several other previous TQTc studies for medications with long half-lives have used a crossover design with 7-to 28-day washout periods. [36][37][38] These crossover design studies were single-dose trials; steady-state concentrations were not achieved. The impact of a study design that uses such a lengthy study period on observed TQTc results is unclear.…”

Section: Discussionmentioning

confidence: 99%

A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects

Abbas

Riley

LaBadie

et al. 2019

Clinical Pharm in Drug Dev

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The effect of steady‐state supratherapeutic sertraline (Zoloft) on QT interval was assessed in a single‐center, randomized, 3‐way crossover, double‐blind, placebo‐ and moxifloxacin‐controlled thorough QT study. Healthy adults received sertraline 400 mg/day, moxifloxacin 400 mg, and placebo, with a washout period (≥14 days) between treatments. A 12‐lead electrocardiogram was recorded in triplicate before dosing and at selected time points up to 72 hours after dosing. Analysis of covariance using a mixed‐effect model with sequence, period, treatment, time, and treatment‐by‐time interaction as fixed effects; subject within sequence as a random effect; and baseline QT corrected for heart rate using Fridericia formula (QTcF) as a covariate was conducted. A 90% confidence interval for the least squares (LS) mean difference in QTcF between active treatment and placebo was computed for each postdose time point. Exposure‐response was assessed using linear mixed‐effect modeling. Fifty‐four subjects were enrolled. Over 24 hours after dosing, the LS mean difference in QTcF for sertraline versus placebo ranged from 5.597 milliseconds to 9.651 milliseconds. The upper bound of the 90% confidence interval for the LS mean difference exceeded a predefined 10‐millisecond significance threshold at the 4‐hour postdose time point only (LS mean, 9.651 milliseconds [90% confidence interval, 7.635‐11.666]). In the exposure‐response analysis, QTcF values increased significantly with increasing sertraline concentration (slope = 0.036 milliseconds/ng/mL; P < .0001). Predicted change from baseline in QTcF at therapeutic maximum plasma sertraline concentration was 3.57 milliseconds. This thorough QTc study demonstrated a positive signal for QTc prolongation for sertraline at the steady‐state 400‐mg/day dose.

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Effects of Nemonoxacin on Thorough ECG QT/QTc Interval: A Randomized, Placebo- and Positive-controlled Crossover Study in Healthy Chinese Adults

Cited by 7 publications

References 15 publications

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

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

Nemonoxacin dosage adjustment in patients with severe renal impairment based on population pharmacokinetic and pharmacodynamic analysis

A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects

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