Pharmacokinetic–pharmacodynamic modelling of the effect of Moxifloxacin on QTc prolongation in telemetered cynomolgus monkeys

Watson, Kenny; Gorczyca, William P.; Umland, John P.; Zhang, Ying; Chen, Xian; Sun, Sunny Z.; Fermini, Bernard; Holbrook, Mark; Graaf, Piet H. van der

doi:10.1016/j.vascn.2011.03.002

Cited by 34 publications

(25 citation statements)

References 39 publications

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“…This suggests that the experts in the fields of ion channel assessments and metabolism assays may need to consider sharing best practice experience to improve predictivity and reproducibility. Sharing of best practice has already taken place for in vivo studies; 9 this is especially important since it appears that the absolute change in QTc (in msec) is smaller in most laboratory animal species than in man 10 …”

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confidence: 99%

Predicting QTc Prolongation in Man From Only In Vitro Data

Leishman

2014

CPT Pharmacom & Syst Pharma

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Mishra et al.1 in their article “Interaction between domperidone and ketoconazole: toward prediction of consequent QTc prolongation using purely in vitro information” describe the use of physiologically based pharmacokinetic (PBPK) modeling and pharmacodynamic models of cardiac repolarization to predict clinical data from preclinical data. Eliminating the risk of cardiac arrhythmias through delayed repolarization often relies on preclinical data during compound selection. Although there are some limitations, there appears to be significant promise in using this modeling approach.

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confidence: 99%

Predicting QTc Prolongation in Man From Only In Vitro Data

Leishman

2014

CPT Pharmacom & Syst Pharma

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“…Meanwhile, drug abuse could cause organ damage both in human and animal [34,35]. The risks of ADRs, which was related to the high concentrations and long-term use, should be monitored, such as QT interval prolongation, tachycardia, palpitation, toxic epidermal necrolysis, rash, digestive system injury, etc [36,37]. Moxifloxacin was metabolized in liver [2].…”

Section: Discussionmentioning

confidence: 99%

Prediction of Pharmacokinetics and Penetration of Moxifloxacin in Human with Intra-Abdominal Infection Based on Extrapolated PBPK Model

Zhu

Yang

Zhang

et al. 2015

Korean J Physiol Pharmacol

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The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model in intra-abdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues in intra-abdominal infected human. 12 male rats with intra-abdominal infections, induced by Escherichia coli, received a single dose of 40 mg/kg body weight of moxifloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480, 1440 min after drug injection. A PBPK model was developed in rats and extrapolated to human using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration versus time profile of moxifloxcinin rats, Cmax was 11.151 µg/mL at 5 min after the intravenous injection and t1/2 was 2.936 h. Plasma concentration and kinetics in human were predicted and compared with observed datas. Moxifloxacin penetrated and accumulated with high concentrations in redmarrow, lung, skin, heart, liver, kidney, spleen, muscle tissues in human with intra-abdominal infection. The predicted tissue to plasma concentration ratios in abdominal viscera were between 1.1 and 2.2. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict drug pharmacokinetics and penetration in human. Moxifloxacin has a good penetration into liver, kidney, spleen, as well as other tissues in intra-abdominal infected human. Close monitoring are necessary when using moxifloxacin due to its high concentration distribution. This pathological model extrapolation may provide reference to the PK/PD study of antibacterial agents.

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Section: Discussionmentioning

confidence: 99%

Prediction of Pharmacokinetics and Penetration of Moxifloxacin in Human with Intra-Abdominal Infection Based on Extrapolated PBPK Model

Zhu

Yang

Zhang

et al. 2015

Korean J Physiol Pharmacol

View full text Add to dashboard Cite

The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model in intraabdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues in intra-abdominal infected human. 12 male rats with intra-abdominal infections, induced by Escherichia coli, received a single dose of 40 mg/kg body weight of moxifloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480, 1440 min after drug injection. A PBPK model was developed in rats and extrapolated to human using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration versus time profile of moxifloxcinin rats, Cmax was 11.151 μ g/mL at 5 min after the intravenous injection and t1/2 was 2.936 h. Plasma concentration and kinetics in human were predicted and compared with observed datas. Moxifloxacin penetrated and accumulated with high concentrations in redmarrow, lung, skin, heart, liver, kidney, spleen, muscle tissues in human with intra-abdominal infection. The predicted tissue to plasma concentration ratios in abdominal viscera were between 1.1 and 2.2. W hen rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict drug pharmacokinetics and penetration in human. Moxifloxacin has a good penetration into liver, kidney, spleen, as well as other tissues in intra-abdominal infected human. Close monitoring are necessary when using moxifloxacin due to its high concentration distribution. This pathological model extrapolation may provide reference to the PK/PD study of antibacterial agents.

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Pharmacokinetic–pharmacodynamic modelling of the effect of Moxifloxacin on QTc prolongation in telemetered cynomolgus monkeys

Cited by 34 publications

References 39 publications

Predicting QTc Prolongation in Man From Only In Vitro Data

Predicting QTc Prolongation in Man From Only In Vitro Data

Prediction of Pharmacokinetics and Penetration of Moxifloxacin in Human with Intra-Abdominal Infection Based on Extrapolated PBPK Model

Prediction of Pharmacokinetics and Penetration of Moxifloxacin in Human with Intra-Abdominal Infection Based on Extrapolated PBPK Model

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