Dataset Information

Computational pharmacokinetics/pharmacodynamics of rifampin in a mouse tuberculosis infection model.

ABSTRACT: One critical approach to preclinical evaluation of anti-tuberculosis (anti-TB) drugs is the study of correlations between drug exposure and efficacy in animal TB infection models. While such pharmacokinetic/pharmacodynamic (PK/PD) studies are useful for the identification of optimal clinical dosing regimens, they are resource intensive and are not routinely performed. A mathematical model capable of simulating the PK/PD properties of drug therapy for experimental TB offers a way to mitigate some of the practical obstacles to determining the PK/PD index that best correlates with efficacy. Here, we present a preliminary physiologically based PK/PD model of rifampin therapy in a mouse TB infection model. The computational framework integrates whole-body rifampin PKs, cell population dynamics for the host immune response to Mycobacterium tuberculosis infection, drug-bacteria interactions, and a Bayesian method for parameter estimation. As an initial application, we calibrated the model to a set of available rifampin PK/PD data and simulated a separate dose fractionation experiment for bacterial killing kinetics in the lungs of TB-infected mice. The simulation results qualitatively agreed with the experimentally observed PK/PD correlations, including the identification of area under the concentration-time curve as best correlating with efficacy. This single-drug framework is aimed toward extension to multiple anti-TB drugs in order to facilitate development of optimal combination regimens.

SUBMITTER: Lyons MA

PROVIDER: S-EPMC4506877 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other

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Computational pharmacokinetics/pharmacodynamics of rifampin in a mouse tuberculosis infection model.

Lyons Michael A MA Lenaerts Anne J AJ

Journal of pharmacokinetics and pharmacodynamics 20150531 4

One critical approach to preclinical evaluation of anti-tuberculosis (anti-TB) drugs is the study of correlations between drug exposure and efficacy in animal TB infection models. While such pharmacokinetic/pharmacodynamic (PK/PD) studies are useful for the identification of optimal clinical dosing regimens, they are resource intensive and are not routinely performed. A mathematical model capable of simulating the PK/PD properties of drug therapy for experimental TB offers a way to mitigate some ...[more]

PMID: 26026426

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Project description:Staphylococcus aureus (S. aureus) is one of the most common pathogenic bacteria responsible for causing a life-threatening peritonitis disease. NZX, as a variant of fungal defensin plectasin, displayed potent antibacterial activity against S. aureus. In this study, the antibacterial and resistance characteristics, pharmacokinetics, and pharmacodynamics of NZX against the S. aureus E48 and S. aureus E48-induced mouse peritonitis model were studied, respectively. NZX exhibited a more rapid killing activity to S. aureus (minimal inhibitory concentration, 1 μg/ml) compared with linezolid, ampicillin and daptomycin, and serial passaging of S. aureus E48 for 30 days at 1/2 × MIC, NZX had a lower risk of resistance compared with ampicillin and daptomycin. Also, it displayed a high biocompatibility and tolerance to physiological salt, serum environment, and phagolysosome proteinase environment, except for acid environment in phagolysosome. The murine serum protein-binding rate of NZX was 89.25% measured by ultrafiltration method. Based on the free NZX concentration in serum after tail vein administration, the main pharmacokinetic parameters for T1/2, Cmax, Vd, MRT, and AUC ranged from 0.32 to 0.45 h, 2.85 to 20.55 μg/ml, 1469.10 to 2073.90 ml/kg, 0.32 to 0.56 h, and 1.11 to 8.89 μg.h/ml, respectively. Additionally, the in vivo pharmacodynamics against S. aureus demonstrated that NZX administrated two times by tail vein at 20 mg/kg could rescue all infected mice in the lethal mouse peritonitis model. And NZX treatment (20 mg/kg) significantly reduced CFU counts in the liver, lung, and spleen, especially for intracellular bacteria in the peritoneal fluid, which were similar or superior to those of daptomycin. In vivo efficacies of NZX against total bacteria and intracellular bacteria were significantly correlated with three PK/PD indices of ƒAUC/MIC, ƒCmax/MIC, and ƒT% > MIC analyzed by a sigmoid maximum-effect model. These results showed that NZX may be a potential candidate for treating peritonitis disease caused by intracellular S. aureus.

Dataset Information

Computational pharmacokinetics/pharmacodynamics of rifampin in a mouse tuberculosis infection model.

Publications

Computational pharmacokinetics/pharmacodynamics of rifampin in a mouse tuberculosis infection model.

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