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Pharmacokinetics-pharmacodynamics analysis of bicyclic nitroimidazole analogues in a murine model of tuberculosis.

Lakshminarayana, Suresh Bangalore and Boshoff, Helena and Cherian, Joseph and Ravindran, Sindhu and Goh, Anne and Jiricek, Jan and Nanjundappa, Mahesh Bangalore and Nayyar, Amit and Gurumurthy, Meera and Singh, Ramandeep and Dick, Thomas and Blasco, Francesca and Dartois, Veronique and Ho, Paul C and Manjunatha, Ujjini Havaldar (2014) Pharmacokinetics-pharmacodynamics analysis of bicyclic nitroimidazole analogues in a murine model of tuberculosis. PLOS ONE, 9 (8).

Official URL: http://www.plosone.org/

Abstract

PA-824 is a bicyclic 4-nitroimidazole, currently undergoing phase II clinical development for the treatment of tuberculosis (TB). Dose fractionation pharmacokinetic-pharmacodynamic (PK-PD) studies in mice indicated that the PD driver of PA-824 in vivo efficacy is the time in which the free drug concentrations in plasma is above the MIC (T>MIC). In this study, a panel of closely related potent bicyclic nitroimidazoles (NI) was profiled. Their in vitro potency, in vitro and in vivo PK and in-vivo mouse efficacy were determined and analyzed to identify the PK-PD driver and evaluate the PK parameters that better correlate with in vivo efficacy. Generally, the NI analogues that displayed the best in vitro PK also showed better in vivo PK properties. In an established murine TB model, the efficacy for ten selected NI analogues ranged between 0.5 and 2.3 log CFU reduction compared to untreated controls. Our findings showed that the in vivo efficacy of bicyclic nitroimidazoles is dependent on T>MIC in lungs. Interestingly, the efficacy of NI analogues correlated better with T>MIC in lungs than in plasma, consistent with their differential lung:plasma distribution. Thus PK-PD analysis and lung distribution studies could potentially be exploited as efficacy surrogates thereby accelerating the drug discovery processes for new nitroimidazole analogs.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9267

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