Abstract
PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the driver of PA-824 in vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT>MIC). In this study, a panel of closely related potent bicyclic 4-nitroimidazoles was profiled in both in vivo PK and efficacy studies. In an established murine TB model, the efficacy of diverse nitroimidazole analogs ranged between 0.5 and 2.3 log CFU reduction compared to untreated controls. Further, a retrospective analysis was performed for a set of seven nitroimidazole analogs to identify the PK parameters that correlate with in vivo efficacy. Our findings show that the in vivo efficacy of bicyclic 4-nitroimidazoles correlated better with lung PK than with plasma PK. Further, nitroimidazole analogs with moderate-to-high volume of distribution and Lung to plasma ratios of >2 showed good efficacy. Among all the PK-PD indices, total lung T>MIC correlated the best with in vivo efficacy (rs = 0.88) followed by lung Cmax/MIC and AUC/MIC. Thus, lung drug distribution studies could potentially be exploited to guide the selection of compounds for efficacy studies, thereby accelerating the drug discovery efforts in finding new nitroimidazole analogs.
Highlights
Every year nearly 8 million new cases of Tuberculosis (TB) are reported globally resulting in 1.4 million deaths [1]
Amino-nitroimidazoles showed improved solubility compared to their respective benzyl ether analogs (Amino-824 vs. PA-824 and NI-269 vs. NI-145)
In murine models of TB, PK-PD relationships have been established for several standard TB drugs, such as rifampicin [35], isoniazid [36], fluoroquinolones (FQ) [37] and TMC207 [38]
Summary
Every year nearly 8 million new cases of Tuberculosis (TB) are reported globally resulting in 1.4 million deaths [1]. There is an urgent need to discover new TB drugs active against drug-resistant forms of TB and compatible with treatment against HIV. PA-824 was shown to be well tolerated in healthy subjects, following oral daily doses for 7 days [9]. These results, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mtb, supported the progression of this compound and its evaluation as a novel treatment against TB. An early bactericidal activity (EBA) study of PA-824 revealed a lack of dose response between 200 and 1200 mg administered daily for 14 days [10]. An additional phase II trial between 50 and 200 mg was undertaken to establish the lowest efficacious dose [12]. 200 mg of PA-824 was found to be efficacious and used in combination with other anti-TB drugs [13]
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