Pharmacokinetics-pharmacodynamics analysis of bicyclic 4-nitroimidazole analogs in a murine model of tuberculosis

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.

Figure 1. Chemical structures of bicyclic 4-nitroimidazole analogs used in this study.

Figure 2. Correlation of PK parameters (C_max, AUC) with in vivo efficacy in mice for bicyclic 4-nitroimidazole analogs in total plasma concentration (A), free plasma concentration (B) and total lung concentration (C).

Each data point represents Δ mean log lung CFU reduction compared to untreated controls (mean value ± SEM from 5 animals). r_s is the Spearman’s rank correlations coefficient.

Figure 3. Correlation of PK-PD indices (C_max/MIC, AUC/MIC and T_>MIC) with in vivo efficacy in mice for bicyclic 4-nitroimidazole analogs in total plasma concentration (A), free plasma concentration (B) and total lung concentration (C).

Each data point represents Δ Mean log lung CFU reduction compared to untreated controls (mean value ± SEM from 5 animals). r_s is the Spearman’s rank correlations coefficient.

Figure 4. Correlation of volume of distribution with in vivo efficacy in mice for bicyclic 4-nitroimidazole analogs.

Each data point represents Δ Mean log lung CFU reduction compared to untreated controls (mean value ± SEM from 5 animals). r_s is the Spearman’s rank correlations coefficient.