PHARMACOKINETICS AND PHARMACODYNAMICS OF OXAZOLIDINONES AND THEIR CONTRIBUTION TO A NOVEL TUBERCULOSIS TREATMENT REGIMEN

Linezolid is clinically effective against multidrug-resistant tuberculosis and is part of the shortest, most effective treatment for extensively drug-resistant tuberculosis (bedaquiline, pretomanid, plus linezolid). However, dose- and duration-dependent toxicities are common. Our studies focused on informing new dosing strategies that maximize efficacy and minimize toxicity. The BALB/c mouse model of tuberculosis was used to study linezolid dosing strategies, first by establishing correlations between pharmacokinetic parameters and linezolid effects on different bacterial growth states, and second by identifying a dosing scheme that optimizes linezolid efficacy while minimizing its toxicity and protecting against resistance to companion agents. Overall, the pharmacokinetic parameter best correlated with efficacy was T>MIC. However, in growth-constrained models, AUC/MIC had similar explanatory power. The pharmacokinetic parameter best correlated with toxicity was Cmin. Next we tested different linezolid dosing regimens in combination with bedaquiline-pretomanid (BPaL). Linezolid dosing producing a plasma AUC equivalent to human 1200mg daily given for 1-2 months achieved the greatest efficacy, with similar results if the drug was stopped, dosed thrice-weekly, or continued daily thereafter. Erythrocyte counts were lower with daily compared to thrice-weekly dosing. We encountered strain-dependent antagonism of linezolid with bedaquiline-pretomanid in mice infected with Mycobacterium tuberculosis HN878 but not the H37Rv iii strain. However, overall efficacy of BPaL was high and similar against both strains likely due to greater sensitivity of the HN878 strain to bedaquiline and linezolid. Even with optimized strategies, linezolid's therapeutic window remains small. Therefore, a potentially safer oxazolidinone, TBI-223, was examined. Using dose fractionation in an acute mouse infection model and exposures mimicking human pharmacokinetics in our in vitro pharmacodynamic system we compared the efficacy of linezolid and TBI-223. Results showed that TBI-223 at 2g may have efficacy similar to linezolid 600mg while avoiding mitochondrial toxicity. We identified front-loaded dosing of linezolid 1200mg daily for the first 1-2 months, then changing to thrice-weekly dosing as a strategy to optimize its therapeutic margin and minimize the risk of resistance to companion drugs. This strategy should minimize toxicity, but will not mitigate it completely. TBI-223, with its larger therapeutic window, may eventually replace linezolid by achieving similar efficacy with less toxicity