Derivation and Clinical Utility of Safety Targets for Linezolid-Related Adverse Events in Drug-Resistant Tuberculosis Treatment

Long-term usage of linezolid can result in adverse events such as peripheral neuropathy, anemia and thrombocytopenia. Therapeutic drug monitoring data from 75 drug-resistant tuberculosis patients treated with linezolid were analyzed using a time-to-event (TTE) approach for peripheral neuropathy and anemia and indirect response modelling for thrombocytopenia. Different time-varying linezolid pharmacokinetic exposure indices (AUC(0–24h,ss), C(av), C(max) and C(min)) and patient characteristics were investigated as risk factors. A treatment duration shorter than 3 months was considered dropout and was modelled using a TTE approach. An exposure–response relationship between linezolid C(min) and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC(0–24h). The final TTE dropout model indicated an association between linezolid C(min) and dropout. New safety targets for each adverse event were proposed which can be used for individualized linezolid dosing. According to the model predictions at 6 months of treatment, a C(min) of 0.11 mg/L and 1.4 mg/L should not be exceeded to keep the cumulative probability to develop anemia and peripheral neuropathy below 20%. The AUC(0–24h) should be below 111 h·mg/L or 270 h·mg/L to prevent thrombocytopenia and severe thrombocytopenia, respectively. A clinical utility assessment showed that the currently recommended dose of 600 mg once daily is safer compared to a 300 mg BID dosing strategy considering all four safety endpoints.