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, C, C and C) 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 and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC. The final TTE dropout model indicated an association between linezolid C 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 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 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.