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 (AUC0–24h,ss, Cav, Cmax and Cmin) 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 Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0–24h. The final TTE dropout model indicated an association between linezolid Cmin 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 Cmin 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 AUC0–24h 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.</p

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 (AUC0–24h,ss, Cav, Cmax and Cmin) 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 Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0–24h. The final TTE dropout model indicated an association between linezolid Cmin 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 Cmin 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 AUC0–24h 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.</p

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 (AUC0–24h,ss, Cav, Cmax and Cmin) 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 Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0–24h. The final TTE dropout model indicated an association between linezolid Cmin 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 Cmin 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 AUC0–24h 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.</p

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 (AUC0–24h,ss, Cav, Cmax and Cmin) 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 Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0–24h. The final TTE dropout model indicated an association between linezolid Cmin 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 Cmin 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 AUC0–24h 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.</p

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 (AUC0–24h,ss, Cav, Cmax and Cmin) 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 Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0–24h. The final TTE dropout model indicated an association between linezolid Cmin 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 Cmin 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 AUC0–24h 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.</p

Current practice for the treatment of acute paracetamol intoxication with N-acetylcysteine in Dutch hospitals

Background Nationally and internationally a discussion is ongoing on the effectiveness, the dose required and the treatment duration of N-acetylcysteine to treat acute paracetamol intoxication. Objective In this paper we present the results of a national survey among hospital pharmacists. In this research the present treatment duration and dosing of N-acetylcysteine is reviewed. Design and methods An electronic survey consisting of 15 questions on the treatment of acute paracetamol intoxications in hospitals has been sent to hospital pharmacists. Results Hospital pharmacists of 67 of the 69 Dutch hospitals (97%) have responded. The majority (52 centres, 78%) indicated to treat acute paracetamol intoxications according to the treatment guideline of the NVZA/NVKFB on toxicologie.org. 64 centres (96%) used the dosing regimen of the above-mentioned treatment guideline, namely 150 mg/kg in 1 hour, followed by 450 mg/kg in 24 hours. The toxicologie.org treatment guideline of 150 mg/L at 4 hours after intake, (or 75 mg/L at 4 hours after intake for sensitive patients) to start N-acetylcysteine therapy, is used by 61 centres (91%). 30% of the centres indicate that there are differences in the treatment of an acute paracetamol intoxication in children and adults. In general, in these centres, it is preferred to start early with N-acetylcysteine in children. Conclusion Despite local differences, in the majority of the hospitals acute paracetamol intoxications are treated according to the toxicologie.org treatment guideline. Because of this, toxicologie.org is an appropriate medium to implement possible future adaptations in the N-acetylcysteine dosing regime in Dutch hospitals.</p

Current practice for the treatment of acute paracetamol intoxication with N-acetylcysteine in Dutch hospitals

Background Nationally and internationally a discussion is ongoing on the effectiveness, the dose required and the treatment duration of N-acetylcysteine to treat acute paracetamol intoxication. Objective In this paper we present the results of a national survey among hospital pharmacists. In this research the present treatment duration and dosing of N-acetylcysteine is reviewed. Design and methods An electronic survey consisting of 15 questions on the treatment of acute paracetamol intoxications in hospitals has been sent to hospital pharmacists. Results Hospital pharmacists of 67 of the 69 Dutch hospitals (97%) have responded. The majority (52 centres, 78%) indicated to treat acute paracetamol intoxications according to the treatment guideline of the NVZA/NVKFB on toxicologie.org. 64 centres (96%) used the dosing regimen of the above-mentioned treatment guideline, namely 150 mg/kg in 1 hour, followed by 450 mg/kg in 24 hours. The toxicologie.org treatment guideline of 150 mg/L at 4 hours after intake, (or 75 mg/L at 4 hours after intake for sensitive patients) to start N-acetylcysteine therapy, is used by 61 centres (91%). 30% of the centres indicate that there are differences in the treatment of an acute paracetamol intoxication in children and adults. In general, in these centres, it is preferred to start early with N-acetylcysteine in children. Conclusion Despite local differences, in the majority of the hospitals acute paracetamol intoxications are treated according to the toxicologie.org treatment guideline. Because of this, toxicologie.org is an appropriate medium to implement possible future adaptations in the N-acetylcysteine dosing regime in Dutch hospitals.</p