Proposed linezolid dosing strategies to minimize adverse events for treatment of extensively drug-resistant tuberculosis.

Background We evaluated clinical trial data (Nix-TB, NCT02333799) to provide data-driven dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis. Methods Based on 104 participants, a pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed. Simulations compared safety outcomes for daily linezolid of 1200 and 600 mg, with and without dose adjustments for toxicity. Severe neuropathy was based on symptom scores from the Brief Peripheral Neuropathy Screen. Severe anemia and thrombocytopenia were defined as ≥grade 3 adverse events according to the Division of Microbiology and Infectious Disease Adult Toxicity table. Results Predicted individual concentration-time profiles were a major predictor in all three toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median: 19% (90%CI: 17-22%) vs 5% (4-7%)) and severe anemia (15% (12-17%) vs 1% (0-2%)) between 1200 and 600 mg daily linezolid. No differences in severe thrombocytopenia were observed (median: 10% decrease from pretreatment in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing dose from 1200 to 600 mg triggered by this marker may prevent 60% (90%CI: 45-72) of severe anemia. Conclusions Simple neuropathy symptom and hemoglobin monitoring may guide linezolid dosing to avoid toxicities, but prospective testing is needed to confirm benefit-to-risk ratio.