Proposed Linezolid Dosing Strategies to Minimize Adverse Events for Treatment of Extensively Drug-Resistant Tuberculosis

Abstract

Background: We evaluated Nix-TB trial data (NCT02333799, N = 109) to provide dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis. .

Methods: 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 NIAID Division of Microbiology and Infectious Disease Adult Toxicity table.

Results: Predicted concentration-time profiles were a major predictor in all toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median, 19%; 90% confidence interval [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, <1% for both daily doses). Generally, neuropathy occurred after 3 to 6 months of treatment and, with protocol-specified management, reversed within 15 months after onset. Simulations indicated that a >10% decrease in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing the 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 the benefit-to-risk ratio.

Keywords: PK–PD modeling; adverse events; drug-resistant tuberculosis; linezolid; tuberculosis therapeutics.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Nix-TB dataset and trial design diagram. Data from participants in Nix-TB with pulmonary extensively drug-resistant tuberculosis (TB) or treatment-intolerant or nonresponsive multidrug-resistant TB treated for 6 months (option to extend to 9 months) were used in this study. All participants were planned to provide predosing PK samples (trough levels) after treatment for 2, 8, and 16 weeks. In a subset of 25 participants, intensive PK sampling was planned at week 16 with samples collected at predose, 0.5, 1, 2, 4, 8, 12, 12.5, 13, 14, 16, 20, and 24 hours after dosing. Complete blood counts were scheduled at screening (up to 9 days prior to treatment initiation), at pretreatment (day 1 prior to dosing), weekly up to 16 weeks of treatment, and at 20 and 26 weeks of treatment. Brief Peripheral Neuropathy Screen was scheduled at screening; weeks 4, 8, 12, 16, 20, and 26 during treatment; and months 3, 6, 12, and 24 post-treatment. Diagram not drawn to scale. aTwo participants had their treatment extended to 9 months. Additional complete blood counts and peripheral neuropathy screening were scheduled at weeks 30, 34, and 39 for these 2 participants (not shown in diagram). Abbreviations: BPaL, bedaquiline, pretomanid, and linezolid; PK, pharmacokinetic.

Figure 2.

Linezolid pharmacokinetic-toxicodynamic models: observed data and visual predictive checks. A, Pharmacokinetic model for linezolid. Initial linezolid dosage: red, 600 mg twice daily; blue, 1200 mg once daily. B, Pharmacokinetic-toxicodynamic model for hemoglobin levels. C, Pharmacokinetic-toxicodynamic model for platelet counts. D, Pharmacokinetic-toxicodynamic model for severe peripheral neuropathy scores. Left, observed data. A, Observed linezolid concentrations (points) and median (thick solid line) stratified by initial linezolid dosage and sampling occasion. B and C, Observed hemoglobin levels and platelet counts (thin solid lines) and median (thick solid line) stratified by initial linezolid dosage. D, Observed percentage of severe peripheral neuropathy scores (thick solid line) stratified by initial linezolid dosage. Middle, VPC for model development data; right, VPC for model testing data. A, B, and C, Median (solid line) and 5th and 95th percentiles (dashed lines) of observed data, and 95% confidence intervals of the median and 5th and 95th percentiles of model predicted simulations (shaded areas). VPCs are prediction-corrected. The model testing data only included 5 patients with intensive pharmacokinetic (PK) sampling at week 16, so confidence intervals of the median and 5th and 95th percentiles substantially overlapped. Therefore, only linezolid trough levels are shown (collected from all patients) in the right column of (A), rather than the full 24-hour profile. D, Observed percentage of severe peripheral neuropathy scores (solid line) and 95% prediction interval of model predicted simulations (shaded area). Additional predictive checks for the PK model and peripheral neuropathy model available in Supplementary Table 9 and Supplementary Figures 6–8. Abbreviations: LLOQ, lower limit of quantification; Rx, treatment; VPC, visual predictive checks

Figure 3.

Distribution of peripheral neuropathy scores in Nix-TB. Distribution of peripheral neuropathy scores vs time in 104 participants (model development, 88 participants; model testing, 16 participants).

Figure 4.

Simulated pharmacokinetic and toxicity profiles after total linezolid daily doses of 600 mg or 1200 mg. A, Simulated steady-state pharmacokinetic profiles evaluated 2 weeks after treatment initiation. Solid blue lines, typical participant (median of simulations); shaded areas, 90% prediction intervals; solid red line, MIC90 of 0.5 mg/L. B, Simulated hemoglobin level profiles for 6 months of treatment with linezolid. Solid blue lines, typical participant; shaded areas, 90% prediction intervals; solid red line, DMID definition of grade 3 toxicity (hemoglobin level <8 g/dL). C, Simulated platelet count profiles for 6 months of treatment with linezolid. Solid blue lines, typical participant; shaded areas, 90% prediction intervals; solid red line, DMID definition of grade 3 toxicity (platelet count <50 × 109/L). D, Simulated expected percentages of severe peripheral neuropathy scores for 6 months of treatment with linezolid and 18 months of follow-up. Simulated percentages of normal, minimal, and modest score available in Supplementary Figure 9. First column, linezolid dosage 300 mg twice daily for 6 months; second column, linezolid dosage 600 mg once daily for 6 months; third column, linezolid dosage 600 mg twice daily for 6 months; fourth column, linezolid dosage 1200 mg twice daily for 6 months. Abbreviations: DMID, Division of Microbiology and Infectious Diseases; MIC90, minimum concentration of antibiotic at which 90% of the isolates are inhibited.

Figure 5.

Reversibility of peripheral neuropathy associated with linezolid treatment. A, Percentage of participants with peripheral neuropathy reversed. Solid line, observed data; shaded area, 95% prediction interval from model simulations that account for actual dosage histories. B, C, and D, Percentage of participants with peripheral neuropathy reversed based on simulated data: B, Initial linezolid dosage 600 mg once daily. C, Initial linezolid dosage 600 mg twice daily. D, Initial linezolid dosage 1200 mg once daily. Neuropathy reversal was assessed by defining the first occurrence of a modest or severe neuropathy score as an event, and linezolid dosage was adjusted at the time of the event using simulations. After dosage adjustment, the time of reversal was defined as the time of the first of 2 consecutive minimal or normal scores. The distribution of time from the event to reversed neuropathy was plotted. Reduced dosage: red, 600 mg once daily; yellow, 300 mg once daily; blue, linezolid discontinued. The point at which each curve crosses the dashed black line is the time from dosage reduction to reversal of neuropathy in 50% of patients. Abbreviation: QD, once daily.

Figure 6.

Predictors of anemia associated with linezolid treatment. A, Receiver operating characteristic curves for univariate models that predict investigator-reported anemia adverse events, defined in the Nix-TB trial. Additional models available in Supplementary Table 11. B, Receiver operating characteristic curves for simulated prediction of severe anemia using the hemoglobin level pharmacokinetic-toxicodynamic model, defined by Division of Microbiology and Infectious Diseases ≥ grade 3 toxicity (hemoglobin level <8 g/dL). Use of a 10% decrease in hemoglobin levels after 4 weeks of linezolid treatment to predict severe anemia maximizes sensitivity (0.82) and specificity (0.84; black circle). Abbreviations: AUROC, area under the receiver operating characteristic curve; t, time after treatment initiation; rel. to, relative to.

Figure 7.

Proposed management strategy to predict and minimize severe anemia associated with linezolid treatment. A, Decision tree algorithm. B, Simulated steady-state pharmacokinetic profiles evaluated 2 weeks after implementing anemia toxicity management strategy (ie, 6 weeks after treatment initiation) for initial linezolid dosage 1200 mg once daily. Solid blue lines, typical participant (median of simulations); shaded areas, 90% prediction interval; solid red line, MIC90 of 0.5 mg/L. C, Simulated hemoglobin level profiles after implementing anemia toxicity management strategy for initial linezolid dosage 1200 mg once daily. Solid blue lines, typical participant (median of simulations); shaded areas, 90% prediction interval; solid red line, Division of Microbiology and Infectious Diseases definition of grade 3 toxicity (hemoglobin level <8 g/dL); black dashed line, intervention timepoint (4 weeks after treatment initiation) where decision is made for toxicity management strategy. Abbreviation: MIC90, minimum concentration of antibiotic at which 90% of the isolates are inhibited.