Pharmacokinetic and pharmacodynamic simulation for the quantitative risk assessment of linezolid‐associated thrombocytopenia

Abstract

What Is Known and Objective Linezolid (LZD) may cause thrombocytopenia, which can result in discontinuation of treatment. In this study, the blood LZD trough concentration was estimated based on population pharmacokinetic (PK) parameters derived from two previously published models in the Japanese population to determine the rate of achieving the target trough value when the risk of thrombocytopenia is low and to clarify its relationship with the onset of thrombocytopenia. Methods This study included adult patients hospitalized at Shimane University Hospital, who received LZD treatment for at least 4 days from January 2010 to December 2017. Patients whose platelet count fell below 70% before LZD administration were categorized as the thrombocytopenic group. Patient PK parameters were calculated based on the population PK models described by Matsumoto et al. and Sasaki et al., and these parameters were designated A and B, respectively. Based on these parameters, the rate of achieving an LZD trough concentration of less than 8 μg/ml, which is the safety target achievement rate, was calculated using a random simulation for each patient. We further analysed the association between the incidence of thrombocytopenia and patient factors, including safety target achievement rate, through univariate, multivariate, and receiver operating characteristic (ROC) analyses. Results and Discussion Patients (n = 77) aged 72 ± 11 years and weighing 56.7 ± 10.9 kg, with a creatinine clearance (CLcr) of 60.5 ± 47.2 ml/min and a cirrhosis prevalence of 9.1%, were analysed. All patients received LZD at a dose of 600 mg twice daily for a total of 10.9 ± 8.9 days. Univariate analyses revealed significant differences (p < 0.05) in the duration of LZD therapy, serum creatinine, creatinine clearance, LZD clearance, and the safety target achievement rate for parameters A and B between the thrombocytopenic and non‐thrombocytopenic groups. A multivariate analysis of these factors stratified with the cutoff values obtained by ROC analysis revealed that the duration of LZD therapy and the safety target achievement rates for parameters A and B were significant factors (odds ratios for duration of LZD therapy: 7.436 [95% confidence interval (CI): 1.918–28.831] and 4.712 [95% CI: 1.567–14.163]; odds ratio for safety target achievement rate: 0.060 [95% CI: 0.016–0.232] and 0.167 [95% CI: 0.056–0.498] for parameters A and B, respectively). When the safety target achievement rates for patients treated with LZD were compared between the thrombocytopenic and non‐thrombocytopenic groups, the safety target achievement rate was higher in the non‐thrombocytopenic group in both the patients treated with LZD for less than 10 days and those for 10 days or more. Therefore, the safety target achievement rate estimated by the PK/PD simulation may represent to be an important index for risk assessment of LZD‐induced thrombocytopenia. What Is New and Conclusion The risk of LZD‐induced thrombocytopenia, which increased with the duration of LZD therapy, may ...

Efficacy and Safety of Rivaroxaban for Extremely Aged Patients with Venous Thromboembolism: A Retrospective, Cross-Sectional Real-World Study

“…[30][31][32] In addition, the application of antibiotics is known to have adverse side effects on the hematopoietic system, which may be manifested as hemolysis or platelet dysfunction. 33,34 We Clinical Interventions in Aging 2024:19 https://doi.org/10.2147/CIA.S405075 DovePress 1113 observed 5 bleeding events (15.15%) in patients with infection and 7 bleeding events (7.59%) in patients without infection (Figure 4C). Patients with infection showed increased incidence of bleeding compared with patients without infection, but no significant difference was observed due to the limited sample size (P=0.3053).…”