Population pharmacokinetics and pharmacodynamics of linezolid‐induced thrombocytopenia in hospitalized patients

Tsuji, Yasuhiro; Holford, Nicholas H.G.; Kasai, Hidefumi; Ogami, Chika; Heo, Young A.; Higashi, Yoshitsugu; Mizoguchi, Akiko; To, Hideto; Yamamoto, Yoshihiro

doi:10.1111/bcp.13262

Cited by 82 publications

(123 citation statements)

References 73 publications

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“…Baseline laboratory values were more commonly abnormal in patients with renal impairment, including total bilirubin (1.0 Ϯ 1.2 versus 0.7 Ϯ 0.8 mg/dl; P Ͻ 0.001), platelet count (231 ϫ 10 3 Ϯ 109 ϫ 10 3 versus 311 ϫ 10 3 Ϯ 167 ϫ 10 3 cells/l; P Ͻ 0.001), and hemoglobin (9.0 Ϯ 1.7 versus 9.6 Ϯ 1.9 g/dl; P Ͻ 0.001). The median (interquartile range [IQR]) duration of linezolid therapy was 21 (14,32) days in patients with renal impairment and 19 (14,33) days in patients without renal impairment (P ϭ 0.89). In total, 92 (27.0%) patients developed thrombocytopenia and 47 (13.8%) developed severe thrombocytopenia.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, a pharmacokinetic/toxicodynamic model identified a C min of 8.06 mg/liter as the threshold associated with a 50% decrease in platelet precursor cells (24). Other pharmacokinetic/toxicodynamic models have also identified inhibition of platelet formation, rather than immune-mediated or non-immune-mediated platelet destruction, as the most likely primary mechanism leading to thrombocytopenia (32,33). A study by Tsuji and colleagues assessed both inhibition of platelet formation and stimulation of platelet elimination as explanatory mechanisms of linezolid-induced thrombocytopenia and estimated that thrombocytopenia occurred via an inhibitory mechanism in 97% of patients, using a mixture model (33).…”

Section: Discussionmentioning

confidence: 99%

“…Other pharmacokinetic/toxicodynamic models have also identified inhibition of platelet formation, rather than immune-mediated or non-immune-mediated platelet destruction, as the most likely primary mechanism leading to thrombocytopenia (32,33). A study by Tsuji and colleagues assessed both inhibition of platelet formation and stimulation of platelet elimination as explanatory mechanisms of linezolid-induced thrombocytopenia and estimated that thrombocytopenia occurred via an inhibitory mechanism in 97% of patients, using a mixture model (33). Importantly, these studies have also identified renal function to be an important determinant of thrombocytopenia risk (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…A study by Tsuji and colleagues assessed both inhibition of platelet formation and stimulation of platelet elimination as explanatory mechanisms of linezolid-induced thrombocytopenia and estimated that thrombocytopenia occurred via an inhibitory mechanism in 97% of patients, using a mixture model (33). Importantly, these studies have also identified renal function to be an important determinant of thrombocytopenia risk (32,33). The single-dose PK of linezolid from 18 healthy volunteers with renal impairment enrolled in the phase 1 clinical trial suggested dose adjustment was not needed in this population (6,7,9).…”

Section: Discussionmentioning

confidence: 99%

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Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety

Crass

Cojutti

Pai

et al. 2019

Antimicrob Agents Chemother

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Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for Ն10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariatestructured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P Ͻ 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of Ͻ60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety

Crass

Cojutti

Pai

et al. 2019

Antimicrob Agents Chemother

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“…Linezolid concentrations were measured using an HPLC method with ultraviolet (UV) detection, according to a previously reported method [12]. Dexamethasone concentrations were measured using an HPLC method with UV detection.…”

Section: Methodsmentioning

confidence: 99%

Effects of a rifampicin pre-treatment on linezolid pharmacokinetics

Oakazaki

Tsuji

Seto

et al. 2019

Preprint

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Keywords 2 1 linezolid; rifampicin; pharmacokinetics; metabolic enzymes 2 2 2 3 Word count: 1,658 words 2 4 Abstract 2 6Linezolid is an oxazolidinone antibiotic that effectively treats methicillin-resistant 2 7Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Since 2 8 rifampicin induces other antibiotic effects, it is combined with linezolid in therapeutic regimes. 9However, linezolid blood concentrations are reduced by this combination, which increases the 3 0 risk of the emergence of antibiotic-resistant bacteria. We herein demonstrated that the 3 1 combination of linezolid with rifampicin inhibited its absorption and promoted its elimination, 3 2 but not through microsomal enzymes. Our results indicate that the combination of linezolid 3 3 with rifampicin reduces linezolid blood concentrations via metabolic enzymes. 3 4 3 5

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From Therapeutic Drug Monitoring to Model‐Informed Precision Dosing for Antibiotics

Wicha

Märtson

Nielsen

et al. 2021

Clin Pharma and Therapeutics

159

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(ISAP), the PK/PD study group of the European Society of Clinical Microbiology, Infectious Diseases (EPASG) Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have evolved as important tools to inform rational dosing of antibiotics in individual patients with infections. In particular, critically ill patients display altered, highly variable pharmacokinetics and often suffer from infections caused by less susceptible bacteria. Consequently, TDM has been used to individualize dosing in this patient group for many years. More recently, there has been increasing research on the use of MIPD software to streamline the TDM process, which can increase the flexibility and precision of dose individualization but also requires adequate model validation and re-evaluation of existing workflows. In parallel, new minimally invasive and noninvasive technologies such as microneedle-based sensors are being developed, which-together with MIPD software-have the potential to revolutionize how patients are dosed with antibiotics. Nonetheless, carefully designed clinical trials to evaluate the benefit of TDM and MIPD approaches are still sparse, but are critically needed to justify the implementation of TDM and MIPD in clinical practice. The present review summarizes the clinical pharmacology of antibiotics, conventional TDM and MIPD approaches, and evidence of the value of TDM/MIPD for aminoglycosides, beta-lactams, glycopeptides, and linezolid, for which precision dosing approaches have been recommended.

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Population pharmacokinetics and pharmacodynamics of linezolid‐induced thrombocytopenia in hospitalized patients

Cited by 82 publications

References 73 publications

Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety

Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety

Effects of a rifampicin pre-treatment on linezolid pharmacokinetics

From Therapeutic Drug Monitoring to Model‐Informed Precision Dosing for Antibiotics

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