Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

Abstract

h Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/ liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10-to 28-day therapy for platelet nadirs of <100 ؋10 9 / liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.

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

“…A model with three transit compartments adequately described the time course of thrombocytopenia. A more complex model with 30 compartments for platelet formation and elimination did not improve the fit.…”

“…The population pharmacokinetics of linezolid have been previously described using noncompartmental and compartmental models . The pharmacokinetic analysis in the present study was performed using a two‐compartment model with first‐order absorption and first‐order elimination.…”

Mielosupresión inducida por linezolid: un caso pediátrico

“…En los ensayos pediátricos, la tasa de efectos adversos relacionada con el uso de linezolid 4,5,6,7 varía entre 18% y 25%. Los más frecuentes son los trastornos gastrointestinales, la cefalea, el rash cutáneo y los trastornos hematológicos; son excepcionales la neuropatía periférica u óptica.…”

Effect of Linezolid on Hematologic Recovery in Newly Diagnosed Acute Myeloid Leukemia Patients Following Induction Chemotherapy

“…Outside of the oncology population, linezolid has been associated with hematologic toxicity, particularly when therapy is extended beyond 10–14 days. Thrombocytopenia has been documented as the most common hematologic toxicity; however, linezolid has also been associated with neutropenia . Limited data are available as to the true impact of linezolid on a recovering bone marrow following chemotherapy‐induced neutropenia.…”