Clinical population pharmacokinetics and toxicodynamics of linezolid

Lauren Marie Boak, Craig Robert Rayner, M Lindsay Grayson, David L Paterson, Dennis Spelman, Sharmila Khumra, Blair Capitano, Alan Forrest, Jian Li, Roger Leigh Nation, Jurgen Bernd Bulitta

Research output: Contribution to journalArticleResearchpeer-review

51 Citations (Scopus)

Abstract

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 toxico-dynamics 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
Original languageEnglish
Pages (from-to)2334 - 2343
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number4
DOIs
Publication statusPublished - 2014

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