• Int. J. Antimicrob. Agents · Sep 2014

    Analysis of thrombocytopenic effects and population pharmacokinetics of linezolid: a dosage strategy according to the trough concentration target and renal function in adult patients.

    • Kazuaki Matsumoto, Akari Shigemi, Ayumi Takeshita, Erika Watanabe, Yuta Yokoyama, Kazuro Ikawa, Norifumi Morikawa, and Yasuo Takeda.
    • Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
    • Int. J. Antimicrob. Agents. 2014 Sep 1; 44 (3): 242-7.

    AbstractThe pharmacokinetic/pharmacodynamic (PK/PD) index for the efficacy of linezolid is a 24-h area under the plasma drug concentration-time curve (AUC₂₄)/minimum inhibitory concentration (MIC) ratio of ≥100. The main adverse event associated with administration of linezolid is thrombocytopenia. Therefore, the aims of the present study were to define PD thresholds that would minimise linezolid-induced thrombocytopenia and to perform a population PK analysis to identify factors influencing the pharmacokinetics of linezolid. Population PK analysis revealed that creatinine clearance (CLCr) significantly affected linezolid pharmacokinetics: the mean parameter estimate of drug clearance (CL; in L/h)=0.0258 × CLCr + 2.03. A strong correlation (r=0.970) was found between AUC₂₄ and trough plasma concentrations (Cmin) [AUC₂₄=18.2 × Cmin + 134.4]. The Cmin value for AUC₂₄=200 (in the case of MIC=2 μg/mL) was estimated to be 3.6 μg/mL. Regarding safety, Cmin was a significant predictor of thrombocytopenia during treatment, and its threshold to minimise linezolid-induced thrombocytopenia was 8.2 μg/mL. A Kaplan-Meier plot revealed that the median time from initiation of therapy to the development of thrombocytopenia was 15 days. Therefore, the target Cmin range was 3.6-8.2 μg/mL. The following formula to achieve a target Cmin in patients with different degrees of renal function was proposed based on these results: initial daily dose (mg/day)=CL × AUC₂₄=(0.0258 × CLCr + 2.03)×(18.2 × Cmin + 134.4). This recommended initial dosage and subsequent dosage adjustment for the target concentration range should avoid adverse events, thereby enabling effective linezolid-based therapies to be continued.Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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