Journal
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Volume 44, Issue 3, Pages 242-247Publisher
ELSEVIER
DOI: 10.1016/j.ijantimicag.2014.05.010
Keywords
Linezolid; Population pharmacokinetics; Thrombocytopenia; Therapeutic drug monitoring
Funding
- Japan Society for the Promotion of Science [21928024]
- Grants-in-Aid for Scientific Research [21928024, 24590659] Funding Source: KAKEN
Ask authors/readers for more resources
The pharmacokinetic/pharmacodynamic (PK/PD) index for the efficacy of linezolid is a 24-h area under the plasma drug concentration-time curve (AUC(24))/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 x CLCr + 2.03. A strong correlation (r=0.970) was found between AUC(24) and trough plasma concentrations (C.) [AUC(24)=18.2 x C-min + 134.4]. The Cmin value for AUC(24)=200 (in the case of MIC=2 mu g/mL) was estimated to be 3.6 mu g/mL. Regarding safety, Cmin was a significant predictor of thrombocytopenia during treatment, and its threshold to minimise linezolid-induced thrombocytopenia was 8.2 mu g/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 C. range was 3.6-8.2 mu g/mL. The following formula to achieve a target C. in patients with different degrees of renal function was proposed based on these results: initial daily dose (mg/day) = CL x AUC(24) = (0.0258 x CLCr + 2.03) x (18.2 x C-min + 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. (C) 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available