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Antimicrobial Agents and Chemotherapy, February 2003, p. 548-553, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.548-553.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Linezolid in Patients Treated in a Compassionate-Use Program

Alison K. Meagher,1 Alan Forrest,1,2 Craig R. Rayner,1,{dagger} Mary C. Birmingham,1 and Jerome J. Schentag1,2*

CPL Associates, LLC, Amherst, New York,1 The School of Pharmacy, State University of New York at Buffalo, Buffalo, New York2

Received 30 October 2001/ Returned for modification 24 August 2002/ Accepted 31 October 2002

Data obtained from 318 adult patients treated under the linezolid compassionate-use protocol were used to develop a population model of the pharmacokinetics of intravenous and oral linezolid. All of the patients received 600 mg of linezolid every 12 h, intravenously and/or orally. Blood samples (2 to 10 per patient; median, 4) were obtained and assayed for linezolid by high-performance liquid chromatography. These data and patient covariates were modeled by iterative two-stage analysis, and model discrimination was done by Akaike's information criterion. Of the patient covariates considered (age, sex, ideal body weight, baseline serum albumin, hepatic or renal dysfunction, underlying malignancy, organ transplantation, surgical status, global severity of illness, site of infection, route of administration, and location of care [intensive-care unit, general floor, or outpatient]), only normalized creatinine clearance (CLCR) and body weight explained significant portions of the variance and were incorporated into the pharmacokinetic model. The final model included central and peripheral compartments with parallel capacity-limited (nonrenal) and first-order (renal [CLR]) clearances. Volumes and clearances were normalized to the ideal body weight, and CLR was modeled as proportional to CLCR. Compared to previously studied adult volunteers, intrinsic clearance was ~60% higher and the maximum rate of metabolism was twice as high in these debilitated patients, resulting in lower area under the time-concentration curve (AUC) values (P < 0.001). The derived 24-h AUC, averaged over the first 7 days of treatment, ranged between 57 and 871 (median, 191) µg/ml · 24 h. Despite these variations, linezolid provided high rates of clinical cure, as well as microbiological success, in the patients treated in the compassionate-use program. The mechanism(s) of these pharmacokinetic differences is unknown and requires further mechanistic study.

* Corresponding author. Mailing address: Departments of Pharmaceutics and Pharmacy, State University of New York at Buffalo, 543 Hochstetter Hall, Buffalo, NY 14260. Phone: (716) 867-0550. Fax: (716) 839-5138. E-mail: schentag{at}buffalo.edu.

{dagger} Present address: Victorian College of Pharmacy, Monash University, Parkville, VIC 3052, Australia.

Antimicrobial Agents and Chemotherapy, February 2003, p. 548-553, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.548-553.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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