JAC Advance Access published online on March 28, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg180
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original Article
1 Department of Clinical
Pharmacology, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo,
MI 49007
* Corresponding author. E-mail: gail.l.jungbluth{at}pharmacia.com.
Received 28 March 2002
; revised 19 September 2002
; accepted 21 January 2003
Aims: To determine the pharmacokinetics
and tolerance of oral and intravenous linezolid, an oxazolidinone
antibiotic, in healthy volunteers following single- and multiple-dose
administration. Methods: In two randomized, double-blind, placebo-controlled,
dose-escalating trials, subjects were exposed either to oral (375,
500 or 625 mg) or intravenous (500 or 625 mg) linezolid or placebo
twice daily. Serial blood and urine samples were obtained after
the first- and multiple-dose administrations for up to 18 days.
Non-compartmental pharmacokinetic analyses were used to describe
the disposition of linezolid. Results: Plasma linezolid concentrations and
area under the concentration-time curves increased proportionally
with dose irrespective of the route of administration. Plasma linezolid concentrations
remained above the MIC90 for susceptible target pathogens
(4.0 mg/L) for the majority of the 12 h dosing interval. Mean clearance,
half-life and volume of distribution were similar irrespective of
dose for both the oral and intravenous routes. Linezolid was well tolerated and
the frequency of drug-related adverse events was similar between
the linezolid and placebo groups. Conclusions: Oral and intravenous linezolid
exhibit linear pharmacokinetics, with concentrations remaining above
the target MIC90 for most of the dosing interval. These
results support a twice-daily schedule for linezolid and demonstrate
the feasibility of converting from intravenous to oral dosing without
a dose adjustment.
Keywords: pharmacokinetics, linezolid, oxazolidinones,
volunteers, Gram-positive, clinical trial
Pharmacokinetics and tolerance of single- and multiple-dose
oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy
volunteers
2 Kalamazoo Center
for Medical Studies, Michigan State University, Kalamazoo, MI, USA
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