Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers.
OBJECTIVE
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.
Stalker
Dennis J
DJ
Department of Clinical Pharmacology, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, MI 49007, USA.
Jungbluth
Gail L
GL
Hopkins
Nancy K
NK
Batts
Donald H
DH
D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D000069349:Linezolid; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*
D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid