Linezolid is the first antibacterial to be approved from the oxazolidinone class. The drug has substantial antimicrobial activity against Gram-positive organisms such as streptococci, staphylococci and enterococci, including species resistant to conventional antibacterial treatment. Linezolid is fully bioavailable following oral administration when compared with intravenous administration. Maximum plasma linezolid concentrations are usually achieved between 1 and 2 hours after oral administration. Food slightly decreases the rate, but not the extent, of absorption. The distribution of linezolid is approximately equivalent to total body water, and there is low protein binding (31%) to serum albumin. The elimination half-life of linezolid is 5-7 hours, and twice-daily administration of 400-600 mg provides steady-state concentrations in the therapeutic range. Linezolid is mainly cleared by non-renal clearance to two metabolites and renal clearance of the parent compound. Approximately 50% of an administered dose appears in the urine as the two major metabolites, and approximately 35% appears as parent drug. A small degree of nonlinearity has been observed, with a 30% decrease in clearance after a 5-fold increase in dose. The nonlinearity is not relevant over the therapeutic dosage range. Plasma linezolid concentrations in elderly patients, patients with mild to moderate hepatic impairment or mild to severe renal impairment are similar to those achieved in young or healthy volunteers. Higher concentrations are observed in women as compared with men, but the difference is not sufficient to warrant an adjustment in dosage. In patients with severe renal impairment requiring haemodialysis, the exposure to the two primary metabolites was 7 to 8-fold higher than in patients with normal renal function. Therefore, linezolid should be used with caution in patients with severe renal insufficiency. A higher clearance of linezolid was found in children as compared with adults, and therefore higher daily dosages per kg bodyweight are required in children. There is no pharmacokinetic interaction when linezolid is coadministered with aztreonam, gentamicin or warfarin. Linezolid is a mild, reversible, inhibitor of monoamine oxidases A and B. Coadministration of linezolid with the adrenergic agents pseudoephedrine and phenylpropanolamine resulted in increases in blood pressure relative to these agents alone or to placebo. The degree of the change in blood pressure was within that associated with normal daily activities. No interaction was observed when linezolid was coadministered with the serotonergic agent dextromethorphan.

Linezolid is a member of a new, unique class of synthetic antibacterial agents called oxazolidinones that are effective against gram-positive bacteria, including vancomycin-resistant organisms. We tested the hypothesis that the linezolid clearance would not be altered in subjects with renal dysfunction. Twenty-four subjects with renal function that ranged from normal to severe chronic impairment were enrolled, including patients with end-stage renal disease who were maintained on hemodialysis. Hemodialysis subjects were studied while they were both on and off dialysis. Linezolid was administered as a single oral 600-mg dose, and plasma and urine samples were assayed for linezolid and metabolites for 48 h for all subjects and for up to 96 h for those subjects with impaired renal function not on dialysis. The total apparent oral clearance of linezolid did not change with renal function and ranged from 92.5 to 109.6 ml/min for subjects not requiring dialysis. For subjects on dialysis, the total apparent oral clearance increased from 76.6 ml/min on their off-dialysis day to 130.0 ml/min on their on-dialysis day. Approximately one-third of the dose was removed by dialysis. However, those subjects with severe renal insufficiency (creatinine clearance, <40 ml/min) and those with end-stage renal disease maintained on hemodialysis had higher concentrations of both metabolites. We conclude that no adjustment of the linezolid dosage is needed in subjects with renal dysfunction or subjects on hemodialysis.

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.

The International Conference on Harmonization (ICH) E5 guidelines were developed to provide a general framework for evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data, with the underlying objective to facilitate global drug development and registration. It is well recognized that all drugs exhibit significant inter-subject variability in pharmacokinetics and pharmacologic response and that such differences vary considerably among individual drugs and depend on a variety of factors. One such potential factor involves ethnicity. The objective of the present work was to perform an extensive review of the world literature on ethnic differences in drug disposition and responsiveness to determine their general significance in relation to drug development and registration. A few examples of suspected ethnic differences in pharmacokinetics or pharmacodynamics were identified. The available literature, however, was found to be heterologous, including a variety of study designs and research methodologies, and most of the publications were on drugs that were approved a long time ago.

Linezolid is a novel oxazolidinone antibiotic that has a spectrum of activity encompassing a variety of Gram-positive bacteria. The objectives of this study were twofold: (1) to compare the absorption of linezolid tablets given immediately following a high-fat meal with the absorption of tablets administered while fasting, and (2) to assess the bioavailability of a 375-mg oral dose given while fasting relative to a 375-mg dose of linezolid sterile solution given intravenously. Venous blood samples were taken over the 48 h following the single dose administration of both the oral and intravenous (IV) treatment. Samples were subsequently frozen for the determination of linezolid concentrations by HPLC. The only statistically significant difference between the fasted and the fed treatment was in peak plasma concentration, with the mean C(max) for fasted subjects being 23% greater than that for subjects after consumption of a high-fat meal. Comparable AUC(0-infinity) values were measured under both conditions, indicating that the overall extent of absorption is the same. Therefore, the difference in C(max), while statistically significant, should not affect the therapeutic efficacy of linezolid when it is administered with food. There were no statistically significant differences in AUC(0-infinity), CL or half-life between the fasted oral treatment and the intravenous treatment. As expected, C(max) was statistically different between the two treatments. However, the mean absolute bioavailability (F) of the tablet, using the IV sterile solution as the reference treatment, was 103% (+/-20%).