CLINICAL PHARMACOLOGY
In a randomized, positive- and placebo-controlled crossover thorough QT study, 40 healthy subjects were administered a single ZYVOX 600 mg dose via a 1 hour IV infusion, a single ZYVOX 1200 mg dose via a 1 hour IV infusion, placebo, and a single oral dose of positive control. At both the 600 mg and 1200 mg ZYVOX doses, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.
The mean pharmacokinetic parameters of linezolid in adults after single and multiple oral and intravenous (IV) doses are summarized in Table 1. Plasma concentrations of linezolid at steady-state after oral doses of 600 mg given every 12 hours (q12h) are shown in Figure 1.
Table 1. Mean (Standard Deviation) Pharmacokinetic Parameters of Linezolid in Adults
Dose of Linezolid |
Cmax
µg/mL |
Cmin
µg/mL |
Tmax
hrs |
AUC *
µg ∙ h/mL |
t1/2
hrs |
CL mL/min |
400 mg tablet
single dose †
every 12 hours
|
8.10 (1.83) 11.00 (4.37) |
---
3.08 (2.25) |
1.52 (1.01) 1.12 (0.47) |
55.10 (25.00) 73.40 (33.50) |
5.20 (1.50) 4.69 (1.70) |
146 (67) 110 (49) |
600 mg tablet
single dose
every 12 hours
|
12.70 (3.96) 21.20 (5.78) |
---
6.15 (2.94) |
1.28 (0.66) 1.03 (0.62) |
91.40 (39.30) 138.00 (42.10) |
4.26 (1.65) 5.40 (2.06) |
127 (48) 80 (29) |
600 mg IV injection
‡
single dose
every 12 hours
|
12.90 (1.60) 15.10 (2.52) |
---
3.68 (2.36) |
0.50 (0.10) 0.51 (0.03) |
80.20 (33.30) 89.70 (31.00) |
4.40 (2.40) 4.80 (1.70) |
138 (39) 123 (40) |
600 mg oral suspension
single dose |
11.00 (2.76) |
--- |
0.97 (0.88) |
80.80 (35.10) |
4.60 (1.71) |
141 (45) |
AUC for single dose = AUC
Data dose-normalized from 375 mg
Data dose-normalized from 625 mg, IV dose was given as 0.5-hour infusion.
Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean ± Standard Deviation, n=16)
Linezolid is rapidly and extensively absorbed after oral dosing. Maximum plasma concentrations are reached approximately 1 to 2 hours after dosing, and the absolute bioavailability is approximately 100%. Therefore, linezolid may be given orally or intravenously without dose adjustment.
Linezolid may be administered without regard to the timing of meals. The time to reach the maximum concentration is delayed from 1.5 hours to 2.2 hours and Cmax is decreased by about 17% when high fat food is given with linezolid. However, the total exposure measured as AUC0-∞ values is similar under both conditions.
Animal and human pharmacokinetic studies have demonstrated that linezolid readily distributes to well-perfused tissues. The plasma protein binding of linezolid is approximately 31% and is concentration-independent. The volume of distribution of linezolid at steady-state averaged 40 to 50 liters in healthy adult volunteers.
Linezolid concentrations have been determined in various fluids from a limited number of subjects in Phase 1 volunteer studies following multiple dosing of linezolid. The ratio of linezolid in saliva relative to plasma was 1.2 to 1 and for sweat relative to plasma was 0.55 to 1.
Linezolid is primarily metabolized by oxidation of the morpholine ring, which results in two inactive ring-opened carboxylic acid metabolites: the aminoethoxyacetic acid metabolite (A), and the hydroxyethyl glycine metabolite (B). Formation of metabolite A is presumed to be formed via an enzymatic pathway whereas metabolite B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. In vitro studies have demonstrated that linezolid is minimally metabolized and may be mediated by human cytochrome P450. However, the metabolic pathway of linezolid is not fully understood.
Nonrenal clearance accounts for approximately 65% of the total clearance of linezolid. Under steady-state conditions, approximately 30% of the dose appears in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The renal clearance of linezolid is low (average 40 mL/min) and suggests net tubular reabsorption. Virtually no linezolid appears in the feces, while approximately 6% of the dose appears in the feces as metabolite B, and 3% as metabolite A.
A small degree of nonlinearity in clearance was observed with increasing doses of linezolid, which appears to be due to lower renal and nonrenal clearance of linezolid at higher concentrations. However, the difference in clearance was small and was not reflected in the apparent elimination half-life.
The pharmacokinetics of linezolid are not significantly altered in elderly patients (65 years or older). Therefore, dose adjustment for geriatric patients is not necessary.
The pharmacokinetics of linezolid following a single IV dose were investigated in pediatric patients ranging in age from birth through 17 years (including premature and full-term neonates), in healthy adolescent subjects ranging in age from 12 through 17 years, and in pediatric patients ranging in age from 1 week through 12 years. The pharmacokinetic parameters of linezolid are summarized in Table 2 for the pediatric populations studied and healthy adult subjects after administration of single IV doses.
The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, clearance is most rapid in the youngest age groups ranging from >1 week old to 11 years, resulting in lower single-dose systemic exposure (AUC) and shorter half-life as compared with adults. As age of pediatric patients increases, the clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is wider inter-subject variability in linezolid clearance and systemic drug exposure (AUC) across all pediatric age groups as compared with adults.
Similar mean daily AUC values were observed in pediatric patients from birth to 11 years of age dosed every 8 hours (q8h) relative to adolescents or adults dosed every 12 hours (q12h). Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg q8h. Pediatric patients 12 years and older should receive 600 mg q12h (see
DOSAGE AND ADMINISTRATION).
Table 2. Pharmacokinetic Parameters of Linezolid in Pediatrics and Adults Following a Single Intravenous Infusion of 10 mg/kg or 600 mg Linezolid (Mean: (%CV); [Min, Max Values])
Age Group |
Cmax
µg/mL |
Vss
L/kg |
AUC *
µg•h/mL |
t 1/2
hrs |
CL mL/min/kg |
Neonatal Patients Pre-term †
< 1 week (N=9) ‡
|
12.7 (30%) [9.6, 22.2] |
0.81 (24%) [0.43, 1.05] |
108 (47%) [41, 191] |
5.6 (46%) [2.4, 9.8] |
2.0 (52%) [0.9, 4.0] |
Full-term §
< 1 week (N=10)
|
11.5 (24%) [8.0, 18.3] |
0.78 (20%) [0.45, 0.96] |
55 (47%) [19, 103] |
3.0 (55%) [1.3, 6.1] |
3.8 (55%) [1.5, 8.8] |
Full-term
≥ 1 week to ≤ 28 days (N=10)
|
12.9 (28%) [7.7, 21.6] |
0.66 (29%) [0.35, 1.06] |
34 (21%) [23, 50] |
1.5 (17%) [1.2, 1.9] |
5.1 (22%) [3.3, 7.2] |
Infant Patients > 28 days to < 3 Months (N=12)
|
11.0 (27%) [7.2, 18.0] |
0.79 (26%) [0.42, 1.08] |
33 (26%) [17, 48] |
1.8 (28%) [1.2, 2.8] |
5.4 (32%) [3.5, 9.9] |
Pediatric Patients 3 months through 11 years (N=59) |
15.1 (30%) [6.8, 36.7] |
0.69 (28%) [0.31, 1.50] |
58 (54%) [19, 153] |
2.9 (53%) [0.9, 8.0] |
3.8 (53%) [1.0, 8.5] |
Adolescent Subjects and Patients 12 through 17 years ¶ (N=36) |
16.7 (24%) [9.9, 28.9] |
0.61 (15%) [0.44, 0.79] |
95 (44%) [32, 178] |
4.1 (46%) [1.3, 8.1] |
2.1 (53%) [0.9, 5.2] |
Adult Subjects # (N= 29) |
12.5 (21%) [8.2, 19.3] |
0.65 (16%) [0.45, 0.84] |
91 (33%) [53, 155] |
4.9 (35%) [1.8, 8.3] |
1.7 (34%) [0.9, 3.3] |
AUC = Single dose AUC
In this data set, "pre-term" is defined as <34 weeks gestational age (Note: Only 1 patient enrolled was pre-term with a postnatal age between 1 week and 28 days)
Dose of 600 mg or 10 mg/kg up to a maximum of 600 mg
Dose normalized to 600 mg
Females have a slightly lower volume of distribution of linezolid than males. Plasma concentrations are higher in females than in males, which is partly due to body weight differences. After a 600-mg dose, mean oral clearance is approximately 38% lower in females than in males. However, there are no significant gender differences in mean apparent elimination-rate constant or half-life. Thus, drug exposure in females is not expected to substantially increase beyond levels known to be well tolerated. Therefore, dose adjustment by gender does not appear to be necessary.
The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any degree of renal insufficiency; however, the two primary metabolites of linezolid may accumulate in patients with renal insufficiency, with the amount of accumulation increasing with the severity of renal dysfunction (see Table 3). The clinical significance of accumulation of these two metabolites has not been determined in patients with severe renal insufficiency. Because similar plasma concentrations of linezolid are achieved regardless of renal function, no dose adjustment is recommended for patients with renal insufficiency. However, given the absence of information on the clinical significance of accumulation of the primary metabolites, use of linezolid in patients with renal insufficiency should be weighed against the potential risks of accumulation of these metabolites. Both linezolid and the two metabolites are eliminated by dialysis. No information is available on the effect of peritoneal dialysis on the pharmacokinetics of linezolid. Approximately 30% of a dose was eliminated in a 3-hour dialysis session beginning 3 hours after the dose of linezolid was administered; therefore, linezolid should be given after hemodialysis.
Table 3. Mean (Standard Deviation) AUCs and Elimination Half-lives of Linezolid and Metabolites A and B in Patients with Varying Degrees of Renal Insufficiency After a Single 600-mg Oral Dose of Linezolid
Parameter |
Healthy Subjects CLCR > 80 mL/min |
Moderate Renal Impairment 30 < CLCR < 80 mL/min |
Severe Renal Impairment 10 < CLCR < 30 mL/min |
Hemodialysis-Dependent |
Off Dialysis *
|
On Dialysis |
Linezolid
|
AUC0–∞, µg h/mL |
110 (22) |
128 (53) |
127 (66) |
141 (45) |
83 (23) |
t1/2, hours |
6.4 (2.2) |
6.1 (1.7) |
7.1 (3.7) |
8.4 (2.7) |
7.0 (1.8) |
Metabolite A
|
AUC0–48, µg h/mL |
7.6 (1.9) |
11.7 (4.3) |
56.5 (30.6) |
185 (124) |
68.8 (23.9) |
t1/2, hours |
6.3 (2.1) |
6.6 (2.3) |
9.0 (4.6) |
NA |
NA |
Metabolite B
|
AUC0–48, µg h/mL |
30.5 (6.2) |
51.1 (38.5) |
203 (92) |
467 (102) |
239 (44) |
t1/2, hours |
6.6 (2.7) |
9.9 (7.4) |
11.0 (3.9) |
NA |
NA |
between hemodialysis sessions
The pharmacokinetics of linezolid are not altered in patients (n=7) with mild-to-moderate hepatic insufficiency (Child-Pugh class A or B). On the basis of the available information, no dose adjustment is recommended for patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of linezolid in patients with severe hepatic insufficiency have not been evaluated.
Linezolid is not an inducer of cytochrome P450 (CYP450) in rats. In addition, linezolid does not inhibit the activities of clinically significant human CYP isoforms (e.g., 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by these major enzymes. Concurrent administration of linezolid does not substantially alter the pharmacokinetic characteristics of (S)-warfarin, which is extensively metabolized by CYP2C9. Drugs such as warfarin and phenytoin, which are CYP2C9 substrates, may be given with linezolid without changes in dosage regimen.
Aztreonam: The pharmacokinetics of linezolid or aztreonam are not altered when administered together.
Gentamicin: The pharmacokinetics of linezolid or gentamicin are not altered when administered together.
Rifampin: The effect of rifampin on the pharmacokinetics of linezolid was evaluated in a study of 16 healthy adult males. Volunteers were administered oral linezolid 600 mg twice daily for 5 doses with and without rifampin 600 mg once daily for 8 days. Co-administration of rifampin with linezolid resulted in a 21% decrease in linezolid Cmax [90% CI, 15% – 27%] and a 32% decrease in linezolid AUC0–12 [90% CI, 27% – 37%]. The mechanism of this interaction is not fully understood and may be related to the induction of hepatic enzymes (see
PRECAUTIONS, Drug Interactions).
Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.
Adrenergic Agents: A significant pressor response has been observed in normal adult subjects receiving linezolid and tyramine doses of more than 100 mg. Therefore, patients receiving linezolid need to avoid consuming large amounts of foods or beverages with high tyramine content (see
PRECAUTIONS, Information for Patients).
A reversible enhancement of the pressor response of either pseudoephedrine HCl (PSE) or phenylpropanolamine HCl (PPA) is observed when linezolid is administered to healthy normotensive subjects (see
PRECAUTIONS, Drug Interactions). A similar study has not been conducted in hypertensive patients. The interaction studies conducted in normotensive subjects evaluated the blood pressure and heart rate effects of placebo, PPA or PSE alone, linezolid alone, and the combination of steady-state linezolid (600 mg q12h for 3 days) with two doses of PPA (25 mg) or PSE (60 mg) given 4 hours apart. Heart rate was not affected by any of the treatments. Blood pressure was increased with both combination treatments. Maximum blood pressure levels were seen 2 to 3 hours after the second dose of PPA or PSE, and returned to baseline 2 to 3 hours after peak. The results of the PPA study follow, showing the mean (and range) maximum systolic blood pressure in mm Hg: placebo = 121 (103 to 158); linezolid alone = 120 (107 to 135); PPA alone = 125 (106 to 139); PPA with linezolid = 147 (129 to 176). The results from the PSE study were similar to those in the PPA study. The mean maximum increase in systolic blood pressure over baseline was 32 mm Hg (range: 20–52 mm Hg) and 38 mm Hg (range: 18–79 mm Hg) during co-administration of linezolid with pseudoephedrine or phenylpropanolamine, respectively.
Serotonergic Agents: The potential drug-drug interaction with dextromethorphan was studied in healthy volunteers. Subjects were administered dextromethorphan (two 20-mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.
Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains.
In clinical trials, resistance to linezolid developed in 6 patients infected with Enterococcus faecium (4 patients received 200 mg q12h, lower than the recommended dose, and 2 patients received 600 mg q12h). In a compassionate use program, resistance to linezolid developed in 8 patients with E. faecium and in 1 patient with Enterococcus faecalis. All patients had either unremoved prosthetic devices or undrained abscesses. Resistance to linezolid occurs in vitro at a frequency of 1 x 10 –9 to 1 x 10 –11. In vitro studies have shown that point mutations in the 23S rRNA are associated with linezolid resistance. Reports of vancomycin-resistant E. faecium becoming resistant to linezolid during its clinical use have been published.1 In one report nosocomial spread of vancomycin- and linezolid-resistant E. faecium occurred 2. There has been a report of Staphylococcus aureus (methicillin-resistant) developing resistance to linezolid during its clinical use.3 The linezolid resistance in these organisms was associated with a point mutation in the 23S rRNA (substitution of thymine for guanine at position 2576) of the organism. When antibiotic-resistant organisms are encountered in the hospital, it is important to emphasize infection control policies.4, 5 Resistance to linezolid has not been reported in Streptococcus spp., including Streptococcus pneumoniae.
In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, or streptomycin.
Linezolid has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.
Enterococcus faecium (vancomycin-resistant strains only)
Staphylococcus aureus (including methicillin-resistant strains)
Streptococcus agalactiae
Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP] 1)
Streptococcus pyogenes
The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for linezolid. However, the safety and effectiveness of linezolid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Enterococcus faecalis (including vancomycin-resistant strains)
Enterococcus faecium (vancomycin-susceptible strains)
Staphylococcus epidermidis (including methicillin-resistant strains)
Staphylococcus haemolyticus
Viridans group streptococci
Pasteurella multocida
NOTE: Susceptibility testing by dilution methods requires the use of linezolid susceptibility powder.
When available, the results of in vitro susceptibility tests should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method 6,7 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of linezolid powder. The MIC values should be interpreted according to criteria provided in Table 4.
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 7,
8 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 µg of linezolid to test the susceptibility of microorganisms to linezolid. The disk diffusion interpretive criteria are provided in Table 4.
Table 4. Susceptibility Interpretive Criteria for Linezolid
Pathogen |
Susceptibility Interpretive Criteria |
Minimal Inhibitory Concentrations (MIC in µg/mL) |
Disk Diffusion (Zone Diameters in mm) |
S |
I |
R |
S |
I |
R |
Enterococcus spp |
≤ 2 |
4 |
≥8 |
≥ 23 |
21–22 |
≤20 |
Staphylococcus spp *
|
≤4 |
--- |
--- |
≥ 21 |
--- |
--- |
Streptococcus pneumoniae
|
≤2 †
|
--- |
--- |
≥ 21 ‡
|
--- |
--- |
Streptococcus spp other than S pneumoniae
|
≤2
|
--- |
--- |
≥ 21
|
--- |
--- |
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard linezolid powder should provide the following range of values noted in Table 5. NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.
Table 5. Acceptable Quality Control Ranges for Linezolid to be Used in Validation of Susceptibility Test Results
QC Strain |
Acceptable Quality Control Ranges |
Minimum Inhibitory Concentration (MIC in µg/mL) |
Disk Diffusion (Zone Diameters in mm) |
Enterococcus faecalis
ATCC 29212 |
1 – 4 |
Not applicable |
Staphylococcus aureus
ATCC 29213 |
1 – 4 |
Not applicable |
Staphylococcus aureus
ATCC 25923 |
Not applicable |
25 – 32 |
Streptococcus pneumoniae
ATCC 49619 *
|
0.50 – 2 †
|
25 – 34 ‡
|
This organism may be used for validation of susceptibility test results when testing S
This quality control range for
This quality control zone diameter range is applicable only to tests performed using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood inoculated with a direct colony suspension and incubated in 5% CO
ANIMAL PHARMACOLOGY & OR TOXICOLOGY
Target organs of linezolid toxicity were similar in juvenile and adult rats and dogs. Dose- and time-dependent myelosuppression, as evidenced by bone marrow hypocellularity/decreased hematopoiesis, decreased extramedullary hematopoiesis in spleen and liver, and decreased levels of circulating erythrocytes, leukocytes, and platelets have been seen in animal studies. Lymphoid depletion occurred in thymus, lymph nodes, and spleen. Generally, the lymphoid findings were associated with anorexia, weight loss, and suppression of body weight gain, which may have contributed to the observed effects.
In rats administered linezolid orally for 6 months, non-reversible, minimal to mild axonal degeneration of sciatic nerves was observed at 80 mg/kg/day; minimal degeneration of the sciatic nerve was also observed in 1 male at this dose level at a 3-month interim necropsy. Sensitive morphologic evaluation of perfusion-fixed tissues was conducted to investigate evidence of optic nerve degeneration. Minimal to moderate optic nerve degeneration was evident in 2 male rats after 6 months of dosing, but the direct relationship to drug was equivocal because of the acute nature of the finding and its asymmetrical distribution. The nerve degeneration observed was microscopically comparable to spontaneous unilateral optic nerve degeneration reported in aging rats and may be an exacerbation of common background change.
These effects were observed at exposure levels that are comparable to those observed in some human subjects. The hematopoietic and lymphoid effects were reversible, although in some studies, reversal was incomplete within the duration of the recovery period.
|