Linezolid

LINEZOLID- linezolid tablet
Glenmark Generics Inc., USA

To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid formulations and other antibacterial drugs, linezolid tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Linezolid tablets contain linezolid, which is a synthetic antibacterial agent of the oxazolidinone class. The chemical name for linezolid is (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide.

The empirical formula is C16 H20 FN3 O4 . Its molecular weight is 337.35, and its chemical structure is represented below:

Chemical Structure of Linezolid
(click image for full-size original)

Linezolid tablets for oral administration contain 600 mg linezolid as white to off-white, oval, biconvex, uncoated tablets. Inactive ingredients are croscarmellose sodium, NF; lactose monohydrate, NF; magnesium stearate, NF; povidone, USP and opadry Y-1-7000. Opadry Y-1-7000 consists of hypromellose, polyethylene glycol 400 and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacokinetics

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 LinezolidCmax µg/mLCmin µg/mLTmax hrsAUC *µg ∙ h/mLt1/2 hrsCLmL/min
Cmax = Maximum plasma concentration; Cmin = Minimum plasma concentration; Tmax = Time to Cmax ; AUC = Area under concentration-time curve; t1/2 = Elimination half-life; CL = Systemic clearance
*
AUC for single dose = AUC0–∞ ; for multiple-dose = AUC0–τ
Data dose-normalized from 375 mg
Data dose-normalized from 625 mg, IV dose was given as 0.5-hour infusion.
400 mg tablet single dose every 12 hours8.10(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 hours12.70(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 hours12.90(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 dose11.00(2.76)0.97(0.88)80.80(35.10)4.60(1.71)141(45)

Figure 1
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Figure 1. Plasma Concentrations of Linezolid in Adults at Steady-State Following Oral Dosing Every 12 Hours (Mean ± Standard Deviation, n=16)

Absorption:

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 AUC0-8 values is similar under both conditions.

Distribution:

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.

Metabolism:

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 B is mediated by a non-enzymatic chemical oxidation mechanism in vitro. Linezolid is not an inducer of cytochrome P450 (CYP) in rats, and it has been demonstrated from in vitro studies that linezolid is not detectably metabolized by human cytochrome P450 and it does not inhibit the activities of clinically significant human CYP isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4).

Excretion:

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.

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