Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Other antibacterials,ATC code: J 01 X X 08 
General properties
Linezolid is a synthetic, antibacterial agent that belongs to a new class of antimicrobials, the oxazolidinones. It has in vitro activity against aerobic Gram positive bacteria and anaerobic micro-organisms. Linezolid selectively inhibits bacterial protein synthesis via a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S of the 50S subunit) and prevents the formation of a functional 70S initiation complex which is an essential component of the translation process.

The in vitro postantibiotic effect (PAE) of linezolid for Staphylococcus aureus was approximately 2 hours. When measured in animal models, the in vivo PAE was 3.6 and 3.9 hours for Staphylococcus aureus and Streptococcus pneumoniae, respectively. In animal studies, the key pharmacodynamic parameter for efficacy was the time for which the linezolid plasma level exceeded the minimum inhibitory concentration (MIC) for the infecting organism.

Breakpoints
Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for staphylococci and enterococci are Susceptible ≤ 4mg/L and Resistant >4 mg/L. For streptococci (including S.
pneumoniae) the breakpoints are Susceptible ≤ 2 mg/L and Resistant >4 mg/L.
Non-species related MIC breakpoints are Susceptible ≤ 2 mg/L and Resistant > 4 mg/L. Non- species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that have not been given a specific breakpoint and not for those species where susceptibility testing is not recommended.

Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.



                                                    Category
Susceptible organisms

Gram positive aerobes:
Enterococcus faecalis
Enterococcus faecium*
Staphylococcus aureus*
Coagulase negative staphylococci
Streptococcus agalactiae*
Streptococcus pneumoniae*
Streptococcus pyogenes*
Group C streptococci
Group G streptococci
Gram positive anaerobes:
Clostridium perfringens
Peptostreptococcus anaerobius
Peptostreptococcus species
Resistant organisms

Haemophilus influenzae
Moraxella catarrhalis
Neisseria species
Enterobacteriaceae
Pseudomonas species
*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications

Whereas linezolid shows some in vitro activity against Legionella, Chlamydia pneumoniae and Mycoplasma pneumoniae, there are insufficient data to demonstrate clinical efficacy.

Resistance

Cross resistance
Linezolid’s mechanism of action differs from those of other antibiotic classes. In vitro studies with clinical isolates (including methicillin-resistant staphylococci, vancomycin-resistant enterococci, and penicillin- and erythromycin-resistant streptococci) indicate that linezolid is usually active against organisms which are resistant to one or more other classes of antimicrobial agents.

Resistance to linezolid is associated with point mutations in the 23S rRNA.

As documented with other antibiotics when used in patients with difficult to treat infections and/or for prolonged periods, emergent decreases in susceptibility have been observed with linezolid. Resistance to linezolid has been reported in enterococci, Staphylococcus aureus and coagulase negative staphylococci. This generally has been associated with prolonged courses of therapy and the presence of prosthetic materials or undrained abscesses. When antibiotic- resistant organisms are encountered in the hospital it is important to emphasize infection control policies.

Information from clinical trials

Studies in the paediatric population:
In an open study, the efficacy of linezolid (10 mg/kg q8h) was compared to vancomycin (10- 15mg/kg q6- 24h) in treating infections due to suspected or proven resistant gram-positive pathogens(including nosocomial pneumonia, complicated skin and skin structure infections, catheter related bacteraemia, bacteraemia of unknown source, and other infections), in children from birth to 11 years. Clinical cure rates in the clinically evaluable population were 89.3% (134/150) and 84.5%(60/71) for linezolid and vancomycin, respectively (95%CI: -4.9, 14.6).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Zyvoxid® 600mg & Zyvoxid® I.V. 2 mg/ml primarily contain (s)-linezolid which is biologically active and is metabolised to form inactive derivatives.

Absorption
Linezolid is rapidly and extensively absorbed following oral dosing. Maximum plasma concentrations are reached within 2 hours of dosing. Absolute oral bioavailability of linezolid (oral and intravenous dosing in a crossover study) is complete (approximately 100%).
Absorption is not significantly affected by food

Plasma linezolid Cmax and Cmin (mean and [SD]) at steady-state following twice daily intravenous dosing of 600 mg have been determined to be 15.1 [2.5] mg/l and 3.68 [2.68] mg/l, respectively.

In another study following oral dosing of 600 mg twice daily to steady-state, Cmax and Cmin were determined to be 21.2 [5.8] mg/l and 6.15 [2.94] mg/l, respectively. Steady-state conditions are achieved by the second day of dosing.

Distribution
Volume of distribution at steady-state averages at about 40-50 litres in healthy adults and approximates to total body water. Plasma protein binding is about 31% and is not concentration dependent.

Linezolid concentrations have been determined in various fluids from a limited number of subjects in volunteer studies following multiple dosing. The ratio of linezolid in saliva and sweat relative to plasma was 1.2:1.0 and 0.55:1.0, respectively. The ratio for epithelial lining fluid and alveolar cells of the lung was 4.5:1.0 and 0.15:1.0, when measured at steady-state Cmax, respectively. In a small study of subjects with ventricular-peritoneal shunts and essentially non-inflamed meninges, the ratio of linezolid in cerebrospinal fluid to plasma at Cmax was 0.7:1.0 after multiple linezolid dosing.

Pharmacokinetic information generated in pediatric patients with ventriculoperitoneal shunts showed variable cerebrospinal fluid (CSF) linezolid concentrations following single and multiple dosing of linezolid; therapeutic concentrations were not consistently achieved or maintained in the CSF. Therefore, the use of linezolid for the empiric treatment of pediatric patients with central nervous system infections is not recommended.

Biotransformation
Linezolid is primarily metabolised by oxidation of the morpholine ring resulting mainly in the formation of two inactive open-ring carboxylic acid derivatives; the aminoethoxyacetic acid metabolite (PNU-142300) and the hydroxyethyl glycine metabolite (PNU-142586). The hydroxyethyl glycine metabolite (PNU-142586) is the predominant human metabolite and is believed to be formed by a non-enzymatic process. The aminoethoxyacetic acid metabolite (PNU-142300) is less abundant. Other minor, inactive metabolites have been characterised.

Elimination
In patients with normal renal function or mild to moderate renal insufficiency, linezolid is primarily excreted under steady-state conditions in the urine as PNU-142586 (40%), parent drug (30%) and PNU-142300 (10%). Virtually no parent drug is found in the faeces whilst approximately 6% and 3% of each dose appears as PNU-142586 and PNU-142300, respectively. The elimination half life of linezolid averages at about 5-7 hours.

Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. A small degree of non-linearity in clearance is observed with increasing doses of linezolid. This appears to be due to lower renal and non-renal clearance at higher linezolid concentrations.
However, the difference in clearance is small and is not reflected in the apparent elimination half life.

Special populations

Renal impairment: After single doses of 600 mg, there was a 7-8 fold increase in exposure to the two primary metabolites of linezolid in the plasma of patients with severe renal insufficiency (i.e., creatinine clearance < 30 ml/min). However, there was no increase in AUC of parent drug. Although there is some removal of the major metabolites of linezolid by haemodialysis, metabolite plasma levels after single 600 mg doses were still considerably higher following dialysis than those observed in patients with normal renal function or mild to moderate renal insufficiency.

In 24 patients with severe renal insufficiency, 21 of whom were on regular haemodialysis, peak plasma concentrations of the two major metabolites after several days dosing were about 10 fold those seen in patients with normal renal function. Peak plasma levels of linezolid were not affected.

The clinical significance of these observations has not been established as limited safety data are currently available (see sections 4.2 and 4.4).

Hepatic impairment: Limited data indicate that the pharmacokinetics of linezolid, PNU- 142300 and PNU-142586 are not altered in patients with mild to moderate hepatic insufficiency (i.e., Child-Pugh class A or B). The pharmacokinetics of linezolid in patients with severe hepatic insufficiency (i.e., Child-Pugh class C) have not been evaluated.
However, as linezolid is metabolised by a non-enzymatic process, impairment of hepatic function would not be expected to significantly alter its metabolism (see sections 4.2 and 4.4).

Paediatric population (< 18 years old):
The pharmacokinetics of linezolid following a single intravenous 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 6 for the pediatric populations studied and healthy adult subjects after administration of single intravenous doses.
The Cmax and the volume of distribution (Vss) of linezolid are similar regardless of age in pediatric patients. However, plasma clearance of linezolid varies as a function of age. With the exclusion of pre-term neonates less than one week of age, weight-based 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 a shorter half life as compared with adults. As the age of pediatric patients increases, the weight-based clearance of linezolid gradually decreases, and by adolescence mean clearance values approach those observed for the adult population. There is increased 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 relative to adolescents or adults dosed every 12 hours. Therefore, the dosage for pediatric patients up to 11 years of age should be 10 mg/kg every 8 hours. Pediatric patients 12 years and older should receive 600 mg every 12 hours [see CLINICAL PARTICULARS, Posology and method of administration].



Table 6. 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]) Cmax               Vss                AUC*             t 1/2              CL Age Group                            mcg/ml              L/kg             mcg•h/ml            hrs            ml/min/kg Neonatal Patients
12.7 (30%)         0.81 (24%)          108 (47%)        5.6 (46%)         2.0 (52%) Pre-term**
[9.6, 22.2]        [0.43, 1.05]         [41, 191]       [2.4, 9.8]         [0.9, 4.0] < 1 week (N=9)†
***
Full-term                          11.5 (24%)         0.78 (20%)           55 (47%)        3.0 (55%)         3.8 (55%) < 1 week (N=10)†                   [8.0, 18.3]        [0.45, 0.96]         [19, 103]       [1.3, 6.1]         [1.5, 8.8] Full-term***
≥ 1 week to ≤ 28 days              12.9 (28%)         0.66 (29%)           34 (21%)        1.5 (17%)         5.1 (22%) (N=10)   †                         [7.7, 21.6]        [0.35, 1.06]          [23, 50]       [1.2, 1.9]         [3.3, 7.2] Infant Patients
11.0 (27%)         0.79 (26%)           33 (26%)        1.8 (28%)         5.4 (32%) > 28 days to < 3 months
†                         [7.2, 18.0]        [0.42, 1.08]          [17, 48]       [1.2, 2.8]         [3.5, 9.9] (N=12)
Pediatric Patients
15.1 (30%)         0.69 (28%)           58 (54%)        2.9 (53%)         3.8 (53%) 3 months through 11
†                       [6.8, 36.7]        [0.31, 1.50]         [19, 153]       [0.9, 8.0]         [1.0, 8.5] years (N=59)
Adolescent Subjects and
Patients                           16.7 (24%)         0.61 (15%)           95 (44%)        4.1 (46%)         2.1 (53%) 12 through 17 years‡          [9.9, 28.9]        [0.44, 0.79]         [32, 178]       [1.3, 8.1]         [0.9, 5.2] (N=36)
Adult Subjects§                    12.5 (21%)         0.65 (16%)           91 (33%)        4.9 (35%)         1.7 (34%) (N= 29)                       [8.2, 19.3]        [0.45, 0.84]         [53, 155]       [1.8, 8.3]         [0.9, 3.3] *      AUC = Single dose AUC0-∞
**     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)
***    In this data set, “full-term” is defined as ≥34 weeks gestational age †      Dose of 10 mg/kg
‡      Dose of 600 mg or 10 mg/kg up to a maximum of 600 mg
§      Dose normalized to 600 mg
Cmax = Maximum plasma concentration; Vss= Volume of distribution; AUC = Area under concentration-time curve; t1/2 = Apparent elimination halflife; CL = Systemic clearance normalized for body weight 
Elderly: The pharmacokinetics of linezolid are not significantly altered in elderly patients aged 65 and over.

Female patients: Females have a slightly lower volume of distribution than males and the mean clearance is reduced by approximately 20% when corrected for body weight. Plasma concentrations are higher in females and this can partly be attributed to body weight differences. However, because the mean half life of linezolid is not significantly different in males and females, plasma concentrations in females are not expected to substantially rise above those known to be well tolerated and, therefore, dose adjustments are not required.