CLINICAL PHARMACOLOGY
Mechanism of Action
Ertapenem sodium is a carbapenem antibiotic [see Clinical Pharmacology].
Pharmacokinetics
Average plasma concentrations (mcg/mL) of ertapenem following a single 30-minute infusion of a 1 g intravenous (IV) dose and administration of a single 1 g intramuscular (IM) dose in healthy young adults are presented in Table 8.
Table 8: Plasma Concentrations of Ertapenem in Adults After Single Dose Administration
| Average Plasma Concentrations (mcg/mL) |
Dose/Route |
0.5 hr |
1 hr |
2 hr |
4 hr |
6 hr |
8 hr |
12 hr |
18 hr |
24 hr |
1 g IV
|
155 |
115 |
83 |
48 |
31 |
20 |
9 |
3 |
1 |
1 g IM |
33 |
53 |
67 |
57 |
40 |
27 |
13 |
4 |
2 |
The area under the plasma concentration-time curve (AUC) of ertapenem in adults increased less-than dose-proportional based on total ertapenem concentrations over the 0.5 to 2 g dose range, whereas the AUC increased greater-than dose-proportional based on unbound ertapenem concentrations. Ertapenem exhibits non-linear pharmacokinetics due to concentration-dependent plasma protein binding at the proposed therapeutic dose [see Clinical Pharmacology]. There is no accumulation of ertapenem following multiple IV or IM 1 g daily doses in healthy adults.
Average plasma concentrations (mcg/mL) of ertapenem in pediatric patients are presented in Table 9.
Table 9: Plasma Concentrations of Ertapenem in Pediatric Patients After Single IV
Dose Administration
Age Group |
Dose |
Average Plasma Concentrations (mcg/mL) |
|
| 0.5 hr |
1 hr |
2 hr |
4 hr |
6 hr |
8 hr |
12 hr |
24 hr |
3 to 23 months |
15 mg/kg
|
103.8 |
57.3 |
43.6 |
23.7 |
13.5 |
8.2 |
2.5 |
- |
| 20 mg/kg
|
126.8 |
87.6 |
58.7 |
28.4 |
- |
12.0 |
3.4 |
0.4 |
| 40 mg/kg
|
199.1 |
144.1 |
95.7 |
58.0 |
- |
20.2 |
7.7 |
0.6 |
2 to 12 years |
15 mg/kg
|
113.2 |
63.9 |
42.1 |
21.9 |
12.8 |
7.6 |
3.0 |
- |
| 20 mg/kg
|
147.6 |
97.6 |
63.2 |
34.5 |
- |
12.3 |
4.9 |
0.5 |
| 40 mg/kg
|
241.7 |
152.7 |
96.3 |
55.6 |
- |
18.8 |
7.2 |
0.6 |
13 to 17 years |
20 mg/kg
|
170.4 |
98.3 |
67.8 |
40.4 |
- |
16.0 |
7.0 |
1.1 |
| 1 g
|
155.9 |
110.9 |
74.8 |
- |
24.0 |
- |
6.2 |
- |
| 40 mg/kg
|
255.0 |
188.7 |
127.9 |
76.2 |
- |
31.0 |
15.3 |
2.1 |
Absorption
Ertapenem, reconstituted with 1% lidocaine HCl injection, USP (in saline without epinephrine), is almost completely absorbed following intramuscular (IM) administration at the recommended dose of 1 g. The mean bioavailability is approximately 90%. Following 1 g daily IM administration, mean peak plasma concentrations (Cmax) are achieved in approximately 2.3 hours (Tmax).
Distribution
Ertapenem is highly bound to human plasma proteins, primarily albumin. In healthy young adults, the protein binding of ertapenem decreases as plasma concentrations increase, from approximately 95% bound at an approximate plasma concentration of <100 micrograms (mcg)/mL to approximately 85% bound at an approximate plasma concentration of 300 mcg/mL.
The apparent volume of distribution at steady state (Vss) of ertapenem in adults is approximately 0.12 liter/kg, approximately 0.2 liter/kg in pediatric patients 3 months to 12 years of age and approximately 0.16 liter/kg in pediatric patients 13 to 17 years of age.
The concentrations of ertapenem achieved in suction-induced skin blister fluid at each sampling point on the third day of 1 g once daily IV doses are presented in Table 10. The ratio of AUC0-24 in skin blister fluid/AUC0-24 in plasma is 0.61.
Table 10: Concentrations (mcg/mL) of Ertapenem in Adult Skin Blister Fluid at each Sampling Point on the Third Day of 1-g Once Daily IV Doses
0.5 hr |
1 hr |
2 hr |
4 hr |
8 hr |
12 hr |
24 hr |
7 |
12 |
17 |
24 |
24 |
21 |
8 |
The concentration of ertapenem in breast milk from 5 lactating women with pelvic infections (5 to 14 days postpartum) was measured at random time points daily for 5 consecutive days following the last 1 g dose of intravenous therapy (3-10 days of therapy). The concentration of ertapenem in breast milk within 24 hours of the last dose of therapy in all 5 women ranged from <0.13 (lower limit of quantitation) to 0.38 mcg/mL; peak concentrations were not assessed. By day 5 after discontinuation of therapy, the level of ertapenem was undetectable in the breast milk of 4 women and below the lower limit of quantitation (<0.13 mcg/mL) in 1 woman.
Metabolism
In healthy young adults, after infusion of 1 g IV radiolabeled ertapenem, the plasma radioactivity consists predominantly (94%) of ertapenem. The major metabolite of ertapenem is the inactive ring-opened derivative formed by hydrolysis of the beta-lactam ring.
Elimination
Ertapenem is eliminated primarily by the kidneys. The mean plasma half-life in healthy young adults is approximately 4 hours and the plasma clearance is approximately 1.8 L/hour. The mean plasma half-life in pediatric patients 13 to 17 years of age is approximately 4 hours and approximately 2.5 hours in pediatric patients 3 months to 12 years of age.
Following the administration of 1 g IV radiolabeled ertapenem to healthy young adults, approximately 80% is recovered in urine and 10% in feces. Of the 80% recovered in urine, approximately 38% is excreted as unchanged drug and approximately 37% as the ring-opened metabolite.
In healthy young adults given a 1 g IV dose, the mean percentage of the administered dose excreted in urine was 17.4% during 0-2 hours postdose, 5.4% during 4-6 hours postdose, and 2.4% during 12-24 hours postdose.
Special Populations
Renal Impairment
Total and unbound fractions of ertapenem pharmacokinetics were investigated in 26 adult subjects (31 to 80 years of age) with varying degrees of renal impairment. Following a single 1 g IV dose of ertapenem, the unbound AUC increased 1.5-fold and 2.3-fold in subjects with mild renal impairment (CLCR 60-90 mL/min/1.73 m2) and moderate renal impairment (CLCR 31-59 mL/min/1.73 m2), respectively, compared with healthy young subjects (25 to 45 years of age). No dosage adjustment is necessary in patients with CLCR ≥31 mL/min/1.73 m2. The unbound AUC increased 4.4-fold and 7.6-fold in subjects with advanced renal impairment (CLCR 5-30 mL/min/1.73 m2) and end-stage renal disease (CLCR <10 mL/min/1.73 m2), respectively, compared with healthy young subjects. The effects of renal impairment on AUC of total drug were of smaller magnitude. The recommended dose of ertapenem in adult patients with CLCR ≤30 mL/min/1.73 m2 is 0.5 grams every 24 hours. Following a single 1 g IV dose given immediately prior to a 4 hour hemodialysis session in 5 adult patients with end-stage renal disease, approximately 30% of the dose was recovered in the dialysate. Dose adjustments are recommended for patients with severe renal impairment and end-stage renal disease [see Dosage and Administration]. There are no data in pediatric patients with renal impairment.
Hepatic Impairment
The pharmacokinetics of ertapenem in patients with hepatic impairment have not been established. However, ertapenem does not appear to undergo hepatic metabolism based on in vitro studies and approximately 10% of an administered dose is recovered in the feces [see Clinical Pharmacology
and
Dosage and Administration].
Gender
The effect of gender on the pharmacokinetics of ertapenem was evaluated in healthy male (n=8) and healthy female (n=8) subjects. The differences observed could be attributed to body size when body weight was taken into consideration. No dose adjustment is recommended based on gender.
Geriatric Patients
The impact of age on the pharmacokinetics of ertapenem was evaluated in healthy male (n=7) and healthy female (n=7) subjects ≥65 years of age. The total and unbound AUC increased 37% and 67%, respectively, in elderly adults relative to young adults. These changes were attributed to age-related changes in creatinine clearance. No dosage adjustment is necessary for elderly patients with normal (for their age) renal function.
Pediatric Patients
Plasma concentrations of ertapenem are comparable in pediatric patients 13 to 17 years of age and adults following a 1 g once daily IV dose.
Following the 20 mg/kg dose (up to a maximum dose of 1 g), the pharmacokinetic parameter values in patients 13 to 17 years of age (N=6) were generally comparable to those in healthy young adults.
Plasma concentrations at the midpoint of the dosing interval following a single 15 mg/kg IV dose of ertapenem in patients 3 months to 12 years of age are comparable to plasma concentrations at the midpoint of the dosing interval following a 1 g once daily IV dose in adults [see Clinical Pharmacology]. The plasma clearance (mL/min/kg) of ertapenem in patients 3 months to 12 years of age is approximately 2-fold higher as compared to that in adults. At the 15 mg/kg dose, the AUC value (doubled to model a twice daily dosing regimen, i.e., 30 mg/kg/day exposure) in patients 3 months to 12 years of age was comparable to the AUC value in young healthy adults receiving a 1 g IV dose of ertapenem.
Drug Interactions
When ertapenem is co-administered with probenecid (500 mg p.o. every 6 hours), probenecid competes for active tubular secretion and reduces the renal clearance of ertapenem. Based on total ertapenem concentrations, probenecid increased the AUC of ertapenem by 25%, and reduced the plasma and renal clearance of ertapenem by 20% and 35%, respectively. The half-life of ertapenem was increased from 4.0 to 4.8 hours.
In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following cytochrome p450 (CYP) isoforms: 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4.
In vitro studies indicate that ertapenem does not inhibit P-glycoprotein-mediated transport of digoxin or vinblastine and that ertapenem is not a substrate for P-glycoprotein-mediated transport.
Microbiology
Mechanism of Action
Ertapenem has in vitro activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. The bactericidal activity of ertapenem results from the inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin binding proteins (PBPs). In Escherichia coli, it has strong affinity toward PBPs 1a, 1b, 2, 3, 4 and 5 with preference for PBPs 2 and 3.
Mechanism of Resistance
Ertapenem is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, and cephalosporinases and extended spectrum beta-lactamases. Ertapenem is hydrolyzed by metallo-beta-lactamases.
Ertapenem 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:
Gram-positive bacteria:
Staphylococcus aureus (methicillin susceptible isolates only)
Streptococcus agalactiae
Streptococcus pneumoniae (penicillin susceptible isolates only)
Streptococcus pyogenes
Gram-negative bacteria:
Escherichia coli
Haemophilus influenzae (beta-lactamase negative isolates only)
Klebsiella pneumoniae
Moraxella catarrhalis
Proteus mirabilis
Anaerobic bacteria:
Bacteroides fragilis
Bacteroides distasonis
Bacteroides ovatus
Bacteroides thetaiotaomicron
Bacteroides uniformis
Clostridium clostridioforme
Eubacterium lentum
Peptostreptococcus species
Porphyromonas asaccharolytica
Prevotella bivia
The following in vitro data are available,
but their clinical significance is unknown
. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ertapenem. However, the efficacy of ertapenem in treating clinical infections due to these bacteria
has not been
established in adequate and well-controlled clinical trials:
Gram-positive bacteria:
Staphylococcus epidermidis (methicillin susceptible isolates only)
Streptococcus pneumoniae (penicillin-intermediate isolates)
Gram-negative bacteria:
Citrobacter freundii
Citrobacter koseri
Enterobacter aerogenes
Enterobacter cloacae
Haemophilus influenzae (beta-lactamase positive isolates only)
Haemophilus parainfluenzae
Klebsiella oxytoca (excluding ESBL producing isolates)
Morganella morganii
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Serratia marcescens
Anaerobic bacteria:
Bacteroides vulgatus
Clostridium perfringens
Fusobacterium spp.
Susceptibility Test Methods:
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility tests for antimicrobial drug products used in resident hospitals 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.
Dilution Techniques:
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 broth dilution method { 1 } or equivalent with standardized inoculum concentrations and standardized concentrations of ertapenem powder. The MIC values should be interpreted according to criteria provided in Table 11 and { 4 }.
Diffusion Techniques:
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure { 2 } requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10-µg ertapenem to test the susceptibility of microorganisms to ertapenem. The disk diffusion interpretive criteria should be interpreted according to criteria provided in Table 11 and { 4 }.
Anaerobic Techniques:
For anaerobic bacteria, the susceptibility to ertapenem as MICs can be determined by standardized test methods { 3 }. The MIC values obtained should be interpreted according to criteria provided in Table 11 and { 4 }.
Table 11: Susceptibility Interpretive Criteria for Ertapenem
Pathogen |
Minimum Inhibitory Concentrations
MIC (μg/mL) |
Disk Diffusion Zone Diameter (mm) |
| S |
I |
R |
S |
I |
R |
Enterobacteriaceae
|
≤0.5 |
1 |
≥2 |
≥22 |
19-21 |
≤18 |
Staphylococcus aureus
For oxacillin-susceptible S. aureus results for carbapenems, including ertapenem, if tested, should be reported according to the results generated using routine interpretive criteria. For oxacillin-resistant S. aureus and coagulase negative staphylococci, other beta lactam agents, including carbapenems, may appear active in vitro but are not effective clinically. Results for beta lactam agents other than cephalosporins with anti-MRSA activity should be reported as resistant or should not be reported.
|
≤2.0 |
4.0 |
≥8.0 |
≥19 |
16-18 |
≤15 |
Haemophilus spp.
|
≤0.5 |
- |
- |
≥19 |
- |
- |
Streptococcus pneumoniae
|
≤1.0 |
2 |
≥4 |
- |
- |
- |
Streptococcus spp. Beta Hemolytic Group
,
,
|
≤1.0 |
- |
- |
- |
- |
- |
Streptococcus spp. Viridans Group
|
≤1.0 |
- |
- |
- |
- |
- |
Anaerobes |
≤4.0 |
8.0 |
≥16.0 |
- |
- |
- |
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound at the infection site 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 at the infection site reaches the concentrations usually achievable; other therapy should be selected.
Quality Control
Standardized susceptibility test procedures require the use of laboratory control microorganisms to ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant. Standard ertapenem powder should provide the following range of values noted in Table 12 and { 4,5 }.
Table 12: Acceptable Quality Control Ranges for Ertapenem
Microorganism
|
Minimum Inhibitory Concentrations MIC Range (µg/mL) |
Disk Diffusion Zone Diameter (mm) |
Escherichia coli ATCC 25922 |
0.004-0.016 |
29-36 |
Haemophilus influenzae ATCC 49766 |
0.015-0.06 |
27-33 |
Staphylococcus aureus ATCC 29213 |
0.06-0.25 |
- |
Staphylococcus aureus ATCC 25923 |
- |
24-31 |
Streptococcus pneumoniae ATCC 49619 |
0.03-0.25 |
28-35 |
Bacteroides fragilis ATCC 25285 |
0.06-0.5
0.06-0.25
|
- |
Bacteroides thetaiotaomicron ATCC 29741 |
0.5-2.0
0.25-1.0
|
- |
Eubacterium lentum ATCC 43055 |
0.5-4.0
0.5-2.0
|
- |
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of ertapenem.
Ertapenem was neither mutagenic nor genotoxic in the following in vitro assays: alkaline elution/rat hepatocyte assay, chromosomal aberration assay in Chinese hamster ovary cells, and TK6 human lymphoblastoid cell mutagenesis assay; and in the in vivo mouse micronucleus assay.
In mice and rats, IV doses of up to 700 mg/kg/day (for mice, approximately 3 times the recommended human dose of 1 g based on body surface area and for rats, approximately 1.2 times the human exposure at the recommended dose of 1 g based on plasma AUCs) resulted in no effects on mating performance, fecundity, fertility, or embryonic survival.
Animal Toxicology and/or Pharmacology
In repeat-dose studies in rats, treatment-related neutropenia occurred at every dose-level tested, including the lowest dose of 2 mg/kg (approximately 2% of the human dose on a body surface area basis).
Studies in rabbits and Rhesus monkeys were inconclusive with regard to the effect on neutrophil counts.
|