Invanz Pharmacology, Pharmacokinetics, Studies, Metabolism - Ertapenem

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 1.

There is no accumulation of ertapenem following multiple IV or IM 1 g daily doses in healthy adults.

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 (C_max) are achieved in approximately 2.3 hours (T_max).

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 (V_ss) of ertapenem is approximately 8.2 liters.

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 2. The ratio of AUC_0-24 in skin blister fluid/AUC_0-24 in plasma is 0.61.

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. 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. (See DRUG INTERACTIONS.) 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. (See PRECAUTIONS, Drug Interactions.) 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. 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 Insufficiency

Hepatic Insufficiency

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

The pharmacokinetics of ertapenem in pediatric patients have not been established.

Microbiology

Aerobic gram-positive microorganisms:

Staphylococcus aureus (methicillin susceptible strains only)

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin susceptible strains only)

Streptococcus pyogenes

Note: Methicillin-resistant staphylococci and Enterococcus spp. are resistant to ertapenem.

Aerobic gram-negative microorganisms:

Escherichia coli

Haemophilus influenzae (Beta-lactamase negative strains only)

Klebsiella pneumoniae Moraxella catarrhalis

Anaerobic microorganisms:

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 microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ertapenem; however, the safety and effectiveness of ertapenem in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical studies:

Aerobic gram-positive microorganisms:

Streptococcus pneumoniae (penicillin-intermediate strains only)

Aerobic gram-negative microorganisms:

Citrobacter freundii Citrobacter koseri Enterobacter aerogenes Enterobacter cloacae

Haemophilus influenzae (Beta-lactamase positive strains)

Haemophilus parainfluenzae

Klebsiella oxytoca (excluding ESBL producing strains) Morganella morganii

Proteus mirabilis

Proteus vulgaris

Serratia marcescens

Anaerobic microorganisms:

Clostridium perfringens Fusobacterium spp.

Susceptibility Tests

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.

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^1,4 or equivalent with standardized inoculum concentrations and standardized concentrations of ertapenem powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae and Staphylococcus spp

Note: Staphylococcus spp. can be considered susceptible to ertapenem if the penicillin MIC is

For testing Haemophilus spp.^a:

^aThis interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Test Medium (HTM)¹ inoculated with a direct colony suspension and incubated in ambient air at 35°C for 20-24 hrs.

^bThe current absence of data in resistant strains precludes defining any results other than "Susceptible". Strains yielding MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.

For testing Streptococcus pneumoniae^c,d:

^cThis interpretive standard is applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood inoculated with direct colony suspension and incubated in ambient air at 35°C for 20-24 hrs.

For testing Streptococcus spp. other than Streptococcus pneumoniae^c,e:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in 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 laboratory control microorganisms to control the technical aspects of the laboratory procedures. 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 MIC values.

Diffusion Techniques

For testing Enterobacteriaceae and Staphylococcus spp.:

For testing Haemophilus spp.^h:

Zone Diameter (mm) Interpretation^b

^hThis zone diameter standard is applicable only to tests performed by disk diffusion with Haemophilus spp. using HTM² inoculated with a direct colony suspension and incubated in 5% CO₂ at 35°C for 16-18 hrs.

For testing Streptococcus pneumoniae^i,j:

Zone Diameter (mm) Interpretation^b

ⁱThese zone diameter standards apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood inoculated with a direct colony suspension and incubated in 5% CO₂ at 35°C for 20-24 hrs.

For testing Streptococcus spp. other than Streptococcus pneumoniae^k,l:

Zone Diameter (mm) Interpretation^b

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ertapenem. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains that will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant. For the diffusion technique, the 10- g ertapenem disk should provide the following zone diameters in these laboratory quality control strains:

Microorganism Zone Diameter Range (mm)

Escherichia coli ATCC 25922 29-36

^mThis quality control range is applicable to Haemophilus influenzae ATCC 49766 tested by disk diffusion using HTM² agar inoculated with a direct colony suspension and incubated in 5% CO₂ at 35°C for 16-18 hrs.

ⁿThis quality control range is applicable to Streptococcus pneumoniae ATCC 49619 tested by disk diffusion using Mueller-Hinton agar supplemented with 5% sheep blood inoculated with a direct colony suspension and incubated in 5% CO₂ at 35°C for 20-24 hrs.

Anaerobic Techniques:

For anaerobic bacteria, the susceptibility to ertapenem as MICs can be determined by standardized test methods³. The MIC values obtained should be interpreted according to the following criteria:

MIC ( g/mL) Interpretation

8.0 Intermediate (I)

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ertapenem powder should provide the following MIC values: