CLINICAL PHARMACOLOGY
Mechanism of Action
Tigecycline is an antibacterial drug [see Clinical Pharmacology ].
Pharmacokinetics
The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.
Table 3. Mean (CV%) Pharmacokinetic Parameters of Tigecycline | Single Dose | Multiple Dosea |
| 100 mg | 50 mg every 12h |
| (N=224) | (N=103) |
|
a 100 mg initially, followed by 50 mg every 12 hours
b 30-minute infusion
c 60-minute infusion
|
| Cmax (mcg/mL)b | 1.45 (22%) | 0.87 (27%) |
| Cmax (mcg/mL)c | 0.90 (30%) | 0.63 (15%) |
| AUC (mcg·h/mL) | 5.19 (36%) | - - |
| AUC0-24h (mcg·h/mL) | - - | 4.70 (36%) |
| Cmin (mcg/mL) | - - | 0.13 (59%) |
| t½ (h) | 27.1 (53%) | 42.4 (83%) |
| CL (L/h) | 21.8 (40%) | 23.8 (33%) |
| CLr (mL/min) | 38.0 (82%) | 51.0 (58%) |
| Vss (L) | 568 (43%) | 639 (48%) |
Distribution
The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues.
Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0-12h (134 mcg·h/mL) in alveolar cells was approximately 78-fold higher than the AUC0-12h in the serum, and the AUC0-12h (2.28 mcg·h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0-12h in serum. The AUC0-12h (1.61 mcg·h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0-12h in the serum of 10 healthy subjects.
In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied.
Metabolism
Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.
Elimination
The recovery of total radioactivity in feces and urine following administration of 14C-tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Approximately 22% of the total dose is excreted as unchanged tigecycline in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.
Specific Populations
Patients with Hepatic Impairment
In a study comparing 10 patients with mild hepatic impairment (Child Pugh A), 10 patients with moderate hepatic impairment (Child Pugh B), and 5 patients with severe hepatic impairment (Child Pugh C) to 23 age and weight matched healthy control subjects, the single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25% and the half-life of tigecycline was prolonged by 23% in patients with moderate hepatic impairment (Child Pugh B). Systemic clearance of tigecycline was reduced by 55%, and the half-life of tigecycline was prolonged by 43% in patients with severe hepatic impairment (Child Pugh C). Dosage adjustment is necessary in patients with severe hepatic impairment (Child Pugh C) [see Use in Specific Populations and Dosage and Administration].
Patients with Renal Impairment
A single dose study compared 6 subjects with severe renal impairment (creatinine clearance <30 mL/min), 4 end stage renal disease (ESRD) patients receiving tigecycline 2 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of TYGACIL is necessary in patients with renal impairment or in patients undergoing hemodialysis.
Geriatric Patients
No significant differences in pharmacokinetics were observed between healthy elderly subjects (n=15, age 65-75; n=13, age >75) and younger subjects (n=18) receiving a single 100-mg dose of TYGACIL. Therefore, no dosage adjustment is necessary based on age [see Use in Specific Populations ].
Gender
In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7±6.5 L/h) and men (22.8±8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.
Race
In a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 subjects classified as “other” participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8±8.8 L/h), Black subjects (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), White subjects (22.1±8.9 L/h), and “other” subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.
Drug Interactions
TYGACIL (100 mg followed by 50 mg every 12 hours) and digoxin (0.5 mg followed by 0.25 mg, orally, every 24 hours) were coadministered to healthy subjects in a drug interaction study. Tigecycline slightly decreased the Cmax of digoxin by 13%, but did not affect the AUC or clearance of digoxin. This small change in Cmax did not affect the steady-state pharmacodynamic effects of digoxin as measured by changes in ECG intervals. In addition, digoxin did not affect the pharmacokinetic profile of tigecycline. Therefore, no dosage adjustment of either drug is necessary when TYGACIL is administered with digoxin.
Concomitant administration of TYGACIL (100 mg followed by 50 mg every 12 hours) and warfarin (25 mg single-dose) to healthy subjects resulted in a decrease in clearance of R‑warfarin and S‑warfarin by 40% and 23%, an increase in Cmax by 38% and 43% and an increase in AUC by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on INR. In addition, warfarin did not affect the pharmacokinetic profile of tigecycline. However, prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.
In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Therefore, TYGACIL is not expected to alter the metabolism of drugs metabolized by these enzymes. In addition, because tigecycline is not extensively metabolized, clearance of tigecycline is not expected to be affected by drugs that inhibit or induce the activity of these CYP450 isoforms.
Microbiology
Mechanism of Action
Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties to tigecycline. In general, tigecycline is considered bacteriostatic; however, TYGACIL has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.
Mechanism(s) of Resistance
To date there has been no cross-resistance observed between tigecycline and other antibacterials. Tigecycline is not affected by the two major tetracycline-resistance mechanisms, ribosomal protection and efflux. Additionally, tigecycline is not affected by resistance mechanisms such as beta-lactamases (including extended spectrum beta-lactamases), target-site modifications, macrolide efflux pumps or enzyme target changes (e.g. gyrase/topoisomerases). Tigecycline resistance in some bacteria (e.g. Acinetobacter calcoaceticus-Acinetobacter baumannii complex) is associated with multi-drug resistant (MDR) efflux pumps.
Interaction with Other Antimicrobials
In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterials.
Tigecycline has been shown to be active against most of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].
Facultative Gram-positive bacteria
Enterococcus faecalis (vancomycin-susceptible isolates)
Staphylococcus aureus (methicillin-susceptible and -resistant isolates)
Streptococcus agalactiae
Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus)
Streptococcus pneumoniae (penicillin-susceptible isolates)
Streptococcus pyogenes
Facultative Gram-negative bacteria
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae (beta-lactamase negative isolates)
Klebsiella oxytoca
Klebsiella pneumoniae
Legionella pneumophila
Anaerobic bacteria
Bacteroides fragilis
Bacteroides thetaiotaomicron
Bacteroides uniformis
Bacteroides vulgatus
Clostridium perfringens
Peptostreptococcus micros
At least 90% of the following bacteria exhibit in vitro minimum inhibitory concentrations (MICs) that are at concentrations that are achievable using the prescribed dosing regimens. However, the clinical significance of this is unknown because the safety and effectiveness of tigecycline in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
Facultative Gram-positive bacteria
Enterococcus avium
Enterococcus casseliflavus
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (vancomycin-susceptible and -resistant isolates)
Enterococcus gallinarum
Listeria monocytogenes
Staphylococcus epidermidis (methicillin-susceptible and -resistant isolates)
Staphylococcus haemolyticus
Facultative Gram-negative bacteria
Acinetobacter baumannii *
Aeromonas hydrophila
Citrobacter koseri
Enterobacter aerogenes
Haemophilus influenzae (ampicillin-resistant)
Haemophilus parainfluenzae
Pasteurella multocida
Serratia marcescens
Stenotrophomonas maltophilia
Anaerobic bacteria
Bacteroides distasonis
Bacteroides ovatus
Peptostreptococcus spp.
Porphyromonas spp.
Prevotella spp.
Other bacteria
Mycobacterium abscessus
Mycobacterium fortuitum
*There have been reports of the development of tigecycline resistance in Acinetobacter infections seen during the course of standard treatment. Such resistance appears to be attributable to an MDR efflux pump mechanism. While monitoring for relapse of infection is important for all infected patients, more frequent monitoring in this case is suggested. If relapse is suspected, blood and other specimens should be obtained and cultured for the presence of bacteria. All bacterial isolates should be identified and tested for susceptibility to tigecycline and other appropriate antimicrobials.
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that 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 based on dilution methods (broth, agar, or microdilution) 1, 3,4 or equivalent using standardized inoculum and concentrations of tigecycline. For broth dilution tests for aerobic organisms, MICs must be determined in testing medium that is fresh (<12h old). The MIC values should be interpreted according to the criteria provided in Table 4.
Diffusion Techniques
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The standardized procedure 2,4 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 mcg tigecycline to test the susceptibility of bacteria to tigecycline. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for tigecycline. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 mcg tigecycline disk should be interpreted according to the criteria in Table 4.
Anaerobic Techniques
Anaerobic susceptibility testing with tigecycline should be done by the agar dilution method 3 since quality control parameters for broth-dilution are not established.
Table 4. Susceptibility Test Result Interpretive Criteria for Tigecycline | Minimum Inhibitory Concentrations (mcg/mL) | Disk Diffusion
(zone diameters in mm) |
| Pathogen | S | I | R | S | I | R |
|
a The current absence of resistant isolates precludes defining any results other than “Susceptible.” Isolates yielding MIC results suggestive of “Nonsusceptible” category should be submitted to reference laboratory for further testing.
b Tigecycline has decreased in vitro activity against Morganella spp., Proteus spp. and Providencia spp.
c Agar dilution
|
| Staphylococcus aureus (including methicillin-resistant isolates) | ≤0.5a | - | - | ≥19 | - | - |
| Streptococcus spp. other than S. pneumoniae | ≤0.25a | - | - | ≥19 | - | - |
| Streptococcus pneumoniae | ≤0.06a | - | - | ≥19 | - | - |
| Enterococcus faecalis (vancomycin-susceptible isolates) | ≤0.25a | - | - | ≥19 | - | - |
| Enterobacteriaceaeb | ≤2 | 4 | ≥8 | ≥19 | 15-18 | ≤14 |
| Haemophilus influenzae | ≤0.25a | - | - | ≥19 | - | - |
| Anaerobesc | ≤4 | 8 | ≥16 | n/a | n/a | n/a |
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound 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 that 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 reaches the concentrations usually achievable; other therapy should be selected.
Quality Control
As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. 1,2, 3,4 Standard tigecycline powder should provide the MIC values provided in Table 5. For the diffusion technique using the 15 mcg tigecycline disk the criteria provided in Table 5 should be achieved.
Table 5. Acceptable Quality Control Ranges for Susceptibility Testing | QC organism | Minimum Inhibitory Concentrations (mcg/mL) | Disk Diffusion
(zone diameters in mm) |
|
ATCC = American Type Culture Collection
a Agar dilution
|
| Staphylococcus aureus ATCC 25923 | Not Applicable | 20-25 |
| Staphylococcus aureus ATCC 29213 | 0.03-0.25 | Not Applicable |
| Escherichia coli ATCC 25922 | 0.03-0.25 | 20-27 |
| Enterococcus faecalis ATCC 29212 | 0.03-0.12 | Not Applicable |
| Streptococcus pneumoniae ATCC 49619 | 0.016-0.12 | 23-29 |
| Haemophilus influenzae ATCC 49247 | 0.06-0.5 | 23-31 |
| Bacteroides fragilis a ATCC 25285 | 0.12-1 | Not Applicable |
| Bacteroides thetaiotaomicron a ATCC 29741 | 0.5-2 | Not Applicable |
| Eubacterium lentum a ATCC 43055 | 0.06-0.5 | Not Applicable |
| Clostridium difficile a ATCC 70057 | 0.12-1 | Not Applicable |
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline. No mutagenic or clastogenic potential was found in a battery of tests, including in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo mouse micronucleus assay. Tigecycline did not affect mating or fertility in rats at exposures up to 5 times the human daily dose based on AUC (28 mcg·hr/mL at 12 mg/kg/day). In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 5 times the human daily dose based on AUC.
Animal Toxicology and/or Pharmacology
In two week studies, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8 times and 10 times the human daily dose based on AUC in rats and dogs, (AUC of approximately 50 and 60 mcg·hr/mL at doses of 30 and 12 mg/kg/day) respectively. These alterations were shown to be reversible after two weeks of dosing.
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