The mean pharmacokinetic parameters of tigecycline after single and multiple IV doses based on pooled data from clinical pharmacology studies are summarized in the table below.¹

Mean (CV%) Pharmacokinetic Parameters of Tigecycline¹

	Single Dose 100 mg (N=224)	Multiple Dose* 50 mg Every 12 Hours (N=103)
Cmax (μg/mL)†	1.45 (22%)	0.87 (27%)
Cmax (μg/mL)‡	0.90 (30%)	0.63 (15%)
AUC (μg•h/mL)	5.19 (36%)	—
AUC0-24h (μg•h/mL)	—	4.70 (36%)
Cmin (μg/mL)	—	0.13 (59%)
t1/2 (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%)

*100 mg initially, followed by 50 mg every 12 hours.
†30-minute infusion.
‡60-minute infusion.

Dose Proportionality

Tigecycline peak concentration and AUC are linearly dose proportional over the dose range of 12.5 to 300 mg. Moderate intersubject variability was observed.²⁵ Upon multiple-dose administration, serum concentration curves often show a modest secondary peak approximately 12 to 16 hours after administration. The secondary peak may be caused by a redistribution of tigecycline from tissues, including the colon.²⁵

Protein Binding

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 μg/mL).¹

Distribution

The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating that tigecycline is extensively distributed beyond the plasma volume and into the tissues.¹ The table below compares various tigecycline concentrations in various body tissues obtained 4 hours after a single 100-mg IV dose.^1,25

Comparative Tissue Concentrations of Tigecycline After a Single 100-mg IV Dose^1,25

Tissue	n	Compared With Serum Concentrations
Gallbladder	6	38-fold
Lung	5	3.7-fold
Colon	6	2.3-fold
Synovial fluid	5	0.58-fold
Bone	6	0.35-fold

In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or a 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.¹ The low bone concentrations, which are inconsistent with animal studies and the well-known tissue distribution of tetracyclines, could be due to difficulties with the extraction technique. Cerebrospinal fluid concentrations are not yet known.^1,25 Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC_0-12h (134 μg•h/mL) in alveolar cells was approximately 78-fold higher than the AUC_0-12h in the serum, and the AUC_0-12h (2.28 μg•h/mL) in epithelial lining fluid was approximately 32% higher than the AUC_0-12h in the serum. The AUC_0-12h (1.61 μg•h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC_0-12h in the serum of 10 healthy subjects.¹

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.¹

Elimination

Following IV administration, tigecycline serum concentrations initially decline rapidly during distribution into body tissues.²⁵ The mean half-life of tigecycline after a single 100-mg dose was 27.1 hours; after multiple dosing of 50 mg every 12 hours, the mean half-life was 42.4 hours.¹ Approximately 59% of a radioactive dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Of the total dose, approximately 22% is excreted as unchanged tigecycline in urine. The majority of the urine recovery (22%) occurred on the first day. Conversely, very little fecal recovery occurred on day 1 (0.03%), with the majority recovered thereafter. The primary route of elimination of tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Secondary routes are renal excretion of unchanged tigecycline, glucuronidation, and amide hydrolysis followed by N-acetylation to form N-acetyl-9-aminominocycline.²⁵

Postantibiotic Effect

The in vitro postantibiotic effect of tigecycline was 3.4 to 4 hours for strains of S. aureus and 1.8 to 2.9 hours for strains of E. coli, including those carrying selected resistance determinants.²⁵ In a localized neutropenic mouse thigh infection model, tigecycline exhibited a long in vivo postantibiotic effect: 8.9 hours for S. pneumoniae and 4.9 hours for E. coli. Both area under the curve (AUC) and time above a fraction of minimum inhibitory concentration (MIC) correlated with efficacy. Because tigecycline exhibited time-dependent bacterial killing properties in combination with a moderate-to-prolonged postantibiotic effect, the AUC/MIC ratio is likely the primary pharmacokinetic/pharmacodynamic determinant of efficacy.²⁵ The clinical significance of postantibiotic effect is unknown.

Indications

TYGACIL^® (tigecycline) is indicated for the treatment of adults with:

• Complicated skin and skin structure infections caused by Escherichia coli, 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 pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis
• Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus,
  S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros
• Community-acquired bacterial pneumonia caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila

Important Safety Information

• TYGACIL is contraindicated in patients with known hypersensitivity to tigecycline
• Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening. TYGACIL should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics
• Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function. Adverse events may occur after the drug has been discontinued
• The safety and efficacy of TYGACIL in patients with hospital-acquired pneumonia have not been established
• TYGACIL may cause fetal harm when administered to a pregnant woman
• The use of TYGACIL during tooth development may cause permanent discoloration of the teeth. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated
• Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis
• Monotherapy should be used with caution in patients with clinically apparent intestinal perforation
• TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL
• To reduce the development of drug-resistant bacteria and maintain the effectiveness of TYGACIL and other antibacterial drugs, TYGACIL should be used only to treat infections proven or strongly suspected to be caused by susceptible bacteria. As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi
• The most common adverse reactions (incidence >5%) are nausea, vomiting, diarrhea, abdominal pain, headache, and increased SGPT
• Prothrombin time or other suitable anticoagulant test should be monitored if TYGACIL is administered with warfarin
• Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective
• The safety and effectiveness of TYGACIL in patients below age 18 and lactating women have not been established

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