Tigecycline

585.65

585.65

1308068-626-2

70JE2N95KR

DTXSID2048581

C72865

Orange powder or cake

J01AA12|J - Antiinfectives for systemic use

3004909090

206

1.1

Powder

1.5±0.1 g/cm3

164-166°C

890.922°C at 760 mmHg

492.6±34.3 °C

1.675

In water, 14.55 mg/L at 25 deg C (est)

Amber Vial, -20°C Freezer

9.1X10-30 mm Hg at 25 deg C (est)

9

3077

3

24/25

QI7619500

Stable if stored as directed; avoid strong oxidizing agents

P201-P280-P305 + P351 + P338-P308 + P313

H319-H360

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tigecycline, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Drug Name: Tygacil; FDA Application No.: (NDA) 021821; Active Ingredient: Tigecycline; Company: PF Prism CV; Original Approval or Tentative Approval Date: June 15, 2005; Chemical Type: 1 New molecular entity (NME); Review Classification: Priority review drug.

|Danger|H319 (89.13%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]|P201, P202, P264, P273, P280, P281, P305+P351+P338, P308+P313, P337+P313, P391, P405, and P501|Aggregated GHS information provided by 46 companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Personal protective equipment as follows: Breathing equipment: NIOSH/MSHA-approved respirator. Protection of hands: chemical-resistant rubber gloves. Eye protection: chemical safety goggles.

Suitable extinguishing agents: water spray, carbon dioxide, dry chemical powder or foam. Protective equipment: wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes.

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves. Measures for cleaning/collecting: absorb solutions with finely- powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, federal, state and local regulations/.

Information for safe handling: avoid inhalation and contact with skin, eyes and clothing; material may be an irritant.|Handling should only be performed by personnel trained and familiar with handling of potent active pharmaceutical ingredients.

Since glycylcyclines are similar to tetracyclines, they share many of the same side effects and contraindications as tetracyclines. These side effects may include nausea/vomiting, headache, photosensitivity, discoloration of growing teeth, and fetal damage.

Tigecycline is reported to cause mild, transient elevations in serum aminotransferase levels in 2% to 5% of recipients, rates similar to those in patients treated with comparator antibiotics. Cases of clinically apparent liver injury with jaundice must be very rare. Product labels for tigecycline mention isolated cases of significant hepatic dyfunction cholestasis and jaundice identified from postmarketing experience. No information is available on the latency, pattern, and duration of liver injury in cases of tigecycline induced hepatotoxicity. The reports of jaundice and deaths from hepatic dysfunction in large clinical trials of tigecycline more likely reflected complications of sepsis and multiorgan failure rather than drug hepatotoxicity.

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.|Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.|Intravenous bolus administration of tigecycline at dosages of 10 mg/kg or greater produced prolongation of thiopental-induced sleeping time and death following thiopental pre-treatment in mice. This issue could be explained by the fact that tigecycline is known to release histamine at high doses. Increased histamine levels are known to decrease blood pressure, which at the same time is also reduced following the administration of an anesthetic dose of thiopental. Consistent with this hypothesis, pre-treatment with antihistamines was related to mortality prevention. Thus, tigecycline and thiopental together may have an additive or synergistic effect, which could be responsible for the additional hypotension and deaths observed after IV administration of thiopental and high doses of tigecycline.

LD50 Mouse iv 100-150 mg/kg|LD50 Rat iv 100 mg/kg

71% to 89%

For the treatment of infections caused by susceptible strains of the designated microorganisms in the following conditions: Complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes and Bacteroides fragilis. Complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates only), Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.|FDA Label|Tygacil is indicated in adults and in children from the age of eight years for the treatment of the following infections:Complicated skin and soft tissue infections (cSSTI), excluding diabetic foot infectionsComplicated intra-abdominal infections (cIAI)Tygacil should be used only in situations where other alternative antibiotics are not suitable.Consideration should be given to official guidance on the appropriate use of antibacterial agents. appropriate use of antibacterial agents.|Treatment of complicated intra-abdominal infections, Treatment of complicated skin and soft-tissue infections|Tygecycline Accord is indicated in adults and in children from the age of eight years for the treatment of the following infections (see sections 4.4 and 5.1):Complicated skin and soft tissue infections (cSSTI), excluding diabetic foot infections (see section 4.4)Complicated intra-abdominal infections (cIAI)Tygecycline Accord should be used only in situations where other alternative antibiotics are not suitable (see sections 4.4, 4.8 and 5.1).Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Tigecycline is a parenteral glycycline antibiotic used for treatment of serious infections due to susceptible organisms. Tigecycline therapy is sometimes accompanied by minor aminotransferase elevations, but has not been definitely associated with clinically apparent liver injury with jaundice.

Antiinfective Agents

Anti-Bacterial Agents|Tygacil is a tetracycline-class antibacterial drug indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the /following condition/ for patients 18 years of age and older: 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. /Included in US product label/|Tygacil is a tetracycline-class antibacterial drug indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the /following condition/ for patients 18 years of age and older: 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. /Included in US product label/|Tygacil is a tetracycline-class antibacterial drug indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the /following condition/ for patients 18 years of age and older: 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. /Included in US product label/

/BOXED WARNING/ WARNING: ALL-CAUSE MORTALITY: An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in Tygacil-treated patients versus comparator. The cause of this mortality risk difference of 0.6% (95% CI 0.1, 1.2) has not been established. Tygacil should be reserved for use in situations when alternative treatments are not suitable.|Increased risk of all-cause mortality has been reported in a pooled analysis of over 7400 patients from 13 phase 3 and 4, active-controlled clinical trials evaluating tigecycline for the treatment of serious infections. Data indicate a 4% mortality rate in tigecycline-treated patients versus 3% in patients treated with comparator anti-infectives. The adjusted risk difference in all-cause mortality between patients receiving tigecycline and those receiving comparators was 0.6%.|Acute pancreatitis, including fatalities, has been reported in patients receiving tigecycline. Some cases have been reported in patients with no known risk factors for pancreatitis. Improvement usually occurs after the drug is discontinued. A diagnosis of pancreatitis should be considered in any patient receiving tigecycline who develops symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. In suspected cases of pancreatitis, consideration should be given to discontinuing tigecycline.|May cause fetal harm; teratogenicity and embryolethality demonstrated in animals. Pregnancy should be avoided during therapy. If the patient becomes pregnant while receiving tigecycline, apprise of potential fetal hazard.|For more Drug Warnings (Complete) data for Tigecycline (14 total), please visit the HSDB record page.

Full genome sequences were determined for five Klebsiella pneumoniae strains belonging to the ST512 clone, producing KPC-3: three strains were resistant to tigecycline, one showed an intermediate phenotype and one was susceptible. Comparative analysis performed using the genome of the susceptible strain as reference sequence identified genetic differences possibly associated with resistance to tigecycline. Results demonstrated that mutations in the ramR gene occurred in two of the three sequenced strains. Mutations in RamR were previously demonstrated to cause the overexpression of the AcrAB-TolC efflux system and were implied in tigecycline resistance in K. pneumoniae. The third strain showed a mutation located at the vertex of a very well conserved loop in the S10 ribosomal protein, which is located in close proximity to the tigecycline target site in the 30S ribosomal subunit. This mutation was previously associated to tetracycline resistance in Neisseria gonorrhea. A PCR-based approach was devised to amplify the potential resistance mechanisms identified by genomics, and applied to two additional ST512 strains showing resistance to tigecycline, identifying mutations in the ramR gene.|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.

Tigecycline is the first clinically-available drug in a new class of antibiotics called the glycylcyclines. Glycylcyclines are a new class of antibiotics derived from tetracycline. These tetracycline analogues are specifically designed to overcome two common mechanisms of tetracycline resistance, namely resistance mediated by acquired efflux pumps and/or ribosomal protection. Glycylcycline antibiotics have a similar mechanism of action as tetracycline antibiotics. Both classes of antibiotics bind to the 30S ribosomal subunit to prevent the amino-acyl tRNA from binding to the A site of the ribosome. However, the glycylcyclines appear to bind more effectively than the tetracyclines.

Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)|Compounds which inhibit the synthesis of proteins. They are usually ANTI-BACTERIAL AGENTS or toxins. Mechanism of the action of inhibition includes the interruption of peptide-chain elongation, the blocking the A site of ribosomes, the misreading of the genetic code or the prevention of the attachment of oligosaccharide side chains to glycoproteins. (See all compounds classified as Protein Synthesis Inhibitors.)

The recovery of total radioactivity in feces and urine following administration of (14)C-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.|... The safety and tolerability of tigecycline administered as single or multiple doses or at various infusion rates were explored in three phase 1, randomized, double-blind, placebo-controlled studies in healthy subjects. Full pharmacokinetic profiles of tigecycline were determined in two of these studies. Subjects in the single-dose study received 12.5 to 300 mg of tigecycline, which differed with respect to the duration of infusion, subjects' feeding status, and ondansetron pretreatment. Subjects in the ascending multiple-dose study received 25 to 100-mg doses of tigecycline as a 1-hr infusion every 12 hr. The variable volume and infusion rate study consisted of administration of 100-mg loading dose of tigecycline, followed by 50 mg every 12 hr for 5 days. Serum samples were analyzed for tigecycline by validated high-pressure liquid chromatography or liquid chromatography/tandem mass spectrometry methods. Systemic clearance ranged from 0.2 to 0.3 liters/hr/kg, and the tigecycline half-life ranged from 37 to 67 hr. Tigecycline had a large volume of distribution (7 to 10 liters/kg), indicating extensive distribution into the tissues. Food increased the maximum tolerated single-dose from 100 to 200 mg, but the duration of infusion did not affect tolerability. ...|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.|Results from animal studies using (14)C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.|For more Absorption, Distribution and Excretion (Complete) data for Tigecycline (6 total), please visit the HSDB record page.

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. A glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) are the primary metabolites.|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 (14)C-tigecycline, tigecycline was the primary (14)C-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.|Tigecycline was minimally metabolised in the animal species tested, consistent with that observed in humans. Consistent with rat and dog data, the 4-epimer of tigecycline (a non-enzymatic epimerization product) was also the most abundant tigecycline-derived component detected in human serum and urine. The major metabolic pathways for tigecycline in humans were glucuronidation (M7: tigecycline glucuronide metabolite, approximately 12%, and its epimer M6) and amide hydrolysis of the tbutylaminoacetylamino side chain (M9: N-acetyl-9- aminominocycline, approximately 3% and its epimer M8, approximately 10% of the administered tigecycline dose). Thehuman metabolites (M7 and M9), have not been observed in rats and dogs, but are present in mice and rabbits. Further studies showed that tigecycline and its epimer as well as M3, M7 and its epimer M6 were detected in both species, mice and rabbits, but M9 and its epimer M8 were only observed in rabbits,although quantitative information on the individual metabolites was not provided.

27-43 hours|... The terminal elimination half-life is approximately 40 hr. ...

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. Tigecycline is not affected by the two major tetracycline resistance mechanisms, ribosomal protection and efflux. Accordingly, tigecycline has demonstrated in vitro and in vivo activity against a broad spectrum of bacterial pathogens. There has been no cross resistance observed between tigecycline and other antibiotics. 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/topoisomerase). In vitro studies have not demonstrated antagonism between tigecycline and other commonly used antibacterial drugs. In general, tigecycline is considered bacteriostatic.|Pro-inflammatory and pro-apoptotic mediators have been involved in the pathogenesis of neurodegenerative diseases. Tigecycline (Tig), a glycylcycline antibiotic and an analog of Minocycline, is shown to exert anti-inflammatory effects that are distinct from its anti-microbial activity. Its neuroprotective mechanism is unknown. In this study, we investigated the direct protective mechanisms of tigecycline against lipopolysaccharide (LPS)-induced Rat pheochromocytoma (PC12) cells. The results showed that tigecycline significantly attenuated the expression and the release of nuclear factor-kappa beta (NF-kappaB), tumor necrosis factor-alpha (TNF-a) and interleukin-1beta (IL-1beta), as well as nitric oxide (NO) levels in LPS-induced PC12 cells. In addition, tigecycline dose-dependently decreased cytochrome c release and caspase-3 activity. This later finding corroborated the results of decreased pro-apoptotic Bad, and increased anti-apoptotic Bcl-2 protein expression thus, confirming a neuroprotective effect of the drug in differentiated PC12 cells induced with LPS. The findings of /this/ study suggest new targets for tigecycline and support the potential for tigecycline to be investigated as a therapeutic agent for neurodegenerative disorders.|Tigecycline is a glycylcycline antibiotic derived from the tetracycline group, that acts by inhibiting protein synthesis at the level of the bacterial ribosome. Tigecycline shows higher binding affinity than tetracyclines, being active against bacterial strains with either mechanism of tetracycline resistance (efflux and ribosomal protection). The fact that tigecycline overcomes most of the known tetracycline resistance mechanisms is interpreted as a result of steric hindrance due to the large substituent at position 9. Tigecycline showed a number of differences between the in vitro/in vivo antibacterial activity with respect to the tetracycline group that could be attributed to the specific interaction with a different region of the ribosomal A-site. Since mutational resistance to tetracyclines at the A-site is considered extremely rare, it is unlikely that mutational resistance to tigecycline will arise at the Asite. Tigecycline is able to inhibit mitochondrial protein synthesis in eukaryotic cells, which may have some toxicological relevance. However, in this respect tigecycline resembles classical tetracyclines and some other antimicrobial drugs inhibiting prokaryotic protein synthesis. In addition, the in vitro data show that tigecycline is active against microorganisms harbouring some tetracycline determinants of resistance.

Emergency and supportive measures: Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, anaphylaxis, and hemolysis if they occur. Replace fluid losses resulting from gastroenteritis with intravenous crystalloids. /Antibacterial agents/|Decontamination: Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antibacterial agents/|Enhanced elimination: Most antibiotics are excreted unchanged in the urine, so maintenance of adequate urine flow is important. The role of forced diuresis is unclear. Hemodialysis is not usually indicated, except perhaps in patients with renal dysfunction and a high level of a toxic agent. /Antibacterial agents/|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|For more Antidote and Emergency Treatment (Complete) data for Tigecycline (6 total), please visit the HSDB record page.

/HUMAN EXPOSURE STUDIES/ Intravenous administration of Tygacil at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting.|/SIGNS AND SYMPTOMS/ Acute pancreatitis, including fatalities, has been reported in patients receiving tigecycline. Some cases have been reported in patients with no known risk factors for pancreatitis. Improvement usually occurs after the drug is discontinued. A diagnosis of pancreatitis should be considered in any patient receiving tigecycline who develops symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. In suspected cases of pancreatitis, consideration should be given to discontinuing tigecycline.|/CASE REPORTS/ /The authors/ describe a 69-year-old female who received tigecycline for treatment of a complicated skin and skin-structure infection. Following 7 days of tigecycline she developed severe abdominal pain and elevated pancreatic enzymes suggesting acute pancreatitis. According to the Naranjo adverse drug reaction probability scale, tigecycline was the probable cause of her acute pancreatitis. Clinicians should be aware of this potential adverse effect of tigecycline. /The authors/ recommend that clinicians monitor patients for signs and symptoms of pancreatitis, including abdominal pain, during treatment with tigecycline.|/EPIDEMIOLOGY STUDIES/ In 12 of 13 phase 3 and 4 comparative clinical trials, all-cause mortality was higher in the tigecycline group versus the comparator group. Study-level mortality risk differences were pooled using a random-effects meta-analysis. Statistical models evaluated the association between patient-level all-cause mortality and baseline factors using logistic regression, recursive partitioning [classification and regression tree (CART) analysis] and survival techniques. The estimated risk difference (tigecycline minus comparator) in all-cause mortality from the meta-analysis was 0.6% (95% confidence interval 0.1-1.2%). Statistical modelling identified baseline bacteraemia associated with mortality only in the tigecycline group. In patients with ventilator-associated pneumonia (VAP) and baseline bacteraemia, mortality was 50.0% (9/18) for tigecycline versus 7.7% (1/13) for the comparator group. Study-level and patient-level analyses have identified that patients in the hospital-acquired pneumonia trial, particularly those with VAP with baseline bacteraemia, were at a higher risk of clinical failure and mortality.|/OTHER TOXICITY INFORMATION/ Increased risk of all-cause mortality has been reported in a pooled analysis of over 7400 patients from 13 phase 3 and 4, active-controlled clinical trials evaluating tigecycline for the treatment of serious infections. Data indicate a 4% mortality rate in tigecycline-treated patients versus 3% in patients treated with comparator anti-infectives. The adjusted risk difference in all-cause mortality between patients receiving tigecycline and those receiving comparators was 0.6%.

9-(tert-butylglycylamido)minocycline

Parenteral: For injection, for IV infustion: 50 mg Tygacil (Wyeth).

Tigecycline is a first-in-class, broad spectrum antibiotic with activity against multiple-resistant organisms. In order to address the unexpectedly low tigecycline concentrations in human bone samples analyzed using a LC/MS/MS method developed elsewhere, we have developed and validated a new and sensitive human bone assay for the quantitation of tigecycline using LC/MS/MS. The new method utilizes the addition of a stabilizing agent to the human bone sample, homogenization of human bone in a strong acidic-methanol extraction solvent, centrifugation of the bone suspension, separation by liquid chromatography, and detection of tigecycline by mass spectrometry. Linearity was demonstrated over the concentration range from 50 to 20,000 ng/g using a 0.1g human bone sample. The intra- and inter-day accuracy of the assay was within 100+/-15%, and the corresponding precision (CV) was <15%. The stability of tigecycline was evaluated and shown to be acceptable under the assay conditions. The extraction recovery of tigecycline with the current method was 79% when using radio-labeled rat bone samples as a substitute for human bone samples. Twenty-four human bone samples collected previously from volunteers without infections who had elective orthopedic surgery after receiving a single dose of tigecycline were re-analyzed using the current validated method. Tigecycline concentrations in these samples ranged from 238 to 794 ng/g with a mean value 9 times higher than the mean concentration previously reported. The data demonstrated that the current method has significantly higher extraction efficiency than the previously reported method.|/The purpose of this study is/ to develop and validate a sensitive and novel bioanalytical method for measuring tigecycline concentrations in human skin using LC-MS/MS. The method utilizes addition of a stabilizing agent to the human skin or surrogate (human liver or rat skin), homogenization of human skin in a strong acidic-methanol extraction solvent, centrifugation of the skin suspension, filtration of the skin suspension supernatant, separation by LC, and detection of tigecycline by MS/MS. Linearity was 50-20,000 ng/g, using a sample size of 100 mg. The intra-and inter-day accuracy and precision of the assay met acceptance criteria. This method has been successfully applied to 17 incurred human skin samples from volunteers with surgical infections who received intravenous doses of tigecycline (100 mg initial loading dose and 50 mg every 12 hr for at least 2 days). Tigecycline concentrations in these samples ranged from 185 to 2853 ng/g.|An isocratic HPLC method with detection at 248 nm was developed and fully validated for the determination of tigecycline in rabbit plasma. Minocycline was used as an internal standard. A Hypersil BDS RP-C18 column (250 x 4.6 mm, 5 microm particle size) was used with the mobile phase phosphate buffer (pH 7.10, 0.070 M)-acetonitrile (76 + 24, v/v) at a flow rate of 1.0 mL/min. The elution time of tigecycline and minocycline was approximately 8.1 and 9.9 min, respectively. Calibration curves of tigecycline were linear in the concentration range of 0.021-3.15 microg/mL in plasma. The LOD and LOQ in plasma were estimated as 7 and 21 ng/mL, respectively. The intraday and interday precision values of the method were in the range of 5.0-7.1 and 5.6-9.1%, while the corresponding accuracy values were in the ranges of 92.8-111.1 and 97.6-102.3%, respectively. At the LOQ, the intraday precision was 18.7%, while intraday and interday accuracy values were 97.3 and 98.0%, respectively. Robustness of the proposed method was studied using a Plackett-Burman experimental design. A pharmacokinetic profile is presented for confirmation of the applicability of the method to pharmacokinetic studies.

Human drugs -> Tygacil -> EMA Drug Category|Antibacterials for systemic use -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human drugs -> Tigecycline Accord -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients