Pharmacokinetics of Tigecycline after Single and Multiple Doses in Healthy Subjects

Abstract

Tigecycline, a novel glycylcycline antibiotic, exhibits strong activity against gram-positive, gram-negative, aerobic, anaerobic, and atypical bacterial species, including many resistant pathogens, i.e., vancomycinresistant enterococci, methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. 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-h infusion every 12 h. The variable volume and infusion rate study consisted of administration of 100-mg loading dose of tigecycline, followed by 50 mg every 12 h 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/h/kg, and the tigecycline half-life ranged from 37 to 67 h. 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. Side effects, mainly nausea and vomiting, which are common to the tetracycline class of antimicrobial agents, were seen in these studies. Tigecycline exhibits linear pharmacokinetics and is safe and well tolerated in the dose ranges examined.Tigecycline, a novel, first-in-class glycylcycline (3,17,22,26), has shown in vitro activity against gram-positive, gram-negative, aerobic, anaerobic, and atypical bacterial species, including antibiotic-resistant strains. In studies with clinical isolates, tigecycline exhibits activity against tetracycline-resistant bacteria such as methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, and glycopeptide-intermediate S.aureus. Penicillin-susceptible and -resistant Streptococcus pneumoniae (10) and vancomycin-resistant enterococci are also susceptible to tigecycline. In addition, tigecycline is active against most gram-negative pathogens, including Enterobacteriaceae, Acinetobacter spp., Stenotrophomonas maltophilia (1, 9, 13), Haemophilus influenzae, and Neisseria gonorrhoeae (5). Tigecycline's expanded broad-spectrum activity is further evidenced by its activity against Legionella pneumophila (6), Chlamydia (20), rapidly growing nontuberculosis mycobacteria (25), and anaerobes (18). A few reports on the pharmacokinetics of tigecycline in animals are documented in the literature. After administration of 14 C-labeled tigecycline to rats, tigecycline tissue levels, with the highe...

A Phase 1 study of intravenous infusions of tigecycline in patients with acute myeloid leukemia

“…Our C max values are from 1.5 to 4 times higher than previously reported values at the same doses, and all AUC calculated values were approximately twofold higher than the reported values 17. Repeat analysis of plasma aliquots from several patients resulted in approximately the same concentrations.…”

“…Increases in transaminases and pancreatic enzymes, and congestive heart failure have been reported in patients treated with tigecycline and are listed as rare drug reactions in the tigecycline package insert 22, 23. In addition, nausea and vomiting are the most frequently reported adverse events for the use of tigecycline 17. In this study, grade‐2 nausea, diarrhea and vomiting were reported in a total of five patients and judged to be possibly related to the treatment.…”

“…Two possible explanations are proposed for this quantitative difference between our data and those reported by Muralidharan et al. 17. The first is based on the analytical technique: the improved sensitivity and specificity of the current UPLC‐MS/MS analytical method relative to those obtained with a typical HPLC‐UV‐based method may provide a more accurate measurement of true tigecycline concentrations.…”

Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets

“…To provide a pharmacologic correlate to these findings, we tested the effect of tigecycline (also known as Tygacil), an FDA-approved glycylcycline antibiotic known to inhibit the prokaryotic ribosome [31][32][33] and to interfere with mitochondrial translation in eukaryotes without affecting the translation of mitochondrial proteins encoded by nuclear genes (Supplementary Figure 2a). 34 The effect of tigecycline on viability of DLBCL subsets was examined at a dose range of 1-5 μM over a 24-72 h time course (Figures 3a-c; Supplementary Figure 2b).…”

In vitro antimalarial activity of tigecycline against Plasmodium falciparum culture-adapted reference strains and clinical isolates from the Brazilian Amazon

“…Pharmacological functional assays have shown that tigecycline inhibits bacterial protein synthesis with a potency that is 3-and 20-fold greater than that of minocycline and tetracycline, respectively 5 . This drug is currently registered only for intravenous use, and a twice-daily dosing regimen is relatively easy to administer and is generally well tolerated 7 . Clinical studies have shown that tigecycline possesses an expanded spectrum of in vitro and in vivo activity against Gram-positive, Gram-negative, atypical, anaerobic, and other difficult-to-treat pathogens 8 .…”