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., vancomycin-resistant 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.

FIG. 1.

Mean tigecycline concentrations in serum in the single ascending dose study in fasting subjects as 1-h infusions (A), as 1-h infusions in the 200-mg dose group (B), and as 4-h infusions (C).

FIG. 1.

Mean tigecycline concentrations in serum in the single ascending dose study in fasting subjects as 1-h infusions (A), as 1-h infusions in the 200-mg dose group (B), and as 4-h infusions (C).

FIG. 1.

Mean tigecycline concentrations in serum in the single ascending dose study in fasting subjects as 1-h infusions (A), as 1-h infusions in the 200-mg dose group (B), and as 4-h infusions (C).

FIG. 2.

Tigecycline concentrations (mean plus the standard deviation) serum in multiple ascending dose study on day 1 (A) and day 10 (B).

FIG. 3.

Relationship between tigecycline dose in the single ascending dose study and C_max (A) and AUC (B).