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...

The pharmacokinetics of tigecycline was evaluated in 46 healthy young and elderly men and women. Except for the volumes of distribution at steady state (approximately 350 liters in women versus 500 liters in men), there were no significant differences in tigecycline pharmacokinetic parameters. Based on pharmacokinetics, no dosage adjustment is warranted based on age or sex.Tigecycline is a novel intravenously administered glycylcycline antibiotic exhibiting an expanded spectrum of in vitro and in vivo activity against gram-positive, gram-negative, atypical, anaerobic, and other difficult-to-treat pathogens (1-8, 10, 13, 18, 20-23, 25, 26). Clinical studies suggest that tigecycline is generally well tolerated and easy to use with a twice-daily dose regimen (17,21). The clinical dosing regimen presently being evaluated is 100 mg followed by 50 mg every 12 h (17).The primary objective of this open-label study was to determine if subject age or sex affects the pharmacokinetic profile of a single 100-mg intravenous dose of tigecycline, and the secondary objective was to compare the levels of observed openlabel safety and tolerability of tigecycline among the age and sex groups.Forty-six healthy men and women from the following three age categories were enrolled: young (18 to 50 years, inclusive), young-elderly (65 to 75 years, inclusive), and elderly (Ͼ75 years). Subjects were in good health on the basis of medical histories, physical examinations, electrocardiograms, and laboratory evaluations. The Institutional Review Board of The Methodist Hospital in Philadelphia, Pennsylvania approved the study, and all subjects gave written informed consent before enrollment. The demographic profile of each age-sex group is presented in Table 1.Tigecycline (100 mg) was administered as a single intravenous dose infused over 60 min. Serial blood samples for the determination of tigecycline concentrations in serum were collected over 120 h after the start of tigecycline infusion, and complete urine output was collected over 48 h after the start of the tigecycline infusion. Tigecycline concentrations in serum and urine were quantified by using validated analytical methods that are similar to those described previously (17).Pharmacokinetic parameters based on serum data for tigecycline were estimated with standard noncompartmental methods (11) using a validated SAS (version 8.02) program. Pharmacokinetic parameters were compared among the age-sex groups by using a two-factor analysis of variance with factors for age, sex, and age-by-sex interaction.Based on the intersubject variability observed in previous studies (17), it was estimated that having at least 20 subjects per sex and at least 17 in the younger cohort compared with the pooled elderly cohorts would provide a statistical power of at least 80% to detect a 30% difference for both the maximum concentrations of the drug in serum and the areas under the concentration-time curve (AUCs) between sexes or age groups.Safety was evaluated from spontaneously reported signs and sympt...

The pharmacokinetic parameters of tigecycline were assessed in subjects with severe renal impairment (creatinine clearance <30 mL/min, n = 6), subjects receiving hemodialysis (4 received tigecycline before and 4 received tigecycline after hemodialysis), and subjects with age-adjusted, normal renal function (n = 6) after administration of single 100-mg doses. Serial serum and urine samples were collected and assayed using validated liquid chromatography with tandem mass spectrometer (LC/MS/MS) methods. Concentration-time data were then analyzed using noncompartmental pharmacokinetic methods. Tigecycline renal clearance in subjects with normal renal function represented approximately 20% of total systemic clearance. Tigecycline clearance was reduced by approximately 20%, and area under the tigecycline concentration-time curve increased by approximately 30% in subjects with severe renal impairment. Tigecycline was not efficiently removed by dialysis; thus, it can be administered without regard to timing of hemodialysis. Based on these pharmacokinetic data, tigecycline requires no dosage adjustment in patients with renal impairment.

Quindine is a potent inhibitor of CYP2D6 (debrisoquine 4-hydroxylase). Its effect on the disposition of chlorpromazine was investigated in ten healthy volunteers using a randomised crossover design with two phases. A single oral dose of chlorpromazine hydrochloride (100 mg) was given with and without prior administration of quinidine bisulphate (250 mg). Chlorpromazine and seven of its metabolites were quantified in the 0- to 12-h urine while plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine were measured over 48 h. All volunteers were phenotyped as extensive metabolisers with respect to CYP2D6 using the methoxyphenamine/O-desmethyl-methoxyphenamine metabolic ratio. Quinidine significantly decreased the urinary excretion of 7-hydroxylchlorpromazine 2.2-fold. Moreover the urinary excretion of this metabolite correlated inversely (rs = -0.80) with the metabolic ratio. The urinary recoveries of chlorpromazine, chlorpromazine N-oxide, 7-hydroxy-N-desmethylchlorpromazine, N-desmethyl-chlorpromazine sulphoxide and the total of all eight analytes were unaltered by quinidine. However, quinidine administration caused significant increases in the urinary excretions of chlorpromazine sulphoxide, N-desmethylchlorpromazine and N, N-didesmethylchlorpromazine sulphoxide, which indicated that compensatory increase in these metabolic routes of chlorpromazine might have been responsible for the lack of change observed in the urinary recovery of the parent drug. Quinidine administration produced modest decreases (1.2- to 1.3-fold) in the mean peak plasma concentrations and mean areas under the plasma concentration-time curves of 7-hydroxychlorpromazine and increases (1.3- to 1.4-fold) in these parameters for the parent drug chlorpromazine, but none of these changes reached statistical significance. Based on ANOVA the sample sizes required to detect these differences as significant (alpha = 0.5) with a probability of 0.8 were determined to vary between 15 and 42. These data suggest that CYP2D6 is involved in the metabolism of chlorpromazine to 7-hydroxychlorpromazine. However, genetic polymorphism in this metabolic process did not play a dominant role in accounting for the extremely large interindividual variations in plasma concentrations encountered with this drug.

Clinical Pharmacology & Therapeutics (1999) 65, 189–189; doi: