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...

Twenty-four healthy male and female subjects, who participated in this randomized, double-blind, crossover study, received single nighttime doses of zaleplon 10 mg (therapeutic dose), zaleplon 20 mg, zolpidem 10 mg (therapeutic dose), zolpidem 20 mg, triazolam 0.25 mg (positive control), and placebo. Subjective behavioral ratings and psychomotor tests were completed before and 1.25 and 8.25 hours after administration of the study drug. The Immediate and Delayed Word Recall tests and the Digit Span Test were used to assess memory. The Digit-Symbol Substitution Test, Paired Associates Learning Test, and Divided Attention Test were used to assess other cognitive skills. Zaleplon 10 mg did not produce any significant changes in memory or learning compared with placebo. All other active treatments, including zolpidem 10 mg, caused psychomotor impairment at the 1.25-hour test battery. Zolpidem 20 mg (twice the therapeutic dose) produced more psychomotor impairment at the 1.25-hour assessment than did any of the other active treatments, including zaleplon 20 mg. At the 8.25-hour time point, test scores for subjects who received zaleplon 10 mg and 20 mg did not differ from the test scores for those who received placebo. However, cognitive impairment persisted up to the 8.25-hour observation for subjects who were administered triazolam 0.25 mg and zolpidem 20 mg. Adverse events associated with the use of zaleplon were transient and mild-to-moderate in severity. Overall, this study shows that zaleplon is a safe hypnotic that does not affect memory, learning, or psychomotor skills associated with vigilance.

Retigabine, a first-in-class selective M-current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo-controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half-life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabine's pharmocokinetics was linearly dose proportional. Steady-state pharmacokinetics was in agreement with single-dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21-360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed-dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.

The pharmacokinetics of tigecycline, when given as a 100-mg loading dose followed by 50 mg every 12 h, were determined in serum and blister fluid. The peak tigecycline concentration and half-life in serum were greater than those in blister fluid. Tigecycline penetrates into blister fluid well, with a mean penetration rate of 74%.Tigecycline is the first of the glycylcyclines, a novel class of antimicrobials structurally related to the tetracyclines, to undergo clinical development (19). Tigecycline is an expanded broad-spectrum antibiotic with activity against gram-negative, gram-positive, anaerobic, and atypical pathogens. It shows in vitro activity against tetracycline-resistant organisms containing genes responsible for efflux or ribosomal protection resistance mechanisms, as well as other resistant pathogens, such as methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci (1,2,5,6,12).Limited pharmacokinetic data are available for tigecycline, and no studies evaluating tigecycline's ability to penetrate the skin have been published. In phase 2 studies, tigecycline has demonstrated good clinical efficacy in the treatment of skin and skin structure infections (17).In the context of skin and soft tissue infections, the evaluation of drug concentrations by using the cantharidin-induced skin blister model mimics situations within an infected tissue (13). Previous studies using this model have been successfully performed at the Center for Anti-Infective Research and Development, Hartford Hospital (14). The purpose of this study was to determine the steady-state pharmacokinetic profile of tigecycline in serum and blister fluid when tigecycline is administered intravenously over 30 min as a 100-mg loading dose followed by 50 mg every 12 h for a total of seven doses.This study was approved by Hartford Hospital's Institutional Review Board. All subjects were given a detailed description of the study, and all provided written informed consent. Ten healthy subjects were enrolled in this single-center, multipledose, open-label study. The subjects were 20 to 37 years of age (mean age, 26.7 years), 172 to 185 cm in height (mean height, 177.3 cm), and 69.5 to 89.1 kg in weight (mean weight, 80.1 kg). Participation included a screening evaluation within 3 weeks of tigecycline administration on day 1 and a 6-day (5-night) inpatient period. Subjects were enrolled after the screening evaluation, and laboratory evaluations (including hematologies, blood chemistries, and urinalyses) and electrocardiograms revealed no clinically significant abnormalities.Each subject received a loading dose of 100 mg of tigecycline (Wyeth Pharmaceuticals, Collegeville, Pa.) infused over 30 min on study day 1, followed by 50 mg infused over 30 min every 12 h, for a total of seven doses. Subjects were served mediumfat meals approximately 30 min before tigecycline administration. Fluids were allowed ad libitum. Consumption of any caffeine-containin...

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...