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 unexpected discovery that certain chemotherapeutic agents used in the treatment of childhood cancers have neurocognitive side effects has prompted a search for techniques that identify those medications that place children at risk. An animal model for the assessment of resultant neurocognitive toxicity is described which makes use of simple classical conditioning. We have shown that rats learn about environmental events more slowly following neonatal administration of methotrexate. The changes after methotrexate exposure are not related to stimulus characteristics or to perceptual abilities, but rather to damage to the neural systems involved in acquisition, retention, or recall. Similar problems with learning have been observed in children treated with methotrexate. An effective animal model such as the one described here may help detect and avoid antineoplastic agents that produce severe cognitive defects in childhood cancer patients.

BACKGROUND/AIMS To assess the safety, tolerability and pharmacokinetics of single ascending doses of rotigaptide, a first‐in‐class cardiomyocyte gap junction modifier, in healthy subjects. METHODS In a randomized, double‐blind, placebo‐controlled, sequential‐group study, ascending single doses of rotigaptide or placebo were administered to 79 men as a 24‐hour IV infusion of 0.03 to 30 mg or as a bolus of 2 or 3 mg. Safety was determined from reported adverse events (AEs), physical exams, vital signs, laboratory tests, and 12‐lead ECGs. Plasma and urine samples were analyzed for rotigaptide using LC/MS/MS method and rotigaptide pharmacokinetics was characterized. RESULTS The most common AEs were asymptomatic orthostatic increase in pulse (n=28) and decrease in blood pressure (n=4), and local irritation, rash, and/or blistering at the electrode site (n=23). All were considered by the investigator as mild or moderate and probably not related to test article. There were no dose‐related trends in AEs or laboratory tests. Rotigaptide disposition was characterized by low Cl (133 mL/min) and low VSS (21.4 L) and the terminal disposition t1/2 was 2.7 h. AUC increased in a dose‐proportional manner. Approximately 61–84% excreted unchanged in urine and no metabolites were apparent in plasma. CONCLUSION Rotigaptide appeared to be safe and well‐tolerated at the doses tested in healthy subjects. Rotigaptide showed predictable0 and linear pharmacokinetics and renal excretion was the primary route of elimination. Clinical Pharmacology & Therapeutics (2005) 79, P77–P77; doi:

BACKGROUND/AIMS To assess the safety, tolerability, and pharmacokinetics of 6‐day continuous intravenous infusion of rotigaptide, a first‐in‐class cardiomyocyte gap junction modifier, in healthy subjects. METHODS This was a randomized, double‐blind, placebo‐controlled, sequential‐group study of ascending doses of rotigaptide. Rotigaptide or placebo was administered to 32 men as a 6‐day continuous IV infusion at doses of 1 to 20 mg/day. Safety was determined from reported adverse events (AEs), physical exams, vital signs, laboratory tests, and 12‐lead ECGs. Plasma and urine samples were analyzed for rotigaptide using a validated LC/MS/MS method and rotigaptide pharmacokinetics was characterized. RESULTS The most common AEs were IV site reactions (n=14), orthostatic pulse and blood pressure changes (n=11), application site reactions (n=5), and increased ALT (n=3) and AST (n=2). All were considered as mild or moderate and probably not related to test article. There were no dose‐related trends in AEs or laboratory tests. Rotigaptide mean steady‐state concentrations ranged from 6.28 to 90.6 ng/mL on day 1 and 5.70 to 97.7 ng/mL on day 6 and were consistent with the predicted levels based on the single‐dose PK. AUCSS increased in a dose‐proportional manner. About 65–84% excreted unchanged in urine and no metabolites were apparent in plasma. CONCLUSION Rotigaptide appeared to be safe and well‐tolerated at the doses tested. Rotigaptide showed predictable, dose and time‐independent pharmacokinetics. Clinical Pharmacology & Therapeutics (2005) 79, P50–P50; doi: