A dose-escalation study of the safety, tolerability, and pharmacokinetics of intravenous gatifloxacin in healthy adult men

被引:51
作者
Gajjar, DA
LaCreta, FP
Uderman, HD
Kollia, GD
Duncan, G
Birkhofer, MJ
Grasela, DM
机构
[1] Bristol Myers Squibb Pharmaceut Res Inst, Dept Clin Pharmacol Expt Med, Princeton, NJ USA
[2] Bristol Myers Squibb Pharmaceut Res Inst, Dept Metab & Pharmacokinet, Princeton, NJ USA
[3] Bristol Myers Squibb Pharmaceut Res Inst, Dept Biostat & Data Management, Princeton, NJ 18543 USA
来源
PHARMACOTHERAPY | 2000年 / 20卷 / 06期
关键词
D O I
10.1592/phco.20.8.49S.35186
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Study Objectives. To examine single- and multiple-dose safety, tolerability, and pharmacokinetics of gatifloxacin administered as daily 1-hour intravenous infusions for 14 days, and to determine the effect of gatifloxacin on glucose tolerance, pancreatic beta-cell function, and electrocardiogram (ECG). Design. Randomized, double-blind, placebo-controlled, ascending-dose study. Setting. Bristol-Myers Squibb, Clinical Pharmacology Unit, Princeton, New Jersey, USA. Patients. Forty healthy male subjects, eight in each of five groups, were enrolled to receive sequential doses of gatifloxacin: 200 mg (10 mg/ml), 200 mg (1 mg/ml), and 400, 600, and 800 mg (2 mg/ml); six subjects per group received active drug and two received placebo. Interventions. A single dose of the drug was administered as an intravenous infusion over 1 hour. After a 72-hour washout period, the drug was administered once/day for 14 days by 1-hour intravenous infusion. Physical examinations, ECGs, spirometry, and clinical laboratory tests, including glucose tolerance test (GTT) and assessment of glucose homeostasis, were performed before treatment and on selected dosing days. A safety evaluation was performed before escalating doses. No intrasubject dose escalation was permitted. Measurements and Main Results. The pharmacokinetics of gatifloxacin were dose linear and time independent after intravenous administration over the range of 200-800 mg. After daily repeated administration, a predictable, modest accumulation was observed; steady state was reached by the third dose. Approximately 80% of the dose was recovered as unchanged drug in urine. Mean changes (before the first dose to the last dose) after oral GTT and in fasting serum glucose, insulin, and C-peptide concentrations were comparable among the gatifloxacin and placebo treatment groups. A mild, transient decrease in serum glucose was associated with the end of the 1-hour infusion of gatifloxacin. No clinically important changes in QTc interval or spirometry occurred. The most frequent treatment-related adverse effects were local intravenous site reactions, which were associated with dose and/or concentration of intravenous solution. Conclusion. Gatifloxacin was safe and well tolerated at intravenous doses of up to 800 mg/day for 14 days. Gatifloxacin pharmacokinetics were linear and time independent.
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页码:49S / 58S
页数:10
相关论文
共 31 条
  • [21] THE APPLICATION OF STATISTICAL MOMENT THEORY TO THE EVALUATION OF INVIVO DISSOLUTION TIME AND ABSORPTION TIME
    RIEGELMAN, S
    COLLIER, P
    [J]. JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS, 1980, 8 (05): : 509 - 534
  • [22] ROWLAND M, 1989, CLIN PHARMACOKINET, P83
  • [23] PHARMACOKINETICS OF HIGH-DOSE INTRAVENOUS CIPROFLOXACIN IN YOUNG AND ELDERLY AND IN MALE AND FEMALE SUBJECTS
    SHAH, A
    LETTIERI, J
    NIX, D
    WILTON, J
    HELLER, AH
    [J]. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1995, 39 (04) : 1003 - 1006
  • [24] COMPARATIVE PHARMACOKINETICS AND SAFETY OF CIPROFLOXACIN 400 MG IV THRICE DAILY VERSUS 750 MG PO TWICE-DAILY
    SHAH, A
    LETTIERI, J
    KAISER, L
    ECHOLS, R
    HELLER, AH
    [J]. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 1994, 33 (04) : 795 - 801
  • [25] Shailer P. A., 1997, Clinical Pharmacology and Therapeutics, V61, P148
  • [26] SISNIEGA JAL, 1999, J RESP DIS S, V20, pS11
  • [27] STONER BP, 1999, 39 INT C ANT AG CHEM
  • [28] TOLERANCE OF INTRAVENOUSLY ADMINISTERED CIPROFLOXACIN
    THORSTEINSSON, SB
    BERGAN, T
    ROHWEDDER, R
    [J]. CHEMOTHERAPY, 1988, 34 (03) : 256 - 260
  • [29] TOLERANCE OF CIPROFLOXACIN AT INJECTION SITE, SYSTEMIC SAFETY AND EFFECT ON ELECTROENCEPHALOGRAM
    THORSTEINSSON, SB
    BERGAN, T
    JOHANNESSON, G
    THORSTEINSSON, HS
    ROHWEDDER, R
    [J]. CHEMOTHERAPY, 1987, 33 (06) : 448 - 451
  • [30] Pharmacokinetics and safety of trovafloxacin in healthy male volunteers following administration of single intravenous doses of the prodrug, alatrofloxacin
    Vincent, J
    Venitz, J
    Teng, R
    Baris, BA
    Willavize, SA
    Polzer, RJ
    Friedman, HL
    [J]. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 1997, 39 : 75 - 80