Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous Moxifloxacin in Pediatric Patients: Dose Optimization in a Phase 1 Study

被引:13
作者
Stass, Heino [1 ]
Lettieri, John [2 ]
Vanevski, Konstantina M. [3 ]
Willmann, Stefan [1 ]
James, Laura P. [4 ,5 ]
Sullivan, Janice E. [6 ]
Arrieta, Antonio C. [7 ]
Bradley, John S. [8 ,9 ]
机构
[1] Bayer, Wuppertal, Germany
[2] Bayer, Whippany, NJ USA
[3] Bayer, Basel, Switzerland
[4] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA
[5] Arkansas Childrens Res Inst, Little Rock, AR USA
[6] Univ Louisville, Norton Childrens Hosp, Kosair Charities Pediat Clin Res Unit, Louisville, KY 40292 USA
[7] Childrens Hosp Orange Cty, Orange, CA 92668 USA
[8] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA
[9] Rady Childrens Hosp San Diego, San Diego, CA USA
关键词
dose finding; fluoroquinolone; moxifloxacin; pediatrics; pharmacokinetics; pharmacodynamics; phase; 1; study; INFECTIOUS-DISEASES-SOCIETY; GUIDELINES; MANAGEMENT; FLUOROQUINOLONES; PENETRATION; METABOLISM; DIAGNOSIS; CHILDREN; THERAPY; UPDATE;
D O I
10.1002/jcph.1358
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The pharmacokinetics, safety, and tolerability of a single dose of moxifloxacin were characterized in 31 pediatric patients already receiving antibiotics for a suspected or proven infection in an open-label phase 1 study. A dosing strategy for each age cohort (Cohort 1: >= 6 years to <= 14 years; Cohort 2: >= 2 years to 3 month to <2 years) was developed using physiology-based pharmacokinetic modeling combined with a stepwise dosing scheme to obtain a similar exposure to adults receiving 400 mg of moxifloxacin. Doses, adjusted to body weight and age, were gradually escalated from 5 mg/kg in Cohort 1 to 10 mg/kg in Cohort 3 based on interim analysis of the pharmacokinetic and safety data. Plasma and urine samples before and after the 60-minute infusion were collected for the analysis of moxifloxacin and its metabolites using a validated high-pressure liquid chromatography assay with tandem mass spectrometry. Moxifloxacin and metabolite concentrations in plasma were within the ranges observed in adults; however, clearance of all analytes was lower in pediatric patients compared with adults. Population pharmacokinetic analyses using the achieved exposure levels in the 3 age cohorts (with known body weight and clearance) predicted similar efficacy and safety profiles to adults. Moxifloxacin was well tolerated in all pediatric age cohorts. Adverse events related to moxifloxacin were mild or moderate in intensity and showed no correlation with increased weight-adjusted doses. Our findings guided the selection of age-appropriate clinical doses for a subsequent phase 3 clinical trial in pediatric patients with complicated intra-abdominal infections.
引用
收藏
页码:654 / 667
页数:14
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