Age and Gender Effects on the Pharmacokinetics of Gatifloxacin

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Gatifloxacin is an 8-methoxy fluoroquinolone effective against a broad spectrum of pathogens common in pediatric infections. The safety and pharmacokinetics of a single dose of gatifloxacin were studied in pediatric patients from 6 months to 16 years of age. Seventy-six pediatric patients (average age, 6.7 ؎ 5.0 years) were administered a single oral dose of gatifloxacin suspension (5, 10, or 15 mg/kg of body weight; 600-mg maximum) in a dose-escalating manner. Subjects were stratified by age into 4 groups. An additional 12 children, greater than 6 years of age, received gatifloxacin as the tablet formulation at a dose of approximately 10 mg/kg. Gatifloxacin's apparent clearance and half-life were 5.5 ؎ 2.1 ml/min/kg and 5.1 ؎ 1.4 h. The maximum concentration of drug in plasma and area under the concentration-time curve (AUC) increased in a manner approximately proportional to the dose. At the 10-mg/kg dose, the bioavailability was similar between the suspension and tablet formulation. The apparent oral clearance of gatifloxacin, normalized for body weight, exhibited a small but statistically significant decrease with increasing age. In all subjects receiving gatifloxacin at 10 mg/kg, the AUC exceeded 20 g ⅐ h/ml (estimated free AUC/MIC ratio of >34 for MIC of <0.5 g/ml). These data suggest that gatifloxacin at a dose of 10 mg/kg every 24 h will achieve therapeutic concentrations in plasma in infants and children.The need for new, effective antimicrobial agents for treatment of infections caused by antibiotic-resistant bacteria has been well documented (5, 23). In infants and children, this need is exemplified by treatment failures caused by antibioticresistant strains of Streptococcus pneumoniae. This organism is the most common cause of upper and lower respiratory tract bacterial infections, bacteremia, and meningitis in the pediatric age group. Clinical isolates with documented resistance to ␤-lactams, macrolides, chloramphenicol, and sulfonamides have been noted with increasing frequency from both children and adults (12,21).Gatifloxacin is an 8-methoxy fluoroquinolone effective against a wide range of bacterial pathogens including antibiotic-resistant S. pneumoniae. This is consistent with its overall increased potency against gram-positive organisms compared to earlier fluoroquinolones, ciprofloxacin, ofloxacin, and levofloxacin. Gatifloxacin demonstrates increased activity against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, group B streptococcus, and viridans group streptococcus (13,14,22). It also has excellent activity against a number of gram-negative enteric and respiratory pathogens including Haemophilus influenzae, Enterobacter spp., Klebsiella spp., Serratia marcescens, Legionella pneumophila, and Proteus spp. (6, 10). As a result, it is approved by the Food and Drug Administration for the treatment of community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, sinusitis, and urinary tract infections in adults.The pharmacokinetics of gatifloxaci...

Section: Discussionsupporting

confidence: 89%

Pharmacokinetics of Gatifloxacin in Infants and Children

Capparelli¹,

Reed

Bradley

et al. 2005

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“…Model bias and precision were evaluated using drug concentration data from the subset of patients from whom actual drug concentration data were obtained. The plasma-sampling schedules included two steadystate time points (peak and trough) and were measured using high-performance liquid chromatographic assay (9). A plot of free-drug AUC 24 s estimated using these concentrations in plasma in conjunction with demographic data versus free-drug AUC 24 s estimated using demographic data alone was made to validate the regression equation used in these analyses.…”

Section: Methodsmentioning

confidence: 99%

Pharmacodynamics of Fluoroquinolones against Streptococcus pneumoniae in Patients with Community-Acquired Respiratory Tract Infections

Ambrose

Grasela

et al. 2001

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285

166

Fluoroquinolone antibiotic agents have demonstrated efficacy in the treatment of respiratory tract infections. This analysis was designed to examine the relationship between drug exposure, as measured by the free-drug area under the concentration-time curve at 24 h (AUC 24 )/MIC ratio, and clinical and microbiological responses in patients with community-acquired respiratory tract infections involving Streptococcus pneumoniae. The study population included 58 adult patients (34 males, 24 females) who were enrolled in either of two phase III, randomized, multicenter, double-blind studies of levofloxacin versus gatifloxacin for the treatment of community-acquired pneumonia or acute exacerbation of chronic bronchitis. Clearance equations from previously published population pharmacokinetic models were used in conjunction with dose and adjusted for protein binding to estimate individual patient free-drug AUC 24 s. In vitro susceptibility was determined in a central laboratory by broth microdilution in accordance with NCCLS guidelines. Pharmacodynamic analyses were performed on data from all evaluable patients with documented S. pneumoniae infection using univariate and multivariable logistic regression; pharmacodynamic breakpoints were estimated using Classification and Regression Tree analysis. A statistically significant (P ‫؍‬ 0.013) relationship between microbiological response and the free-drug AUC 24 /MIC ratio was detected. At a free-drug AUC 24 /MIC ratio of <33.7, the probability of a microbiological response was 64%, and at a free-drug AUC 24 /MIC ratio of >33.7, it was 100% (P < 0.01). These findings may provide a minimum target free-drug AUC 24 /MIC ratio for the treatment of infections involving S. pneumoniae with fluoroquinolone antibiotics and provide a paradigm for the selection of fluoroquinolones to be brought forward from drug discovery into clinical development and dose selection for clinical trials. Further, when target free-drug AUC 24 /MIC ratios are used in conjunction with stochastic modeling techniques, these findings may be used to support susceptibility breakpoints for fluoroquinolone antibiotics and S. pneumoniae.The relationship that exists between drug exposure and the MIC for an infectious organism has been shown to be predictive of microbiological eradication (3,4,5,14). Existing data suggest that, for fluoroquinolones, an area under the concentration-time curve at 24 h (AUC 24 )/MIC ratio of 100 to 125 correlates with optimal clinical and microbiological outcomes in seriously ill patients infected with gram-negative enteric pathogens and Pseudomonas aeruginosa (7,8). However, over the past several years there has been considerable controversy as to whether or not this pharmacodynamic target applies to all patient populations and all organisms.Data from in vitro and animal models of infection have recently emerged and suggest that, for Streptococcus pneumoniae, the optimal free-drug AUC 24 /MIC ratio is much lower than 100 to 125. For instance, an in vitro model of pneumococcal infec...

“…The most common TEAE was nausea, which was more common in women (48%) than in men (24%). Only 1 (8%) of 13 subjects over 75 years of age reported nausea, compared with 4 of 15 (27%) subjects in the young-elderly group and 11 of 18 (61%) The aging process is known to affect the disposition of drugs by altering both body composition and organ function and, thus, may influence the pharmacokinetics of some drugs (9,12,14,15,19); these effects have been reviewed recently with respect to age (16) and sex (24). Overall, the results of this study demonstrate that the pharmacokinetic parameters of tigecycline do not differ significantly between sexes of the same age group or across age groups.…”

mentioning

confidence: 99%

Effects of Age and Sex on Single-Dose Pharmacokinetics of Tigecycline in Healthy Subjects

Muralidharan

Fruncillo

Micalizzi

et al. 2005

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...